MXPA06004880A - Novel phosphorus-containing thyromimetics - Google Patents

Abstract

The present invention relates to compounds of phosphonic acid containing T3 mimetics, stereoisomers, pharmaceutically acceptable salts, co-crystals, and prodrugs thereof and pharmaceutically acceptable salts and co-crystals of the prodrugs, as well as their preparation and uses for preventing and/or treating metabolic diseases such as obesity, NASH, hypercholesterolemia and hyperlipidemia, as well as associated conditions such as atherosclerosis, coronary heart disease, impaired glucose tolerance, metabolic syndromex and diabetes.

Description

TIROMY ETHICS CONTAINING FOSFORO NOVEDOSOS Field of the Invention The present invention is directed toward compounds that contain phosphonic acid which are thyroid receptor binders, pharmaceutically acceptable salts, and for prodrugs of these compounds in addition to their preparation and uses for prevention and / or treatment of metabolic diseases such as obesity, NASH, hypercholesterolemia and hyperlipidemia in addition to associated conditions such as atherosclerosis, coronary heart disease, impaired glucose intolerance and diabetes. The invention also relates to the specific delivery of thyroid receptor binding ligands and the use of these compounds for the prevention and treatment of diseases responsive to modulation of T3-sensitive genes in the liver. BACKGROUND OF THE INVENTION The following description of the background is provided to aid in understanding, but is not admitted to be, or to describe, the prior art. All publications and their cited references are incorporated by reference in all their elements. Thyroid hormones (TH) are synthesized in the thyroid in response to thyroid stimulating hormone (TSH), which is secreted by the thyroid gland.

Ref ..- 172103 pituitary gland in response to various stimulants (e.g., thyrotropin releasing factor (TRF) of the hypothalamus). Thyroid hormones are o-aryl iodine tyrosine analogues excreted in the primary circulation as T4. T4 rapidly deviates in the liver and kidney from thyroxine 5 '-iodinase to T3, which is the most potent TH. T3 is metabolized to inactivate metabolites via a variety of routes, including pathways involving deiodination, glucuronidation, sulfation, deamination, and decracking. Most metabolic pathways reside in the liver. HT have profound physiological effects in animals and humans. Hyperthyroidism is associated with increased body temperature, general nervousness, weight loss despite increased appetite, muscle atrophy and fatigue, increased bone resorption and improved calcification, and a variety of cardiovascular changes, including increased heart rate, volume of increased stroke, increased cardiac index, cardiac hypertrophy, decreased peripheral vascular resistance, and increased pulse pressure. Hypothyroidism is usually associated with opposite effects. The biological activity of HT is greatly mediated through thyroid hormone (TR) receptors. The TR belong to the receptor superfamily known as nuclear receptors, which, together with their common precursor, the retinoid X receptor, form heterodimers that act as inducible transcription factors by linkers. Like other nuclear receptors, TRs have a binding domain to the binding and a DNA binding domain and a regulated gene expression through interactions dependent on binding with DNA response elements (thyroid response elements, TRE). Currently, the literature shows that TRs are encoded by two different genes (TR and TRß), which produce several isoforms through alternative splicing (Williams, Mol Cell Biol. 20 (22): 8329-42 (2000); Nagoya, et al., Biochem Biophys Res. Common 226 (2): 426-30 (1996)).

The main isoforms that have been identified up to now are TRa-1, TRa-2, TRß-1 and TRß-2. TRa-1 is expressed ubiquitously in the rat with the largest expression in skeletal muscle and brown lipids. TRβ-1 is also expressed ubiquitously with higher expression in the liver, brain and kidney. TRß-2 is expressed in the anterior pituitary gland and specific regions of the hypothalamus in addition to the developing brain and inner ear. In the rat and mouse liver, the TRβ-1 is the predominant isoform (80%). The TR isoforms found in human and rat are highly homogeneous with respect to their amino acid sequences which suggest that each one serves a specialized function. THS is a previous pituitary hormone that regulates the production of thyroid hormone. The formation and secretion of TSH in turn is regulated by the hypothalamic tirotropin (TRF) release factor. TSH controls the absorption of iodide by the thyroid, the subsequent release of iodinated thyroglobulin thyronins (eg, T3, T4) in addition to possibly the intrapituitary conversion of T4 circulating to T3. Compounds that mimic T3 and t4 can negatively regulate both TSH and TRF secretions resulting in suppression of TSH levels and decreased levels of T3 and other iodinated thyronins. Negative regulation of TSH is postulated based on cotransfection and non-transgenic studies (Abel et al, J. Clin.Invest., 104, 291-300, (1999)) to increase activation through the TRβ thyroid receptor, possibly the isoform TRß-2, which is expressed largely in the pituitary. The most widely recognized effects of HT are an increase in metabolic rate, oxygen consumption and heat production. The treatment of T3 increases oxygen consumption in isolated perfused liver and isolated hepatocytes. (Oh, and collaborators, J. Nutr. 125 (l): 112-24 (1995); Oh, and collaborators, Proc. Soc. Exp. Biol. Med. 207 (3): 260-7 (1994)) The mitochondria of hyperthyroid rats exhibits increased oxygen consumption (Carreras, et al., Am J Physiol Herat Cric Physiol. 281 (6): H2282- 8 (2001) and major activities of enzymes in oxidative pathways (Dummler et al., Biochem J. 317 (3): 913-8 (1996), Sch ehl, et al., FEBS Lett. 375 (3): 206- 10 (1995), Harper et al., Can J Physiol Pharmacol 72 (8): 899-908 (1994).) Conversely, the mitochondria of hypothyroid rats show a decreased oxygen consumption.The increased metabolic rates are associated with Increased mitochondrial genesis and the 2- to 8-fold increase associated with mitochondrial RNA levels Some of the energy produced from the increased metabolic rate is captured as ATP (adenosine 5'-triphosphate), which is stored or used to drive biosynthetic pathways (for example, gluconeogenesis, lipogenesis, lipoprotein synthesis.) Much of the energy, however, is loses in the form of heat (thermogenesis), which is associated with an increase in mitochondrial proton loss possibly arising from the effects mediated by HT on the mitochondrial membrane, uncoupled proteins, enzymes involved in the transport of inefficient glycerol 3-phosphate such as dehydrogenase sn-glycerol 3-mitochondrial phosphate (GPDH), and / or enzymes associated with proton loss such as the adenine nucleotide transporter (ANT), Na + / K + -ATPase, Ca2 + -ATPase and ATP synthase. TH also stimulate the metabolism of cholesterol to bile acids. Hyperthyroidism leads to decreased plasma cholesterol levels, which is probably due to increased liver LDL receptor expression. Hypothyroidism is a well-established cause of hypercholesterolemia and elevated LDL serum. L-T3 is known to reduce plasma cholesterol levels. The effects of T3 are attributed to TRβ since the TRβ-deficient mice are resistant to induced reduction of T3 in cholesterol levels. The effects on cholesterol levels have been postulated to result in direct effects on the expression of the LDL receptor, the enzymes involved in the conversion of cholesterol to bile acids such as the cholesterol 7a-hydroxylase (CYP7A) enzyme that limits the frequency and / or possibly enzymes involved in cholesterol synthesis such as HMG CoA reductase. In addition, HT is known to affect the levels of other lipoproteins linked to atherosclerosis. TH stimulates apo AI and the secretion of apo AI in HDL while reducing apo AII. Consequently, it can be expected that T3 and the T3 mimics inhibit the atherosclerotic process in the animal fed cholesterol. THs simultaneously increase the synthesis and oxidation of de novo fatty acid through the effects of enzymes such as ACC, FAS, and spot-14. TH increase the circulation of free fatty acid levels (FFA) in part by increasing the production of FFA from adipose tissue via induced lipolysis of TH. In addition, THS increases the levels of mitochondrial enzyme involved in the oxidation of FFA, for example, palmitoyltransferase 1 of carnitine (CPT-1) and enzymes involved in storage and energy consumption. The liver represents a major target organ of TH. The microconfiguration analysis of hepatic gene expression of livers of hypothyroid mice and mice treated with T3 shows changes in mRNA levels for 55 genes (14 positively regulated and 41 negatively regulated) (Feng, et al., Mol. Endocrinol. 7): 947-55 (2000) Others have estimated that approximately 8% of liver genes are regulated by T3, and many of these genes are important for both fatty acid and cholesterol synthesis and metabolism. have other effects on the liver, which include effects on carbohydrates through glycogenolysis and increased gluconeogenesis and decreased insulin action.The heart is also a major target organ of TH.The systemic vascular resistance is less than TH, increases the volume of blood and produces inotropic and chronotropic effects. The results of general HT in increased cardiac output, which may suggest that T3 or T3 mimics may be used to treat patients with compromised cardiac function (eg, patients undergoing coronary artery bypass graft (CABG) or cardiac arrest) ) (EÜA Patent No. 5,158,978). The changes in cardiac function are a result of changes in the expression of the cardiac gene. Increased protein synthesis and increased cardiac body weight are easily observed in animals treated with T3 and represent the side effect of T3 that limits therapeutic use. Non-transgenic TRβ mice exhibit high levels of TSH and T4 and increased heart rate suggesting that they retain cardiac sensitivity and therefore that the cardiac effects are via TRa. Nontransgenic TRa exhibit reduced heart rates. THs also play a role in the development and function of brown and white adipose tissue. Both TRa and TRβ are expressed in brown adipose tissue (BAT). TH induces differentiation of white adipose tissue (WAT) in addition to a variety of lipogenic genes, including ACC, FAS, glucose-6-phosphate dehydrogenase and spot-14. THs in general play an important role in the regulation of basal oxygen consumption, fat stores, lipogenesis and lipolysis (Oppenheimer, et al., J. Clin.Invest.87 (1): 125-32 (1991)). HT has been used as an anti-obesity drug for more than 50 years. In the 1940s, HT was used alone, whereas in the 1950s it was used in combination with diuretics and in the 1960s in combination with amphetamines. Hyperthyroidism is associated with increased food intake but is also associated with a general increase in basal metabolic rate (BMR). Hyperthyroidism is also associated with decreased body weight (ca. 15%) considering that hypothyroidism is associated with a 25-30% increase in body weight. The treatment of patients with hypothyroidism with T3 leads to a decrease in body weight for most patients but not for all (17% of patients maintain weight). The effectiveness of TH treatment is complicated by the need for supraphysiological doses of T3 and the associated side effects, which include heart problems, muscle weakness and erosion in excess body mass. Long-term therapy has also been associated with bone loss. With these side effects, the medical community has tended to use thyroxine in low doses as a supplement for dietary treatments. In these doses, TH has minimal effect on body weight or BMR. The effectiveness of T3 to induce weight loss can be attenuated by defects in the action of TH. Compared to normal animals, higher doses of T3 are acquired in ob / ob mice to affect oxygen consumption, which was observed only in muscle, without changes in the liver and BAT. (Oh, and collaborators, J. Nutr. 125 (1): 112-24 (1995); Oh, and collaborators, Proc. Soc. Exp. Biol. Med. 207 (3): 260-7 (1994)). These effects were at least partially attributed to the decreased absorption of T3 by the liver. The T3 analogues have been reported. Many were designed for use as cholesterol lowering agents. Analogs that lower cholesterol and various lipoproteins (eg, LDL and Lp (A) cholesterol) have been reported without adverse generation of cardiac effects (eg, ünder Ood, et al., Nature 324: 425-9 (1986)). In some cases the improved therapeutic profile is attributed to the specific increase for TR-ß where in other cases it may be due to improved liver distribution. (Stanton, et al., Bioorg, Med. Chem. Lett., 10 (15): 1661-3 (2000); Dow et al., Bioorg, Med. Chem. Lett., 13 (3): 379-82 (2003). ). T3 and T3 mimics are thought to inhibit atherosclerosis by modulating the levels of certain lipoproteins known to be independent risk factors or potential risk factors for atherosclerosis, including low-density lipoprotein (LDL) cholesterol, lipoprotein cholesterol. high density (HDL), apo AI, which is a major apoprotein constituent of high density lipoprotein (HDL) and lipoprotein (A) or Lp (a) particles.

Lp (a) is an important risk factor, elevated in many patients with premature atherosclerosis. Lp (a) is considered to be highly atherogenic (de Bruin et al., J. Clin. Endo. Metab., 76, 121-126 (1993)). In humans, Lp (a) is a liver acute phase protein that promotes the binding of LDL to cell surfaces independent of LDL receptors. Accordingly, Lp (A) is believed to provide supplemental cholesterol to certain cells, for example, cells involved in inflammation or repair. Lp (a) is an independent risk factor for premature atherosclerosis. Lp (a) is synthesized in the liver. Apolipoprotein AI or apoAI is the major component of HDL, which is an independent risk factor for atherosclerosis. ApoAI is believed to promote the efflux of cholesterol from peripheral tissues and high levels of HDL (or apoAI), resulting in a decreased risk of atherosclerosis. Hyperthyroidism worsens glycemic control in type 2 diabetics. TH therapy is reported to stimulate hepatic gluconeogenesis. The enzymes specific for gluconeogenesis and important to control the trajectory and its physiological role to produce glucose are known to be influenced by TH therapy. Phosphoenolpyruvate carboxykinase (PEPCK) is upregulated by TH (Park et al, J. Biol. Chem., 274.211 (1999)) while others find that the 6-phosphatase glucose is upregulated (Feng et al., Mol.

Endrocrinol. , 14, 947 (2000)). TH therapy is also associated with reduced glycogen levels. TH therapy results in the improvement of unstimulated and stimulated glucose use of insulin and impaired insulin resistance in mouse ob / ob muscle. (Oh et al., J. Nutr., 125, 125 (1995)). There is still a need for novel thyromimetics that can be used to modulate cholesterol levels, to treat obesity, and other metabolic disorders especially with reduced undesirable effects. Brief Description of the Figures Figure la. Detail the link from T3 to the TRal receiver using a homologous displacement reaction. Figure Ib. It details the binding of T3 to the receptor Rβl receptor using a homologous displacement reaction. Figure him. It details the binding of Compound 17 to the TRal receptor using a heterologous displacement reaction. Figure Id. Details the binding of Compound 17 to the TRβ1 receptor using a heterologous displacement reaction. Figure him. It details the binding of Compound 7 to the TRal receptor using a heterologous displacement reaction. Figure lf. Details the link of Compound 7 to the receiver TRßl using a heterologous displacement reaction. Figure 2a. Details the dose response of serum cholesterol levels for compound 17 in rats fed cholesterol. Figure 2b. Details the dose response of serum cholesterol levels for compound 7 in rats fed cholesterol. Figure 3a. It details the effect of Compound 17 on the weight of the heart in rats fed cholesterol. Figure 3b. Details the effect of Compound 7 on the weight of the heart in rats fed cholesterol. Figure 4a. Details the effect of Compound 17 on cardiac GPDH activity in rats fed cholesterol.

Figure 4b. It details the effect of Compound 7 on cardiac GPDH activity in rats fed cholesterol.

Figure 5. Details the dose response of serum cholesterol levels for compound 13-1-cis in rats fed cholesterol. Brief Description of the Invention The present invention relates to phosphonic acid-containing compounds that bind to thyroid receptors in the liver. The activation of these receptors results in the modulation of the expression of the gene regulated by thyroid hormones. The present invention also relates to pharmaceutically acceptable salts and co-crystals, prodrugs, and pharmaceutically acceptable salts and co-crystals of these prodrugs of these compounds. The compounds can be used to treat diseases and disorders including metabolic diseases. In one aspect, compounds containing phosphonic acid are useful for improving efficacy, improving the therapeutic index, for example, decreasing non-liver related toxicities and side effects, or for improving liver selectivity, ie, increasing the distribution of an active drug to the liver in relation to the extrahepatic tissues and more specifically increase the distribution of the active drug to the nuclei of liver cells in relation to the nuclei of extrahepatic tissue cells (including heart, kidney, and pituitary). Prodrugs of compounds containing phosphonic acid are useful for increasing oral bioavailability and sustained administration of compounds containing phosphonic acid. In another aspect, the present invention relates to compounds of Formula I, II, III, and VIII. The compounds of Formula I, II, III, and VIII can be in active form or a prodrug thereof. Also included are pharmaceutically acceptable salts, including but not limited to acid addition salts and physiological salts, and co-crystals of the compounds of Formula I, II, III, and VIII. Also included in the present invention are prodrugs of the compounds of Formula I, II, III, and VIII which are active forms, and pharmaceutically acceptable salts, including but not limited to acid addition salts and physiological salts, and crystals of it. Also included are methods for making and using the compounds of the present invention.

Formula I Formula II Formula VIII Some of the compounds of Formula I, II, III, and VIII have asymmetric centers, are included in the present invention are racemic mixtures, enantiomerically enriched mixtures, diastereomeric mixtures, including diastereomerically enriched mixtures, and individual stereoisomers of the compounds of Formula I, II, III and VIII and prodrugs thereof. Definitions As used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise. The T groups that have more than one atom are read from left to right where the left atom of the group T is connected to the phenyl group that carries the groups R1 and R2, and the right atom of the group T is linked to the phosphorus atom in X. For example, when T is -0-CH2- or -N (H) C (0) -this means ~ phenyl-0-CH2-P (0) YR1; lY 'R11 and ~ phenyl- N (H) C (O) -P (0) YR1: LY'R1: L. The term "alkyl" refers to a straight or branched chain or cyclic hydrocarbon radical with only simple carbon-carbon bonds. Representative examples include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, and cyclohexyl, all of which may be optionally substituted. The alkyl groups are C? -C? 2. The term "aryl" refers to aromatic groups having 5-14 ring atoms and at least one ring having a conjugated pi electron system and include carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted. The carbocyclic aryl groups are groups having 6-14 ring atoms wherein the ring atoms in the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic and polycyclic or fused carbocyclic aryl groups of compounds such as optionally substituted naphthyl groups. The aryl or heterocyclic heterocyclic groups are groups having 5-14 ring atoms wherein 1 to 4 heteroatoms are ring atoms in the aromatic ring and and the rest of the atoms in the ring are carbon atoms. Suitable heteroatoms include oxygen, sulfur, nitrogen, and selenium. Suitable heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl, and the like, all optionally substituted. The term "biaryl" represents aryl groups having 5-14 atoms containing more than one aromatic ring including both fused ring systems and aryl groups substituted with other aryl groups. Such groups may be optionally substituted. Suitable biaryl groups include naphthyl and biphenyl. The term "optionally substituted" or "substituted" includes groups substituted by 1 to 6 substituents, independently selected from lower alkyl, lower aryl, lower aralkyl, lower cyclic alkyl, lower heterocycloalkyl, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkoxy, lower heteroaryl, lower heteroaryloxy, lower heteroarylalkyl, lower heteroaralkoxy, azido, amino, halo, lower alkylthio, oxo, lower acylalkyl, lower carboxy, carboxyl, carboxycarido, nitro, lower acyloxy, lower aminoalkyl, lower alkylarylaryl, lower alkylaryl, lower alkylaminoalkyl, lower alkoxyaryl, lower arylamino, lower aralkylamino, sulfonyl, lower carboxamidoalkylaryl, lower carboxamidoaryl, lower hydroxyalkyl, lower haloalkyl, lower alkylaminoalkylcarboxy, aminocarboxamido lower alkyl, cyano, lower alkoxyalkyl, lower perhaloalkyl, and arylalkyl lower alkyl. "Substituted aryl" and "substituted heteroaryl" refer to aryl and heteroaryl groups substituted with 1-3 substituents. These substituents are selected from the group consisting of lower alkyl, lower alkoxy, perhalo lower alkyl, halo, hydroxy, and amino. The term "aralkyl" refers to an alkylene group substituted with an aryl group. Suitable aralkyl groups include benzyl, picolyl, and the like, and may be optionally substituted. "Heteroarylalkyl" refers to an alkylene group substituted with a heteroaryl group. The term "alkylaryl" refers to an aryl group substituted with an alkyl group. "Lower alkyl" refers to such groups wherein alkyl is lower alkyl.

The term "lower" is herein referred to in connection with respectively defined organic radicals or compounds such as up to and including 10, in one aspect up to and including 6, and in another aspect 1 up to 4 carbon atoms. Such groups may be straight, branched or cyclic chain. The term "cyclic alkyl" or "cycloalkyl" refers to alkyl groups that are cyclic of 3 to 10 carbon atoms, and in one aspect are 3 to 6 carbon atoms, suitable cyclic groups include norbornyl and cyclopropyl.

Such groups can be substituted. The term "heterocyclic", "heterocyclic alkyl" or "heterocycloalkyl" refers to cyclic groups of 3 to 10 atoms, and in one aspect is 3 to 6 atoms, which contains at least one heteroatom, in a further aspect are 1 to 3 heteroatoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. Heterocyclic groups can be linked through a nitrogen or through carbon atoms in the ring. The heterocyclic alkyl groups include cyclic unsaturated, fused cyclic, and spirocyclic groups. Suitable heterocyclic groups include pyrrolidinyl, morpholino, orpholinoethyl, and pyridyl. The terms "arylamino" (a), and "aralkylamino" (b), respectively, refer to the group -NRR 'wherein respectively, (a) R is aryl and R' is hydrogen, alkyl, aralkyl, heterocycloalkyl, or aryl , and (b) R is aralkyl and R 'is hydrogen, aralkyl, aryl, alkyl or heterocycloalkyl. The term "acyl" refers to -C (0) R where R is alkyl, heterocycloalkyl, or aryl. The term "carboxy esters" refers to -C (0) OR where R is alkyl, aryl, aralkyl, cyclic alkyl, or heterocycloalkyl, all optionally substituted. The term "carboxyl" refers to -C (0) OH. The term "oxo" refers to = 0 in an alkyl or heterocycloalkyl group. The term "amino" refers to -NRR 'wherein R and R' are independently selected from hydrogen, alkyl, aryl, aralkyl and heterocycloalkyl, all except H are optionally substituted; and R and R 'can form a cyclic ring system. The term "carboxylamido" refers to -C0NR2 where each R is independently hydrogen or alkyl. The term "sulfonylamido" or "sulfonylamido" refers to -S (= 0) 2NR2 where each R is independently hydrogen or alkyl. The term "halogen" or "halo" refers to -F, -Cl, -Br and -I. The term "alkylaminoalkylcarboxy" refers to the group alkyl-NR-alk-C (0) -0- where "alk" is an alkylene group, and R is an H or lower alkyl. The term "sulfonyl" or "sulfonyl" refers to -S02R, where R is H, alkyl, aryl, aralkyl, or heterocycloalkyl. The term "sulfonate" or "sulfonate" refers to -S020R, where R is -H, alkyl, aryl, aralkyl, or heterocycloalkyl. The term "alkenyl" refers to an unsaturated group having 2 to 12 atoms and containing at least one carbon-carbon double bond and includes straight chain, branched chain, and cyclic groups. The alkenyl groups may be optionally substituted. Suitable alkenyl groups include allyl. "1-alkenyl" refers to alkenyl groups where the double bond is between the first and second carbon atoms. If the 1-alkenyl group is linked to another group, for example, this is a substituent W linked to the cyclic phosphonate, this binds to the first carbon. The term "alguinyl" refers to unsaturated groups having 2 to 12 atoms and containing at least one carbon-carbon triple bond and includes straight chain, branched chain and cyclic groups. The alkynyl groups may be optionally substituted. Suitable alkynyl groups include ethynyl. "1-alkynyl" refers to alkynyl groups where the triple bond is between the first and the second carbon atom. If the 1-alkynyl group is linked to another group, for example, this is a substituent W linked to the cyclic phosphonate, this binds to the first carbon. The term "alkylene" refers to a divalent straight chain, branched chain or cyclic saturated aliphatic group. In one aspect the alkylene group contains up to and including 10 atoms. In another aspect the alkylene chain contains up to and including 6 atoms. In a further aspect the alkylene groups contain up to and including 4 atoms. The alkylene group can be either straight, branched or cyclic. The term "acyloxy" refers to the ester group -0-C (0) R, where R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, or heterocycloalkyl. The term "aminoalkyl" refers to the group NR 2 -alk- wherein "alk" is an alkylene group and R is selected from -H, alkyl, aryl, aralkyl, and heterocycloalkyl. The term "alkylaminoalkyl" refers to the group alkyl-NR-alk- wherein each "alk" is an independently selected alkylene, and R is H or lower alkyl. "Lower alkylaminoalkyl" refers to groups wherein the alkyl and the alkylene group is lower alkyl and alkylene, respectively. The term "arylaminoalkyl" refers to the group aryl-NR-alk- wherein "alk" is an alkylene group and R is -H, alkyl, aryl, aralkyl, or heterocycloalkyl. In "lower arylaminoalkyl", the alkylene group is lower alkylene. The term "alkylaminoaryl" refers to the alkyl-NR-aryl group wherein "aryl" is a divalent group and R is -H, alkyl, aralkyl, or heterocycloalkyl. In "lower alkylarylaryl", the alkyl group is lower alkyl. The term "alkoxyaryl" refers to an aryl group substituted with an alkyloxy group. In "lower alkyloxyaryl", the alkyl group is lower alkyl. The term "aryloxyalkyl" refers to an alkyl group substituted with an aryloxy group. The term "aralkyloxyalkyl" refers to the group aryl-alk-O-alk- where "alk" is an alkylene group. "Aralkyloxyalkyl" refers to such groups wherein the alkylene groups are lower alkylene. The term "alkoxy" or "alkyloxy" refers to the group alkyl-O-. The term "alkoxyalkyl" or "alkyloxyalkyl" refers to the group alkyl-O-alk- wherein "alk" is an alkylene group. In "lower alkoxyalkyl", each alkyl and alkylene is alkyl and lower alkylene, respectively. The terms "alkylthio" and "alkylthio-" refer to the group alkyl-S-. The term "alkylthioalkyl" refers to the group alkyl-S-alk- where "alk" is an alkylene group. In "lower alkylthioalkyl" each alkyl and alkylene is alkyl and lower alkylene, respectively. The term "alkoxycarbonyloxy" refers to alkyl-O-C (0) -0-. The term "aryloxycarbonyloxy" refers to aryl-O-C (0) -0-. The term "alkylthiocarbonyloxy" refers to alkyl-S-C (0) -0-. The term "amido" refers to the group NR2 that follows for an acyl or sulfonyl group such as NR2-C (0) -, RCIOj-NR1-, NR2-S (= 0) 2- and RS (= 0) 2- NR1-, wherein R and R1 include -H, alkyl, aryl, aralkyl, and heterocycloalkyl. The term "carboxamido" refers to NR2-C (0) - and RC (O) -NR1-, where R and R1 include -H, alkyl, aryl, aralkyl, and heterocycloalkyl. The term does not include urea, -NR-C (O) -NR-. The terms "sulfone gone" or "sulfonamido" refers to NR2-S (= 0) 2- and RS (= 0) 2-NR1-, where R and R1 include -H, alkyl, aryl, aralkyl, and heterocycloalkyl. The term does not include sulfonylurea, -NR-S (= 0) 2-NR-.

The term "carboxamidoalkylaryl" and "carboxamidoaryl" refers to an aryl-alk-NR1-C (0), and ar-NR1-C (0) -alk-, respectively where "ar" is aryl, "alk" is alkylene , R1 and R include H, alkyl, aryl, aralkyl, and heterocycloalkyl. The term "sulfonamidoalkylaryl" and "sulfonamidoaryl" refers to an aryl-alk-NR1-S (= 0) 2-, and ar-NRx-S (= 0) 2-, respectively where "ar" is aryl, "alk "is alkylene, R1 and R include -H, alkyl, aryl, aralkyl, and heterocycloalkyl. The term "hydroxyalkyl" refers to an alkyl group substituted with -OH. The term "haloalkyl" refers to an alkyl group substituted with a halo. The term "cyano" refers to -C = N. The term "nitro" refers to -N02. The term "acylalkyl" refers to an alkyl-C (O) -alk-, where "alk" is alkylene. The term "aminocarboxamidoalkyl" refers to the group NR2-C (0) -N (R) -alk- wherein R is an alkyl group or H and "alk" is an alkylene group. "Aminocarboxamido lower alkyl" refers to such groups wherein "alk" is lower alkylene. The term "heteroarylalkyl" refers to an alkylene group substituted with a heteroaryl group. The term "perhalo" refers to groups in which each C-H bond has been replaced with a C-halo bond in an aliphatic or aryl group. Suitable perhaloalkyl groups include -CF3 and -FCCl2. The term "carboxylic acid moiety" refers to a compound having a carboxylic acid group (-C00H), and salts thereof, a carboxylic acid ester, or a carboxylic acid substitute. Carboxylic acid substitutes include a tetrazole group, a hydroxyacid group, a thiazolidinedione group, an acylsulfonamide group, and a 6-azauracil; and prodrugs of these. The phosphonic acids and prodrugs thereof are not within the scope of the carboxylic acid substitutes. The term "co glass" as used herein means a crystalline material comprised of two or more unique solids at room temperature, each containing different physical characteristics, such as structure, melting point and heat of fusion. The co-crystals of the present invention comprise a co-crystal former H-linked to a compound of the present invention. The co-crystal former can be H-linked directly to the compound of the present invention or can be H-linked to an additional molecule which is attached to the compound of the present invention. The additional molecule can be H-linked to the compound of the present invention or ionically bound to the compound of the present invention. The additional molecule can also be a second API. The solvates of the compounds of the present invention which also do not comprise a co-crystal former are not "co-crystals" according to the present invention. The co-crystals, however, may include one or more solvate molecules in the crystalline lattice. That is, the solvates of the co-crystals, or a co-crystal which also comprises a solvent or compound that is a liquid at room temperature, is included in the present invention as a co-crystal. The co-crystals may also be a co-crystal between a co-crystal former and a salt of a compound of the present invention, but the compound of the present invention and the co-crystal former are constructed or bound together through of hydrogen bonds. Other modes of molecular recognition may also be present including, pi stacking, host-host complex formation and Van der Waals interactions. Of the interactions listed above, hydrogen bonding is the dominant interaction in co-crystal formation, (and a required interaction according to the present invention) whereby a non-covalent bond is formed between a hydrogen bond donor of one of the portions and a hydrogen-bond receptor of the others. The crystalline material comprised of solid compound of the present invention and one or more liquid solvents (at room temperature) are included in the present invention as "solvates". A "hydrate" is when the solvent is water. Other forms of the present invention include, but are not limited to, anhydrous forms and solvates of solvates. The ratio of the compound of the present invention to co-crystal former or solvent can be specified as stoichiometric or non-stoichiometric. The 1: 1, 1.5: 1, 1: 1.5, 2: 1, 1: 2, and 1: 3 API: co-crystal / solvent ratios are examples of stoichiometric ratios. The term "binding" means the specific association of the compound of interest to the thyroid hormone receptor. A method of binding measurement in this invention is the ability of the compounds to inhibit the association of 125I-T3 with a mixture of thyroid hormone receptors using nuclear extracts or purified or partially purified thyroid hormone receptor (e.g., alpha or beta) ) in a heterologous assay. The term "energy expenditure" means basal or resting metabolic rate as defined by Schoeller et al., J. Appl Physiol.; 53 (4): 955-9 (1982). Increases in the resting metabolic rate can also be measured using increases in the consumption of 02 and / or efflux of C02 and / or increases in the temperature of the organ or body. The phrase "therapeutically effective amount" means an amount of a compound or a combination of compounds that alleviates, attenuates or eliminates one or more of the symptoms of a particular disease or condition or prevents, modifies, or delays the onset of one or more of the symptoms of a particular disease or condition. The term "pharmaceutically acceptable salt" includes salts of compounds of Formula I and their prodrugs derived from the combination of a compound of this invention and an organic or inorganic acid or base. Suitable acids include acetic acid, atypical acid, benzensulfonic acid, (+) - 7, 7-dimethyl-2-oxo-bicyclo [2.2.1] reptan-1-methanesulfonic acid, citric acid, 1,2-ethanedisulfonic acid, dodecyl acid sulphonic, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, hippuric acid, hemietanolic chlorohydrate acid, HBr, Hcl, Hi, 2-hydroxyethanesulfonic acid, lactic acid, lactobionic acid, maleic acid, methanesulfonic acid, methyl bromide acid, acid Methyl sulfuric acid, 2-naphthalenesulfonic acid, nitric acid, oleic acid, 4,4'-methylenebis [3-hydroxy-2-naphthalenecarboxylic acid], phosphoric acid, polygalacturonic acid, stearic acid, succinic acid, sulfuric acid, sulfosalicylic acid, acid tannic, tephthalic acid, and p-toluenesulfonic acid. The term "patient" means an animal. The term "animal" includes birds and mammals, in one embodiment a mammal, includes a dog, cat, cow, horse, goat, sheep, pig or human. In one modality the animal is a human. In another modality the animal is a male. In another modality the animal is a female. The term "prodrug" as used herein refers to any compound that when administered to a biological system generates a biologically active compound as a result of instant chemical reactions, chemical reactions catalyzed by enzyme, and / or metabolic chemical reactions, or a combination of each. Standard prodrugs are formed using coupled groups for functionality, for example, HO-, HS-, HOOC-, R2N ~, associated with the drug, which unfold in vivo. Standard prodrugs include but are not limited to carboxylate esters wherein the alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl group in addition to hydroxyl esters, thiol and amines where the coupled group is an acyl group, an alkoxycarbonyl, aminocarbonyl, phosphate or sulfate . The illustrated groups are exemplary, not exhaustive, and one skilled in the art can prepare other known prodrug varieties. The prodrugs of the compounds of Formula I fall within this scope. The prodrugs must undergo some form of chemical transformation to produce the compound that is biologically active or is a precursor of the biologically active compound. In some cases, the prodrug is biologically active, usually less than the drug per se, and serves to improve the efficacy or safety of the drug through improved oral bioavailability, and / or pharmacodynamic half-life, etc. The prodrug forms of the compounds can be used, for example, to improve bioavailability, improve the acceptability of the subject such as by unpleasant masking or degradation characteristics such as bitter taste or gastrointestinal irritability, altered solubility such as for intravenous use, provide for prolonged or sustained release or delivery, easy formulation improvement, or to provide specific site delivery of the compound. Prodrugs are described in The Organic Chemistry of Drug Design and Drug Action, by Richard B. Silverman, Academic Press, San Diego, 1992. Chapter 8: "Prodrugs and Drug Delivery Systems" pp.352-401; Design of Prodrugs, edited by H. Bundgaard, Elsevier Science, Amsterdam, 1985; Design of Biopharmaceutical Properties Through Prodrugs and Analogs, Ed. By E. B. Roche, American Pharmaceutical Association, Washington, 1977; and Drug Delivery Systems, ed. By R. L. Juliano, Oxford Univ. Press, Oxford, 1980. The term "phosphonate prodrug" refers to compounds that chemically or enzymatically degrade to a phosphonic acid group in vivo. As used herein the term includes, but is not limited to, the following groups and combinations of these groups: Acyloxyalkyl esters which are well described in the literature (Farquhar et al., J. Pharm. Sci., 72: 324-325 (1983)). Other acyloxyalkyl esters are possible in which a cyclic alkyl ring is formed. These esters have been shown to generate phosphorus-containing nucleotides within the cells through a postulated sequence of reactions that initiate with deesterification and followed by a series of elimination reactions (eg, Freed et al., Biochem. Pharm. , 38: 3193-3198 (1989)). Another class of these double esters known as alkyloxycarbonyloxymethyl esters, as shown in formula A, wherein R is alkoxy, aryloxy, alkylthio, arylthio, alkylamino, and arylamino; R ', and R "are independently -H, alkyl, aryl, alkylaryl, and heterocycloalkyl have been studied in the area of β-lactam antibiotics (Nishimura et al., J. Antibiotics, 40 (1): 81-90 (1987), for a review see Ferres, H., Drugs of Today, 19: 499 (1983)). More recently Cathy, M. S., et al. (abstract from AAPS Western Regional Meeting, April, 1997) shows that these prodrugs of alkyloxycarbonyloxymethyl ester in (9 - [(R) -2-phosphonomethoxy) propyl] adenine (PMPA) are bioavailable up to 30% in dogs.

A. wherein R, R ', and R "are independently H, alkyl, aryl, alkylaryl, and alicyclic; (See WO 90/08155; WO 90/10636). Other acyloxyalkyl esters are possible in which a cyclic alkyl ring is formed as shown in Formula B. These esters have been shown to generate phosphorus-containing nucleotides within the cells through a postulated sequence of reactions beginning with deesterification and followed by a series of elimination reactions (eg, Freed et al., Biochem. Pharm., 38: 3193-3198 (1989)).

Formula B wherein R is -H, alkyl, aryl, alkylaryl, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino, or cycloalkyl. Another class of these double esters known as alkyloxycarbonyloxymethyl esters, as shown in Formula A, wherein R is alkoxy, aryloxy, alkylthio, arylthio, alkylamino, and arylamino; R ', and R "are independently -H, alkyl, aryl, alkylaryl, and heterocycloalkyl have been studied in the area of β-lactam antibiotics (Nishimura et al., J. Antibiotics, 40 (1): 81-90 (1987), for a review see Ferres, H., Drugs of Today, 19: 499 (1983)). More recently Cathy, M. S., et al. (abstract from AAPS Western Regional Meeting, April, 1997) shows that these prodrugs of alkyloxycarbonyloxymethyl ester in (9 - [(R) -2-phosphonomethoxy) propyl] adenine (PMPA) are bioavailable up to 30% in dogs. Aryl esters have also been used as phosphonate prodrugs (eg, DeLambert et al., J. Med. Chem. 37 (7): 498-511 (1994); Serafinowska et al., J. Med. Chem. 38 (8): 1372-9 (1995) Phenyl as well as mono- and poly-substituted phenyl progesters have generated the phosphonic acid precursor in animal and human-conducted studies (Formula C.) Another approach has been described where Y is a carboxylic ortho ester for phosphate (Khamnei et al., J. Med. Chem. 39: 4109-15 (1996)).

Formula C wherein Y is -H, alkyl, aryl, alkylaryl, alkoxy, acyloxy, halogen, amino, alkoxycarbonyl, hydroxy, cyano, and heterocycloalkyl. Benzyl esters have also been reported to generate the phosphonic acid precursor. In some cases, using substituents to the position can accelerate hydrolysis. Benzyl analogues with a 4-acyloxy or 4-alkyloxy group [Formula D, X = -H, OR or 0 (CO) R or 0 (CO) OR] can generate the 4-hydroxy compound more easily through the action of enzymes, for example, oxidases, esterases, etc. Examples of this class of prodrugs are described in Mitchell et al., J. Chem. Soc. Perkin Trans. I 2345 (1992); WO 91/19721.

Formula D wherein X and Y are independently -H, alkyl, aryl, alkylaryl, alkoxy, acyloxy, hydroxy, cyano, nitro, perhaloalkyl, halo, or alkyloxycarbonyl; and R 'and R "are independently -H, alkyl, aryl, alkylaryl, halogen, and cyclic alkyl. Thio-containing phosphonate proesters may also be useful in the administration of drugs for hepatocytes. These proesters contain a protected thioethyl portion as shown in formula E. One or more of the phosphonate oxygens can be esterified. Since the mechanism that results in de-esterification requires the generation of a free thiolate, a variety of thiol protecting groups are possible. For example, disulfide is reduced by a process mediated by reductase (Puech et al., Antiviral Res. 22: 155-174 (1993)). The thioesters will also generate free thiolates after the esterase-mediated hydrolysis Benzaria, et al., J. Med. Chem., 39 (25): 4958-65 (1996)). Cyclic analogues are also possible and are shown to release the phosphonate in isolated rat hepatocytes. The cyclic disulfide shown below has not been previously described and is novel.

Formula E wherein Z is alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, or alkylthio. Other examples of suitable prodrugs include proester classes exemplified by Biller and Magnin (U.S. 5,157,027); Serafinowska et al., J. Med. Chem ,. 38 (8): 1372-9 (1995); Starrett et al., J. Med. Chez, 37: 1857 (1994); Martin et al. J. Pharm. Sci. 76: 180 (1987); Alexander et al., Collect. Czech Chem. Commun, 59: 1853 (1994); and EP 0 632 048 Al. Some of the structural classes are optionally substituted, including fused lactones that are bonded to the omega position (formula El and E-2) and optionally substituted 2-oxo-l, 3-dioxolenes bonded through a methylene to phosphorus oxygen (formula E-3) such as: dioxolanmethyl E-1 E-2 E-3 wherein R is -H, alkyl, cycloalkyl, or heterocycloalkyl; and wherein Y is -H, alkyl, aryl, alkylaryl, cyano, alkoxy, acyloxy, halogen, amino, heterocycloalkyl, and alkoxycarbonyl. The prodrugs of Formula E-3 are examples of "optionally substituted heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate". Phosphonate propyl proesters can also be used to administer drugs in hepatocytes. These proesters may contain a hydroxyl or derivatives of the hydroxyl group to the 3-position of the propyl groups as shown in formula F. The R and X groups may form a cyclic ring system as shown in formula F. One or more of the phosphonate oxygens can be esterified.

Formula F wherein R is alkyl, aryl, heteroaryl; X is hydrogen, alkylcarbonyloxy, alkyloxycarbonyloxy; and Y is alkyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, halogen, hydrogen, hydroxy, acyloxy, amino. The phosphoramidate derivatives have been explored as phosphate prodrugs (e.g., McGuigan et al., J. Med. Chem., 42: 393 (1999) and references cited herein) as shown in Formula G and H.

Formula G Formula H Cyclic phosphoramidates have also been studied as phosphonate prodrugs due to their greater speculated stability compared to non-cyclic phosphoramidates (eg, Starrettetal., J. Med. Chez., 37: 1857 (1994)). Another of phosphoramidate prodrug was reported as the combination of S-acyl-2-thioethyl ester and phosphoramidate (Egron et al., Nucleosides &Nucleotides, 18, 981 (1999)) as shown in Formula J: Formula J Other prodrugs are possible based on literature reports such as substituted ethyl esters, bis (trichloroethyl) esters as described by McGuigan, et al., Bioorg Med. Chem. Lett., 3: 1207-1210. (1993), and the combined phenyl and benzyl nuclide stress reported by Meier, C. et al., Bioorg Med. Chem. Lett. 7: 99-104 (1997).

Other prodrugs are possible based on literature reports such as substituted ethyl es for example, bis (trichloroethyl) esters as described by McGuigan, et al., BioorgMed. Chem. Lett., 3: 1207-1210 (1993), and the combined nucleotide esters of phenyl and benzyl reported by Meier, C. et al., Bioorg Med. Chera. Lett 7: 99-104 (1997). The structure It has an ejime of symmetry that goes through the oxygen-phosphorus double bond where R6 = R6, V = W, and V and W are either both pointing upwards or both pointing downwards.

The same is the real structure where each -NR6 is replaced with -O-. The term "cyclic phosphonate ester of 1,3-propane diol", "cyclic phosphonate diester of 1,3-propane diol", "2-oxo-2? 5 [1,2,3] dioxaphosphonane", "2-oxo [ l, 3, 2] dioxaphosphonane "," dioxaphosphonane "refers to the following: ? \ sM \ The phrase "together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing -7 atoms, optionally containing 1 heteroatoms, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy that is bonded to a carbon atom that is 3 atoms from both Y groups linked to phosphorus "include the following: The structure shown above (left) has 3 additional carbon atoms that form a 5-membered cyclic group. Such cyclic groups must possess the substitution listed for oxidation. The phrase "together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, optionally containing a heteroatom, which are fused to an aryl group bonded to the beta position and gamma to the Y linked to the phosphorus" include the next: The phrase "together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, bonded to the additional carbon atoms that are 3 atoms of a Y bond to phosphorus "include the following: The above structure has an acyloxy substituent which is 3 carbon atoms of a Y, and an additional substituent, -CH3, in the new 6-membered ring. These have at least one hydrogen from each of the following positions: the carbon is bonded to Z; both alpha carbons for carbon labeled "3"; and the carbon bonded to "OC (0) CH3" above. The phrase "together W and W 'are connected by means of 2-5 additional atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl" include the following: The above structure has V = aryl, and a cyclopropyl group fused with spiro for W and W '. The term "cyclic phosphon (amide)" refers to where Y is independently -0- or -NRV-. The carbon bound to V must have a C-H bond. The carbon bonded to Z must also have a C-H bond. The name of the compounds is given to have the ring that carries the groups R5 and R3 is a substituent on the ring that carries the groups R1 and R2. The name of the prodrugs is given to have the diaryl system with a linker T (Formula I or III) or D (Formula II) is a substituent on the phosphorus atom contained in X. For example: Acid [3-R1- 5-R2-4- (4'-R5-3'-R3-benzyl) phenoxy] methylphosphonic represents the formula: [3-Rx-5-R -4- (4'-R-3'-R3 phenoxy)] phenoxy] methylphosphonic represents the formula: N- [3 - ^ - 5-. R _4_ (4'_R _3 / _RJ phenoxy) phenyl] carbamoylphosphonic acid represents the formula: 2- [(3-R1-5-R2-4- (4 '-R5-3' -R3-benzyl) phenoxy) methyl] -4-aryl-2-oxo-2? 5- [1.3.2 ] -dioxaphosphonane: 2- [(3-R1-5-R2-4- (4 '-R5-3' -R3-phenoxy) phenoxy) methyl] -4-aryl-2-oxo-2? 5- [1, 3, 2 ] -dioxafosfano: The term "cis" stereochemical refers to the spatial relationship of the group V and the carbon bonded to the phosphorus atoms in a 6-membered ring. The formula below shows a stereochemical cis.

The term "trans" stereochemical refers to the spatial relationship of group V and carbon, linked to the phosphorus atoms, in the 6-membered ring. The formula below shows a stereochemical trans.

The formula below shows another stereochemical trans.

The terms "S-configuration", "S-isomers" and "S-prodrug" refer to the absolute configuration S of carbon C. The formula below shows the S-stereochemical formula.

The terms "R configuration", "R isomer" and "R prodrug" refer to the absolute configuration R of carbon C. The formula below shows the R stereochemistry.

The term "percentage of enantiomeric excess (% ee)" refers to optical purity. This is obtained by using the following formula: [R] - [S] X 100 =% R-% S [R] + [S] where [R] is the amount of the R isomer and [S] is the amount of the isomer S. This formula provides the% ee when R is the dominant isomer. The term "enantioenriched" or "enantiomerically enriched" refers to a sample of a chiral compound consisting of more than one enantiomer than the other. The extent to which a sample is enantiomerically enriched is quantified by the enantiomeric ratio or the enantiomeric excess. The term "liver" refers to the liver organ. The term "increase" refers to increasing or improving a specific property. The term "liver specificity" refers to the relationship: [drug or a drug metabolite in liver tissue] [drug or a drug metabolite in the blood or other tissue] as measured in animals treated with the drug or a prodrug. The relationship can be determined by measuring tissue levels at a specific time or it can represent an AUC based on measured values at 3 or more time points. The term "phosphonic acid-containing compounds" refers to compounds containing P03H2 or P03 ~ 2. The term "fructose-1, 6-biphosphatase inhibitor" or "FBPase inhibitor" refers to compounds that inhibit the activity of the FBPase enzyme and thereby block the conversion of fructose 1, 6-bisphosphate, the substrate of the enzyme, for fructose 6-phosphate. These compounds have an IC 50 equal to or less than 50 μM in human liver FBPase measured according to the procedure found in US Patent No. 6,489,476. The term "increased or improved liver specificity" refers to an increase in the liver specificity ratio in animals treated with a compound of the present invention and a control compound. In one embodiment, the test compound is a phosphonic acid compound of the present invention and in another embodiment the test compound is a prodrug thereof. In one embodiment, the control compound is a phosphonic acid compound of the present invention. In another embodiment, the control compound is the corresponding carboxylic acid derivative of the phosphonic acid test compound. The term "improved oral bioavailability" refers to an increase of at least 50% in the absorption of the dose of the parent drug, unless otherwise specified. In a further aspect the increase in oral bioavailability of the prodrug (compared to the parent drug) is at least 100%, which is a doubling of absorption. The measurement of oral bioavailability usually refers to measurements of the prodrug, drug, or drug metabolite in blood, plasma, tissue, or urine after oral administration compared to measurements after systemic administration of the orally administered compound.

The terms "treat" or "treatment" of a disease include a delay in the progress or development of a disease after beginning or currently investing some or all of the affectations of the disease. The treatment also includes palliative treatment. The term "prevention" includes a delay in the progress or development of a disease before beginning or preventing the onset of the disease. The term "thyroid hormone receptors" (TR) refers to intracellular proteins located in the nucleus of the cell that, after the binding of thyroid hormone, stimulates the transcription of specific genes by binding to DNA sequences called hormone-sensitive elements. thyroid (TRE). In this way, TR regulates the expression of a wide variety of genes involved in metabolic processes (for example, cholesterol homeostasis and fatty acid oxidation) and growth and development in many tissues, including liver, muscle and heart. There are at least two forms of TR; TR alpha (on chromosome 17) and TR beta (on chromosome 3). Each of these isoforms also has two main isoforms: TR alpha-1 and TR alpha-2; and TR beta-1 and TR beta-2, respectively. TR are high affinity receptors for thyroid hormones, especially triiodothyronine. The term "ACC" refers to acetyl CoA carboxylase.

The term "FAS" refers to fatty acid synthase. The term "spot-14" refers to a 17 kilodalton protein expressed in lipogenic tissues and is postulated to play a role in the stimulation of thyroid hormone lipogenesis. (Campbell, MC et al., Endocrinology : 1210 (2003). The term "CPT-1" refers to palmitoyltransferase-1 carnitine. The term "CYP7A" refers to cholesterol hydroxylase 7-alpha, which is a cytochrome P450 enzyme linked to the membrane that catalyzes the 7 alpha hydroxylation of cholesterol in the presence of molecular oxygen and NADPH-ferrihemoprotein reductase. This enzyme, encoded by CYP7, converts cholesterol to 7-alpha-hydroxycholesterol which is the first step and speed limitation in the synthesis of bile acids. The term "apoAI" refers to Apolipoprotein AI found in HDL and cilomicrons. It is an activator of LCAT and a binding for the HDL receiver. The term "mGPDH" refers to mitochondrial glycerol-3-phosphate dehydrogenase. The term "hypercholesterolemia" refers to the presence of a large abnormal amount of cholesterol in circulating blood cells and plasma.

The term "hyperlipidemia" or "lipemia" refers to the presence of a large abnormal amount of circulating blood lipids. The term "atherosclerosis" refers to a condition characterized by deposits of lipids irregularly distributed in the intima of the large and medium sized arteries where the deposits cause fibrosis and calcification. Atherosclerosis increases the risk of angina, stroke, heart attack, or other cardiac or cardiovascular conditions. The term "obesity" refers to the condition of being obese. Being obese is defined as a BMI of 30.0 or greater; and extreme obesity is defined in a BMI of 40 or greater. "Overweight" is defined as a body mass index of 25.0 to 29.9 (This is generally about 10 percent of an ideal body weight). The term "coronary heart disease" or "coronary disease" refers to a mismatch between the myocardial functional requirements and the ability of the coronary vessels to supply sufficient blood flow. It is a form of myocardial ischemia (insufficient blood supply to the heart muscle) caused by a decreased capacity of the coronary vessels. The term "diabetes" refers to a heterogeneous group of disorders that share common glucose intolerance. It refers to disorders in which the utilization of carbohydrate is reduced and that of improved lipid and protein; and may be characterized by hyperglycemia, glycosuria, ketoacidosis, neuropathy, or nephropathy. The term "non-insulin dependent diabetes mellitus" (NIDDM or type 2 diabetes) refers to a heterogeneous disorder characterized by insulin secretion impaired by the pancreas and insulin resistance in tissues such as liver, muscle and adipose tissue. Manifestations of the disease include one or more of the following: glucose intolerance, fasting hyperglycemia, glycosuria, increased hepatic glucose production, reduced hepatic glucose uptake and glycogen storage, reduced whole-body glucose uptake and utilization , dyslipidemia, fatty liver, ketoacidosis, microvascular diseases such as retinopathy, nephropathy and neuropathy, and macrovascular diseases such as coronary heart disease. The term "impaired glucose tolerance (IGT) (for its acronym in English)) "se" refers to a condition known to precede the development of type 2 diabetes manifested. It is characterized by abnormal blood glucose excursions followed by a meal. Current criteria for IGT diagnosis are based on 2-h plasma glucose levels after an oral glucose test of 75g (144-199 mg / dL). Despite the population variable for the studied population, the IGT progresses to fully cover the NIDDM at a rate of 1.5 to 7.3% per year, with an average of 3-4% per year. Individuals with IGT are believed to have an increased risk of 6 to 10 times in the development of NIDDM. IGT is an independent risk factor for the development of cardiovascular disease. The term "Nonalcoholic Hepatitis Steato (NASH)" refers to an inflammatory condition of the liver characterized by fat accumulation, hepatocellular injury, and fibrosis or cirrhosis, and may affect 2-3 percent of adults in western countries. NASH is preceded by non-alcoholic fatty liver disease, or NAFLD, which is characterized by accumulation of fat in the liver and liver injury with sugar. The pathogenesis of NASH is multifactorial. Insulin resistance in addition to the resulting hyperinsulinemia can be important factors in the accumulation of hepatocellular fat, considering intracellular excess of fatty acids, oxidative stress, depletion of adenosine triphosphate, and mitochondrial dysfunction can be causes of hepatocellular injury and development of an inflammatory condition in the steatotic liver. NASH, frequently but not always, is associated with severe obesity and is intimately related to clinical and biological markers of insulin resistance syndrome. The accumulation of fat in the liver is thought to contribute significantly to the development of hepatic insulin resistance. The term "insulin resistance" is defined clinically as the impaired capacity of a known amount of exogenous or endogenous insulin to increase the absorption and utilization of total body glucose. Since insulin regulates a wide variety of metabolic processes in addition to glucose homeostasis (eg, lipid and protein metabolism), the manifestations of insulin resistance are diverse and include one or more of the following: glucose intolerance, hyperirisulinemia, a characteristic dyslipidemia (high triglycerides, low-density lipoprotein cholesterol, and low, dense low-density lipoprotein cholesterol), obesity, upper body fat distribution, fat accumulation in the liver (nonalcoholic fatty liver disease) , NASH (nonalcoholic steatohepatitis), increased hepatic glucose production, reduced hepatic glucose uptake and glycogen storage, hypertension and increased prothrombotic and antifibrinolytic factors. This aggregate of cardiovascular metabolic abnormalities is commonly referred to as "The Insulin Resistance Syndrome" or "The Metabolic Syndrome" and can lead to the development of type 2 diabetes, accelerated atherosclerosis, hypertension or polycystic ovarian syndrome. The "Metabolic Syndrome" or "Metabolic Syndrome X" is characterized by a group of metabolic risk factors in a person. They include: • Central obesity (excessive fatty tissue in and around the abdomen) • Atherogenic dyslipidemia (disorders of blood fat - mainly high triglycerides and low HDL cholesterol - which builds adoptive plaque on the walls of the artery) • High blood pressure (130/85 mmHg or greater) • Insulin resistance or glucose intolerance (the body can not use insulin or blood sugar properly) • Prothrombotic state (eg, high fibrinogen or plasminogen activator inhibitor [-1]) blood) • Pro-inflammatory state (for example, high sensitivity C-reactive protein in the blood) According to the present invention, the "Metabolic Syndrome" or "Metabolic Syndrome X" is identified by the presence of three or more of these components: • Central obesity as measured by waist circumference: Men: Greater than 40 inches (101.6 cm). Women: Greater than 35 inches (88.9 cm). • Triglycerides in fasting blood greater than or equal to 150 mg / dL • HDL cholesterol in blood: • Men: Less than 40 mg / dL • Women. Less than 50 mg / dL • Blood pressure greater than or equal to 130/85 mmHg • Fasting glucose greater than or equal to 110 mg / dL The term "thyroid sensitive element" or "TRE" is refers to an element that usually consists of average sites repeated directly with the consensus AGGTCA sequence. (Harbers et al., Nucleic Acids Res. 24 (12): 2252-2259 (1996)). TREs contain two medium sites of the AGG TCA portion which can be arranged as direct repeats, inverted repeats, or outward repeats. The term "thyroid sensitive genes" refers to genes whose expression is affected by triiodothyronine (Menjo et al., Thyroid 9 (9): 959-67 (1999); Helbing et al., Mol. Endocrinol 17 (7): 1395-409 (2003)).

The term "TSH" or "thyrotropin" refers to the thyroid stimulating hormone. The term "atherogenic proteins" refers to proteins that induce, stimulate, ameliorate or prolong atherosclerosis and diseases related to atherosclerosis, including but not limited to coronary heart disease. Atherogenic proteins include apo AI and Lp (a). The term "thyroid hormone, or TH" includes for example natural iodinated thyroglobulin thyrones (e.g., T3, T4), in addition to drugs such as Levothyroxine sodium which is the sodium salt an isomer levorotatory of T4 and a drug commonly used as replacement therapy in hypothyroidism. Other uses include the treatment of non-endemic goiter, chronic lymphocytic thyroiditis and thyrotropin-dependent thyroid carcinoma. Litoronin sodium is the sodium salt of a levorotatory isomer of T3. Liotrix is a 4: 1 mixture of levothyroxine and litronine. The thyroid is a preparation derived from extracted and degreased thyroid glands of animals. The term "thyromimetic" or "mimetic T3" as used herein, is projected to cover any portion which binds to a thyroid receptor and acts as an agonist, antagonist or partial agonist / antagonist of T3. The tynomimetic can also be specified as an agonist, an antagonist, a partial agonist or a partial antagonist. The tynomimetics of the present invention presumably link the T3 binding site and can inhibit the binding of T3 to a thyroid hormone receptor using a heterologous displacement reaction. The tynomimetics of the present invention that can produce one or more of the effects mediated by L-triiodothyronine that occurs naturally in a target tissue or cell can be considered an agonist or partial agonist. The thyromimetics of the present invention which can inhibit one or more of the effects mediated by the L-triiodothyronine that occurs naturally in a target tissue or cell can be considered an antagonist, partial agonist or inverse agonist. The term "metabolic disease" includes diseases and conditions such as obesity, diabetes and lipid disorders such as hypercholesterolemia, hyperlipidemia, hypertriglyceridemia in addition to disorders that are associated with abnormal levels of lipoproteins, lipids, carbohydrates and insulin such as metabolic syndrome X, diabetes , glucose intolerance, atherosclerosis, coronary heart disease, cardiovascular disease. The term "mitochondrial biogenesis" or "mitochondrial genesis" refers to the speed at which the nascent mitochondria are synthesized. The mitochondrial biogenesis that occurs during cell replication provides enough new mitochondria for both the stem cells and daughters. The mitochondrial biogenesis that occurs in the absence of cell replication leads to an increase in the number of mitochondria within a cell. As used herein, the term "significant" or "statistically significant" means a result (that is, experimental test result) where the value of p is = 0.05 (that is, the chance of a type I error is less than 5%) as determined by an accepted measurement in the technique of statistical significance appropriate to the experimental design.

All references cited herein are incorporated by reference in all their elements.

Detailed Description of the Invention The present invention relates to methods of preventing or treating metabolic diseases with compounds containing phosphonic acid, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs, wherein the compounds containing phosphonic acid They bind to a thyroid hormone receptor. Thyroid hormones and thyroid hormone mimetics bind to thyroid hormone receptors in the nucleus of cells and can change expression levels of genes that encode proteins that play an important role in metabolic diseases. Metabolic diseases that can be prevented or treated with thyroid hormone mimetics include obesity, lipid disorders such as hypercholesterolemia, hyperlipidemia, and hypertriglyceridemia as described in more detail below. Other metabolic disorders that can be prevented or treated with thyroid hormone mimetics include NASH, diabetes, glucose intolerance, and insulin resistance. Conditions associated with these diseases, such as atherosclerosis, coronary artery disease, and cardiac injury, can also be treated with these compounds that bind thyroid hormone receptors. Prior to the discoveries of the present invention, phosphonic acids were believed to be a poor replacement for carboxylic acids based on differences in geometry, size, and charge. Phosphonic acids may also show reduced binding affinities against enzymes that use or link the analogous carboxylic acid. Phosphonic acids may also exhibit differences in cellular and in vivo potency, oral bioavailability, pharmacokinetics, metabolism, and safety. The T3 and T3 mimetics previously reported contain a carboxylic acid believed to be important for the binding and activation of T3 sensitive genes. The carboxylic acid may also be important in the transport and distribution of these compounds through various transport proteins. Transport proteins can improve the transport of certain compounds, particularly negatively charged compounds, to the nuclei. Prior to the discoveries of the present invention it was not clear, therefore, whether the replacement of a carboxylic acid with a phosphonic acid could produce a compound that is effective as a T3 mimetic because of the following: 1. it was not known whether a T3 mimetic with a phosphonic acid instead of the carboxylic acid could be transported inside the liver cells through the cell membrane; 2 . if the phosphonic acid containing the T3 mimetic was transported through the cell membrane of the liver cells, it was not known whether the compound could be transported through the nuclear membrane in the nuclei; 3 . if the phosphonic acid containing the T3 mimetic was transported through both the cellular and nuclear membranes of the liver cells, it was not known if the compound could bind the TR receptor with sufficient affinity to be effective; Four . if the phosphonic acid containing the T3 mimetic was transported through both the cellular and the nuclear membranes of the liver cells, and bound to the TR receptor with sufficient affinity for receptor activity, it was not known whether the compound could act as an agonist or antagonist of receptor activity; 5. if the phosphonic acid containing the T3 mimetic was transported through both the cellular and the nuclear membranes of the liver cells, and bound to the TR receptor with sufficient affinity for receptor activity, and acted as an activity agonist of receptor, it was not known whether the compound could have a sufficiently high tissue selectivity and have a therapeutic index large enough to be effective in the treatment of the diseases and disorders described herein while avoiding unwanted side effects involving the heart. 6. finally, even if the phosphonic acid containing the T3 mimetic was transported through both the cellular and the nuclear membranes of the liver cells, and bound to the TR receptor with sufficient affinity for receptor activity, and acted as a receptor activity agonist, and has a sufficiently high tissue selectivity and has a therapeutic impact sufficiently large to be effective in the treatment of the diseases and disorders described herein while avoiding unwanted side effects involving the heart, it was not known if the phosphonic acid containing the compounds of the present invention could be rapidly cleared from the blood by the kidneys thereby making the compound less useful as a drug compound. Thus, it was unexpected when the present inventors discovered that the phosphonic acid T3 mimetic compounds of the present invention were capable of being transported effectively through the cell membrane within the cells of the liver through the nuclear membrane where the receptors bind. thyroid and activate sensitive genes of thyroid hormone. Furthermore, surprisingly the present inventors discovered that the compounds of the present invention bind to thyroid receptors with sufficient binding affinity to be effective in activating the receptors. Even more surprisingly, the present inventors discovered that the compounds of the present invention act as agonists rather than antagonists and thus are effective in activating thyroid hormone sensitive genes and for the use described herein, such as cholesterol lowering. Still more surprisingly, the present inventors discovered that the compounds of the present invention are effective in activating thyroid hormone sensitive genes and for the uses described herein, such as cholesterol lowering, even for compounds of the present invention that bind to thyroid hormone receptors with reduced affinity compared to the corresponding carboxylic acid derivative. Even more surprisingly, the present inventors discovered that the compounds of the present invention have sufficiently high tissue selectivity and have a sufficiently large therapeutic index to be effective in the treatment of the diseases and disorders described herein while avoiding undesired side effects. that involve the heart It is well known that many phosphonic acids in the blood are rapidly cleaned by the kidneys, thus greatly diminishing their usefulness as drugs in many cases. When the inventors of the present invention discovered that the prodrugs of the compounds of the present invention were excreted into the blood stream as active phosphonic acids after being processed in the liver, it was not known if the active compound could be cleared quickly by the kidneys or if the phosphonic acid could be reabsorbed or transported inside the liver. Therefore, it was unexpected when the present inventors discovered that the active phosphonic acid compounds of the present invention were not cleaned rapidly by the kidneys. It was also unexpected when the present inventors discovered that the active phosphonic acid compounds of the present invention were reabsorbed or transported back into the liver. Indeed, it was surprisingly found that the liver was the main mode of cleaning the compounds evaluated. In one aspect, the compounds containing phosphonic acid, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs used in these methods bind at least one thyroid hormone receptor with a Ki of = 100 nM relative to T3, o = 90nM, <; 80nM, = 70nM, < 60nM, < 50nM, < 40nM, < 30nM, < 20nM, < lOnM, < 50nM, < InM, < 0.5 nM. The binding of thyroid hormone receptor is easily determined using assays described in the literature. For example, nuclear extracts from animal livers can be prepared according to the methods described by Yokohama et al., (J. Med. Chem., 38: 695-707 (1995)). Binding assays can also be performed using purified thyroid hormone receptors. For example, using the methods used by Chiellini et al. (Bioorg, Med. Chem. 10: 333-346 (2002)), binding affinities of competitive binding are determined using 125IT3 and the human thyroid receptors TRal and TRßl. The most recent methods, advantageously, make it possible to determine the selectivity of the thyroid receptor. The methods described in Example A were used to determine the binding of the compounds of this invention. In another aspect, the compounds containing phosphonic acid, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs used in these methods cause at least 50%, 2 times, 3 times, 4 times, 6 times or more. 8 times increase or decrease in the expression of one or more of the sensitive genes of the thyroid hormone. Changes in gene expression can be detected in cells or in vivo. Prodrugs of phosphonic acids may increase cellular uptake but in some cases are poorly converted to phosphonic acid due to low levels of enzymes required for conversion. Changes in gene expression in vivo require any phosphonic acid of the invention to be absorbed by the tissue after administration or for the prodrug to remain intact after administration sufficiently long to distribute to the target organ and cells. After distribution to the cells, the enzymes responsible for cleavage of the prodrug must act on the prodrug to convert it to phosphonic acid. The phosphonic acid must then be able to be transported to the nucleus. If a portion of the phosphonic acid is excreted from the cell it must be transported back through the cell membrane and the nuclear membrane. The prodrugs of the present invention are activated in the liver and excreted by the liver as phosphonic acid compounds that are again transported back through the cell and nuclear membrane and into the nucleus. In spite of being excreted from the liver and having been transported in the nucleus and in spite of having reduced potency, in vivo, the phosphonic acids and their prodrugs lead to surprisingly powerful biological activity. This surprising high biological activity is attributed to the ability of the compounds of the present invention to modulate known genes to be regulated by T3. For example, increased mGPDH > 1.5 times in the liver of an animal administered with a dose of 1 mg / kg of the drug.

The liver is an important target organ of thyroid hormone with an estimated 8% of hepatic genes regulated by thyroid hormone. The cDNA microarray hybridization labeled with quantitative fluorescence was used to identify the thyroid responsive genes in the liver as shown in Table 1 below (Feng et al., Mol.Endocrinol., 14: 947-955 (2000)). In the study, hepatic RNA from hypothyroid and T3 treated mice was used. Thyroid hormone treatment affected the expression of the genes of 2225 different mouse genes sampled with 14 which increases > 2 times and 41 decreasing > 60% TABLE I GENES REGULATED BY T3 List of Hepatic Genes Regulated by T3 Determined r Microarray Analysis of cDNA.

Cell Proliferation, Replication. 614275 B61 U26188 2.3 597868 Bcl-3 M90397 2.5 493127 Similar protein cmesma AF131865 2.0 (Kip 1 p) 582689 Protein that binds P40201 0.4 Chromodynamium-helicase-DNA CHD-1 524471 Protein NfiBl (exon 1-12) Y07685 0.3 516208 RNA Helicase dependent on J04847 0.3 Putative ATP PL 10 558121 Murino vik5 variant in S53216 0.1 cmasa 573247 Protein Cll X81624 0.3 522108 Stimulation factor D43804 0.3 thymic stromal 613942 Activation enzyme of D10576 0.3 ubiquitin The X signal transduction. 573046 ß-2 Adrenergic Receptor X15643 3.4 583258 U60001 kinase inhibitor 2.1 C protein (mPKCI) 616040 G inhibitor protein of M13963 0.3 adenylate cyclase, strand at 583353 Terminal 04123 0.3 deoxynucleotidyltransferase 550956 Pl60 protein kinase that U58513 0.2 serpentine spiral shape, associated with Rho. 582973 Protein kinase C, type T AB011812 0.3 442989 Kinase? of protein M94632 0.5 607870 Lamín A D13181 0.3 The genes reported to be affected by thyroid hormone are identified using a variety of techniques including microarray analysis. Studies have identified genes that are affected by T3 and T3 mimics that are important in metabolic diseases. T3-sensitive genes in the liver include genes that affect lipogenesis, including spot 14, fatty acid transport protein, melee enzyme, fatty acid synthase (Blennemann et al., Mol Cell Endocrinol. 110 (l-2): l -8 (1995)) and CYP4A. The HMG CoA and LDL receptor reductase genes have been identified as affecting cholesterol synthesis and as being sensitive to T3. CPT-1 is a T3-sensitive gene involved in fatty acid oxidation. Genes that affect energy expenditure include mitochondrial genes such as mitochondrial 3-phosphate sn-glycerol dehydrogenase (GPDH), and / or enzymes associated with proton leakage such as the adenine nucleotide transporter (ANT), Na + / K + -ATPase, Ca2 + -ATPase and ATP synthase are also T3 sensitive genes. Sensitive T3 genes that affect glycogenesis and glycogenesis include glucose 6-phosphatase and PEPCK. Thyroid sensitive genes in the heart are not well described as those in the liver but can be determined using similar techniques as described by Feng et al. Many of the genes described to be affected in the heart are the same as those described above for the liver. Common genes evaluated include mitochondrial sn-glycerol 3-phosphate dehydrogenase (mGPDH), and heavy and light myosin chains (Danzi et al., Thyroid 12 (6): 467-72 (2002)). The compounds used in the methods bind to thyroid receptors and produce a change in some expression gene. Evidence for agonist activity was obtained using standard assays described in the literature. A commonly used assay involves a reporter cell assay in which the cells, for example, HeLa cells, Hek293 cells, Chinese ovarian cells, are transfected with an expression vector for human TRal or TRßl and subsequently with a reporter vector encoding a secreted form of alkaline phosphatase that contains that expression that is under the control of a thyroid hormone response element. Agonist activity is measured by expression of the cells to the compounds, especially phosphonic acid prodrugs of the compounds that are cleaved to phosphonic acid by cell homogenates, followed by determination of alkaline phosphatase activity in the cell culture medium using a chemiluminescent assay (Grover et al., Proc Nati Acad Sci USA) 100 (17): 10067-72 (2003)).

In one aspect, the thromomimetics of phosphonic acid and its prodrugs and salts are useful in the prevention and treatment of arteriosclerosis by modulation levels of atherogenic proteins, for example, .Lp (a), apoAI, apoAII, LDL, HDL. Clinically patent hypothyroidism is associated with accelerated and premature coronary atherosclerosis and subclinical hypothyroidism is considered a condition with an increased risk for these diseases (Vanhaelst et al., And Bastenie et al., Lancet 2 (1967)). T3 and T3 mimetics modulate atherogenic proteins in a way that may provide benefits for patients at risk of developing atherosclerosis or having patients with atherosclerosis or diseases associated with atherosclerosis. T3 and T3 mimetics are known to decrease the levels of Lp (a), for example, in the monkey with 3,5-dichloro-4-914-hydroxy-3- (1-methylethyl) phenoxy] benzeneacetic acid (Grover and collaborators, Proc Nati Acad Sci USA 100, 10067-10072 (2003)). In human hepatoma cells, the T3 mimetic CGS23425 ([[4- [4-hydroxy-3- (1-methylethyl) phenoxy] -3,5-dimethylphenyl] amino] oxoacetic acid) increased the expression of apoAI via activation of thyroid hormone receptor (Taylor et al., Mol.Pharm., 52, 542-547 (1997)). Thus, in one aspect, the thyromimetics containing the phosphonic acid, its salts and prodrugs can be used to treat or prevent atherosclerosis, coronary heart disease and cardiac injury because the compounds are expected to be distributed in the liver (Examples F and H) and modulate the expression and production of atherogenic proteins. In another aspect, the thyromimetics containing the phosphonic acid and its prodrugs and salts are useful for the prevention and / or treatment of metabolic diseases such as obesity, hypercholesterolemia and hyperlipidemia and conditions such as atherosclerosis, coronary heart disease, heart injury without affecting the thyroid function, thyroid production of thyronine iodine circulating such as T3 and T4, and / or the ratio of T3 to T4. Previously reported compounds containing a carboxylic acid moiety, for example, GC-1 ([4- [[4-hydroxy-3- (1-methylethyl) phenyl] methyl] -3,5-dimethylphenoxy] acetic acid) ( Trost et al., Endocrinology, 141, 3057-3064 (2000)) and 3, 5-Dichloro-4- [4-hydroxy-3- (1-methylethyl) phenoxy] benzenacetic acid (Grover et al., Proc Nati Acad Sci USA) , 100, 10067-10072 (2003)) report that these selective TRβ compounds, depending on the dose, lower cholesterol and TSH levels. The effects on cholesterol and TSH occur at the same dose or at established doses so as not to be pharmacologically different (for example, 2 times). Particularly the T3 mimetics useful in these methods can minimize the effects on thyroid function, thyroid production of circulating iodine thyronines such as T3 and T4, and / or the ratio of T3 to T4. In contrast to the above T3 mimetics, the compounds of the present invention are more easily distributed to the liver and result in pharmacological effects at doses that do not adversely affect thyroid function, the thyroid production of circulating iodine thyronines such as T3 and T4, and / or the relationship of T3 to T4. In one embodiment the compounds of the present invention have a therapeutic index, defined as the difference between the dose at which a significant effect is observed for a use described herein, eg, cholesterol lowering, and the dose at which there is a significant decrease in T3 or significant decrease in T4, or significant change in the ratio of T3 to T4, is at least 50 times, 100 times, 200 times, 300 times, 400 times, 500 times, 600 times, 700 times, 800 times, 900 times, 1,000 times, 2,000 times, 3,000 times, 4,000 times, 5,000 times, 6,000 times, 7,000 times, 8,000 times, 9,000 times, or at least 10,000 times. In a modality, better than a significant amount, the amount of change in T3 or T4 is a selected decrease of; at least 5%, 10%, %, 20%, 25%, or at least 30% of circulation levels. Side effects associated with TH-based therapies limit their use for the treatment of obese patients and according to the Physician's Desk Reference (PDR) 11 T3 is now contraindicated for patients with obesity. 3, 5-Dichloro-4- [4-hydroxy-3- (1-methylethyl) phenoxy] benzenacetic acid and other T3 mimetics are reported to result in weight loss in animals, eg, rodent and monkey models. Weight loss by these compounds can increase from their effects on the liver as well as peripheral tissues. TH is known to have a multitude of side effects of the liver that can result in increased metabolism and weight loss. TH plays an important role in the development and function of brown and white adipose tissue. HT can induce WAT differentiation, proliferation and accumulation of intracellular lipid. TH induces lipogenic genes in WAT such as glucose-6-phosphate dehydrogenase, fatty acid synthase and spot-14. TH also regulates lipolysis in fat to produce weight loss in a coordinated manner, that is, lipolysis in fat to release fatty acids followed by the use of fatty acid in tissues, for example, liver, muscle and heart. Weight loss through the administration of liver-specific T3 analogues requires that oxygen consumption decrease in the liver resulting in T3 being sufficient to result in total net body energy expenditure. The contribution of the liver to energy expenditure is estimated to be 22% based on measurements of oxygen consumption. (Hsu, A et al, Am J Clin Nutr. 77 (6): 1506-11 (2003)). Thus, the compounds of the present invention can be used to maintain or reduce the weight in an animal. The mitochondria is the source of energy for all cellular respiration. The synthesis of new mitochondria is a complex process which requires over 1000 genes (Goffart et al., Exp Physiol. Jan. 88 (1): 33-40 (2003)). The mechanisms that control mitochondrial biogenesis are not well defined, but are known to include exercise (Jones et al, Am J Physiol Endocrinol Metab, 2003 Jan. 284 (1): E96-101), on expression of PGC-1 (Lehman and collaborators, J Clin Invest 2000 Oct. 106 (7): 847-56) or AMP activated protein kinase (Bergeron et al., Am J Physiol Endocrinol Metab 2001 Dec. 281 (6): E1340-6). An increase in mitochondrial density leads to a higher rate of energy expenditure. Thyroid hormone has been shown to play a key role in mitochondrial biogenesis by increasing the expression of nuclear respiratory factor 1 and PGC-1 (Weitzel et al., Exp Physiol, 2003 Jan. 88 (1): 121-8). Compounds that increase the expression of NRF-1 and / or PGC-1 can lead to an increase in mitochondrial density within the cell. Such an increase can cause the cell to have a higher velocity of energy expenditure. Methods for analyzing NRF-1 and PGC-1 include immunoblotting with specific antibodies, or analysis of mRNA levels.

The compounds that caused the increases in NRF-1 or PGC-1 can therefore lead to a higher energy expenditure. Even small increases in energy expenditure for prolonged periods of time (weeks or years) can cause a decrease in weight under isocaloric circumstances. More methods to evaluate mitochondrial biogenesis include the analysis of mitochondrial proteins such as cytochrome c and cytochrome c oxidase, either by immunostaining or analysis of mRNA levels. Mitochondrial density can also be measured by counting the number of mitochondria in electron micrographs. In one aspect, thyromimetics containing the phosphonic acid and its prodrugs and salts can be used to cause weight loss or prevent weight gain without side effects. Which may be advantageous for using compounds that result in high liver specificity.

(Examples F and G) In another aspect, compounds that result in increased levels of genes associated with oxygen uptake, eg, GPDH (Example B), are particularly useful in weight loss and weight gain control. In another aspect, compounds that demonstrate weight loss in doses that do not affect cardiac function, eg, heart rate, systolic contraction force, diastolic relaxation duration, vascular tone, heart weight may be particularly useful in loss. of weight and control of weight gain. In a further aspect, compounds that cause weight loss without affecting thyroid function, thyroid production of circulating iodinated thyronines such as T3 and T4, and / or the ratio of T3 to T4 are particularly useful. In addition to their use in obesity and weight control, thyromimetics containing phosphonic acid and its prodrugs and salts can be used to treat diabetes and related conditions such as impaired glucose tolerance, insulin resistance and hyperinsulinemia. Patients with type 2 diabetes "T2DM" exhibit chronic high blood glucose levels. Fasting high blood glucose in T2DM is related to the overproduction of glucose by a path in the liver known as the path of gluconeogenesis. The flow rate in this path is controlled in part by enzymes in the way such as PEPCK, fructose 1, 6-bisphosphatase and glucose-6-phosphatase in addition by hormones such as insulin, which can influence the expression and activities of these enzymes. T3 is known to worsen diabetes. While the reason that T3 worsens diabetes is not known, the effect of T3 on the increased expression of the PEPCK gene and glucose-6-phosphatase may be the cause of increased glucose levels. T3 is known to increase the lipolysis of accumulations of triglycerides in fat and to increase the levels of circulation of free fatty acids. (KS, et al., Metabolism (1999) Oct; 48 (10): 1318-21) The effect of T3 on free fatty acid levels may also be responsible for the negative effect on diabetes due to high free fatty acid levels improving the flow through the path of glycogenesis. The compounds of this invention, while mimicking T3, result in preferential activation of liver T3 genes, are not expected to increase lipolysis in peripheral tissues which is expected to avoid high levels of T3-induced circulation. free fatty acids and their effects in the increase of glycogenesis flow and decrease in insulin sensitivity. Increased hepatic insulin sensitivity will decrease PEPCK and the expression of the glucose-6-phosphatase gene will thus reduce glycogenesis. Activation of TR in the liver should also decrease the fat content in the liver, which in turn is expected to improve diabetes and steatohepatitis (eg, NASH), thus providing another use for the compounds of the present invention. A decrease in the fat content in the liver is associated with increased hepatic insulin sensitivity (Shulman, 2000) and consequently should improve glycemic control in type 2 diabetes through decreased glucose production and improved glucose uptake. The overall effect on the patient will be better glycemic control, thus providing another use for the compounds of the present invention. TH also stimulates the expression of the GLUT-4 transporter in the skeletal muscle which produces concomitant increases in the absorption of basal glucose. Studies in insulin-resistant, obese Zucker rats demonstrated that TH therapy induces GLUT-4 expression in skeletal muscle and total improvement in hyperinsulinemia, despite the fact that plasma glucose levels were moderately elevated (Torrance et al. , Endocrinol., 138,1204- (1997)). Thus, another embodiment of the present invention relates to the use of compounds of the present invention to prevent or treat hyperinsulinemia. TH therapy results in increased energy expenditure. Increased energy expenditure can result in increased weight loss, which in turn can result in increased glycemic control. Diet and exercise are often used initially to treat diabetes. Exercise and weight loss increase insulin sensitivity and improve glycemia. Thus, further uses of the compounds of the present invention include increased energy expenditure, increased insulin sensitivity and improved glycemia. In one aspect, the phosphonic acid-containing compounds of the present invention are useful for increasing the levels of genes associated with gluconeogenesis (Example B). In another aspect, the compounds of the present invention are useful for decreasing hepatic glycogen levels. In addition, the compounds of the present invention result in improvement of hyperinsulinemia and / or decreased glucose levels in diabetic animal models at doses that do not affect cardiac function, eg, heart rate, systolic contraction force, duration of diastolic relaxation. , vascular tone, weight of the heart. In a further aspect, the compounds of the present invention result in improvement of hyperinsulinemia and / or decreased glucose levels in diabetic animal models in doses that do not affect thyroid function, thyroid production of circulating iodine thyronines such as T3 and T4, and / or the ratio of T3 to T4.

As discussed above, prior use of T3 and T3 mimetics to treat metabolic diseases have been limited by the suppressive side effects in the heart. Previous attempts to overcome this limitation have focused on the selective targeting of the liver over the heart using T3 mimetics that selectively bind TRβ over TRa. Because the heart primarily expresses TRa, previous investigators have attempted to increase the therapeutic index of T3 mimetics by increasing the selectivity of compounds for TRβ which is expressed in the liver. Previous attempts have not focused on T3 mimetics that are selectively distributed to the liver over the heart or at least have not been successful. Thus, better than selection for a particular tissue or organ, previous work has been directed to the discovery of T3 mimetics that selectively act at the receptor level after the drug is not selectively distributed to both heart and liver tissues. It was therefore unexpected when the present inventors discovered that the phosphonic acid compounds of the present invention are selectively distributed to the liver over the heart. The selective distribution to the liver on the heart was also found with the prodrugs, which although they were processed in the liver, were excreted from the liver into the blood stream as active phosphonic acid compounds. Thus, the compounds of the present invention are able to selectively target the liver and thereby increase the therapeutic index compared to T3 and T3 mimetics containing carboxylic acid. The compounds of the present invention can therefore be dosed at levels that are effective in the metabolic treatment and other disorders where the liver is the target of the drug without significantly affecting the heart's function. Due to the selectivity of the phosphonic acid-containing compounds of the present invention for liver over the heart, it is not necessary for the compound to have higher selectivity for TRβ on TRa, although this may be desired. Indeed, surprisingly some of the compounds of the present invention selectively bind TRa on TRβ and are highly effective for the uses disclosed herein without having the negative side effects normally associated with TRa selective compounds. Thus, included as an embodiment of the present invention are the compounds of Formula I, II and III which selectively bind to TRβ on TRa by at least 5 times, 10 times, 20 times, 30 times, 40 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times, 200 times, 300 times, 400 times or at least 500 times, and compounds of Formula I, II and III that selectively bind TRa on TRβ through at least 5 times, 10 times, 20 times, 30 times, 40 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times, 200 times, 300 times, 400 times or at least 500 times. Changes in the therapeutic index are easily determined using assays and methods well described in the literature. Genes in extrahepatic tissues are monitored using methods well understood by those skilled in the art. The assays include the use of cDNA microarray analyzes of tissues isolated from treated animals. The sensitivity of the heart to T3 makes analysis of T3 sensitive genes in the heart in addition to the functional consequences of these changes in cardiac properties a further strategy for evaluation of the therapeutic index of the compounds of the present invention. The measured cardiac genes include mGPDH, heavy and light chain of myosin. One method of measuring the effects of T3 mimetics on the heart is by using assays that measure T3 mediated myosin heavy chain gene transcription in the heart. The compounds of the present invention were evaluated using the methods described in Examples B, D, and I. In one embodiment, the compounds of the present invention have a therapeutic index defined as the difference between the dose at which a significant effect is observed for a use broken down herein, eg, cholesterol lowering, and the dose at which a significant effect is observed in a characteristic or function, as broken down in the present (eg, heart rate), is at least 50 times, 100 times, 200 times, 300 times, 400 times, 500 times, 600 times, 700 times, 800 times, 900 times, 1,000 times, 2,000 times, 3,000 times, 4,000 times, 5,000 times, 6,000 times, 7,000 times, 8,000 times, 9,000 times, or at least 10,000 times. Examples of use disclosed herein include but are not limited to reducing lipid levels, increasing the ratio of HDL to LDL or apoAI to LDL, reducing weight or preventing weight gain, maintaining or improving glycemic control, decreased blood glucose levels, increased mitochondrial biogenesis, increased expression of PGC-1, activated protein kinase of AMP or nuclear respiratory factor, inhibition of hepatic glycogenesis or for the treatment or prevention of a disease or disorder selected from the group consisting of atherosclerosis, hypercholesterolemia, obesity, NASH, NAFLD, insulin resistance, diabetes, metabolic syndrome X, glucose intolerance, hyperlipidemia, coronary heart disease, thyroid disease, thyroid cancer, depression, glaucoma, cardiac arrhythmias , cardiac injury, and osteoporosis. Example where the characteristic or function is a characteristic / cardiac function include but are not limited to cardiac hypertrophy (ratio of heart weight to body weight), heart rate, and various hemodynamic parameters, including systolic and diastolic blood pressure, left ventricular pressure final systolic and maximum contraction and relaxation speeds. A variety of methods are described that provide a means for evaluating the functional sequences of the cardiac action of T3, including the measurement of cardiac hypertrophy (ratio of heart weight to body weight), heart rate, and various hemodynamic parameters, They include systolic and diastolic blood pressure, left ventricular end systolic pressure and maximum contraction and relaxation velocities using the methods described by Trost et al., (Endocrinol., 141: 3057-64 (2000)). The compounds of the present invention were evaluated using the methods described in Examples B, D, and I. Other methods are also available for evaluating the therapeutic index which includes effects on muscle devastation and bone density. The compounds of the present invention were evaluated, using the methods described in Examples C and G. The therapeutic index was determined by administration to animals of a wide range of doses and determination of the minimum dose capable of inducing a response in the relative liver. at the dose capable of inducing a response in the heart. Phosphonic acids are often poorly transported within cultured cells. Consequently, cell reporter assays, while often useful for confirming agonist activity, may not provide an appropriate indication of potency. Thus, evidence of agonist activity is often more readily obtained in vivo for compounds of the present invention. In vivo assays include but are not limited to treatment of animals with phosphonic acids of the invention or a prodrug of phosphonic acid and monitoring the expression of T3 sensitive genes in the liver or the functional consequences of T3 sensitive gene changes . In one aspect, compounds useful in novel methods bind to thyroid receptors and produce changes in the expression of two or more hepatic genes. Animals used for evaluation compounds useful in the methods include normal rats and mice, animals made hypothyroid using methods well described in the literature, including non-transgenic thyroid hormone receptor mice (eg, TRa ~ _ such as those used in Grover et al., 2003), or animals exhibiting high cholesterol (e.g. rat or hamster fed high cholesterol), obesity and / or diabetes (eg, fa / fa rat, Zucker diabetic fat rat, ob / ob mice, db / db mice, rodents fed high fat). (Liureau et al., Biochem Pharmacol. 35 (10): 1691-6 (1986); Trost et al., Endocrinology 141 (9): 3057-64 (2000); and Grover, PNAS 2003). The drug or prodrug is administered by a variety of routes including bolus, oral, and continuous infusion (Examples B, D e l). The animals are treated for 1-28 days and the liver, heart and blood are isolated. Changes in transcription of the gene relative to animals treated with vehicle and animals treated with T3 were determined using Northern blot analysis, RNAse protection or reverse transcription and subsequent PCR. While methods are available to monitor changes in thousands of liver genes, only a small number need to be monitored to demonstrate the biological effect of the compounds is this invention. Commonly, genes such as spot-14, FAS, mGPDH, CPT-1 and LDL receptor are monitored. The changes of > 1.5 times in two or more genes is considered proof that the compound modulates T3 sensitive genes in vivo. Alternative methods for measuring changes in gene transcription include monitoring the activity or level of expression of the protein encoded by the gene. For example, in cases where the genes encode enzyme activities (e.g., FAS, mGPDH), direct measurements of enzyme activity in appropriately extracted liver tissue can be made using standard enzymatic techniques. In cases where the genes encode receptor functions (eg, the LDL receptor), binding binding studies or antibody-based assays (eg, Westerns) can be developed to quantitate the number of receptors expressed. Depending on the gene, TR agonists will increase or decrease the activity of the enzyme or increase or decrease receptor binding or number. The functional consequences of changing the expression levels of T3-sensitive hepatic genes are many multiples and were easily demonstrated using well-described trials in the literature. The administration of the phosphonic acid-containing compounds that bind TR to animals can result in changes in lipids, including hepatic and / or plasma cholesterol levels; changes in lipoprotein levels that include LDL cholesterol, lipoprotein a (Lp (a)); changes in hepatic glycogen levels; and changes in energy expenditure as measured by changes in oxygen consumption and in some cases animal weight. For example, the effect on cholesterol is determined by using animals fed cholesterol such as normal rats and hamsters, or non-transgenic TRa ~ _ mice. Cholesterol is measured using standard tests. The compounds of the present invention were evaluated using the methods described in Example D and I. Hepatic glycogen levels are determined from livers isolated from treated animals. The compounds of the present invention are evaluated using the methods described in Examples D and E. Changes in energy expenditure are monitored by measuring changes in oxygen consumption (MVo2). A variety of methods are well described in the literature and include measurement in the whole animal using Oximax chambers (US 6441015). The livers of treated rats can also be evaluated (Fernández et al., Toxicol Ltt 69 (2): 205-10 (1993)) as well as isolated mitochondria of liver (Carreras, et al., Am J Physiol Herat Circ Physiol. 6) H2282-8 (2001)). The hepatocytes of treated rats can also be evaluated (Ismael-Beigi F et al., J Gen Physiol. 73 (3): 369-83 (1979)). The compounds of the present invention are evaluated using the methods described in Examples C and G. Phosphonic acid-containing compounds that bind to a TR modulate the expression of certain genes in the liver resulting in effects on lipids (e.g., cholesterol) ), glucose, lipoproteins, and triglycerides. Such compounds can lower cholesterol levels which is useful in the treatment of patients with hypercholesterolemia. Such compounds can lower lipoprotein levels such as Lp (a) or LDL and are useful in the prevention or treatment of patients with atherosclerosis and heart disease. The compounds can raise lipoprotein levels such as apoAI or HDL and are useful in the prevention and treatment of patients with atherosclerosis and heart disease. The compounds can cause a reduction in weight. The compounds can lower glucose levels in patients with diabetes. In another aspect are compounds that in the presence of liver cells or microsomes result in compounds of Formula I, II and III where X is -P (0) (0H) 2. Methods for reducing plasma lipid levels in an animal are also provided, the method comprising the step of administering to a patient an amount of a compound of Formula I, II, III or VIII of a prodrug thereof, or a pharmaceutically acceptable salt or co-crystal thereof. In one embodiment the compound is an active form. In another embodiment, the compound is a prodrug. In another embodiment, the compound of the formula I, II, III, or VIII or a prodrug thereof comprises an enantiomerically enriched enriched stereoisomer, or a stereoisomer coated at the end. In another embodiment, the compound is administered as a racemic mixture. In another embodiment, the compound is administered as an enantiomerically enriched mixture. In another embodiment, the compound is administered as a diastereomeric mixture. In yet another embodiment the compound is administered as an individual stereoisomer. Methods of reducing plasma lipid levels in an animal wherein the lipid is cholesterol are also provided, the method comprising the step of administering to a patient an amount of a compound of Formula I, II, III, VIII. , a prodrug thereof, or a pharmaceutically acceptable salt or co-crystal thereof. In one embodiment the compound is in an active form. In another embodiment, the compound is a prodrug. In another embodiment, the compound of Formula I, II, III, or VIII or a prodrug thereof comprises a stereocenter. In another embodiment, the compound is administered as a racemic mixture. In another embodiment, the compound is administered as an enantiomerically enriched mixture. In another embodiment, the compound is administered as a diastereomeric mixture. In yet another embodiment the compound is administered as an individual stereoisomer. In one embodiment, cholesterol reduction methods result in a decrease in total cholesterol. In one embodiment, cholesterol reduction methods result in a reduction of high density lipoprotein (HDL). In one embodiment, cholesterol reduction methods result in a reduction of low density lipoprotein (LDL). In one embodiment, cholesterol reduction methods result in a reduction of very low density lipoprotein (VLDL). In another modality the LDL is reduced to an extension greater than that of HDL. In another modality, VLDL is reduced to a greater extent than HDL. In another modality, VLDL is reduced to a greater extent than LDL. In one embodiment of the lipid reduction method, the lipid is triglycerides. In one embodiment, the lipid is liver triglycerides. In another embodiment, the lipid is in the form of a lipoprotein. In another embodiment, the lipoprotein is Lp (a). In another embodiment, the lipoprotein is apoAII. Methods of increasing the ratio of HDL to LDL, HDL to VLDL, LDL to VLDL, apoAI to VLDL in an animal are also provided, the method comprising the step of administering to a patient an amount of a compound of Formula I, II, III, VIII, a prodrug thereof, or a pharmaceutically acceptable salt or co-crystal thereof. In one embodiment the compound is in an active form. In another embodiment, the compound is a prodrug. In another embodiment, the compound of Formula I, II, III, or VIII or a prodrug thereof comprises a stereocenter. In another embodiment, the compound is administered as a racemic mixture. In another embodiment, the compound is administered as an enantiomerically enriched mixture. In another embodiment, the compound is administered as a diastereomeric mixture. In yet another embodiment the compound is administered as an individual stereoisomer. Methods of treating hypercholesterolemia in an animal are also provided, the method comprising the step of administering to a patient an amount of a compound of Formula I, II, III, or VIII, a prodrug thereof, or a pharmaceutically acceptable salt or co-crystal thereof. In one embodiment the compound is in an active form. In another embodiment, the compound is a prodrug. In another embodiment, the compound of Formula I, II, III, or VIII or a prodrug thereof comprises a stereocenter. In another embodiment, the compound is administered as a racemic mixture. In another embodiment, the compound is administered as an enantiomerically enriched mixture. In another embodiment, the compound is administered as a diastereomeric mixture. In yet another embodiment the compound is administered as an individual stereoisomer. Also provided are methods of prevention or treatment of atherosclerosis in an animal, the method comprising the step of administering to a patient an amount of a compound of Formula I, II, III, or VIII, a prodrug thereof, or a pharmaceutically acceptable salt or co-crystal of these. In one embodiment the compound is in an active form. In another embodiment, the compound is a prodrug. In another embodiment, the compound of Formula I, II, III, or VIII or a prodrug thereof comprises a stereocenter. In another embodiment, the compound is administered as a racemic mixture. In another embodiment, the compound is administered as an enantiomerically enriched mixture. In another embodiment, the compound is administered as a diastereomeric mixture. In yet another embodiment the compound is administered as an individual stereoisomer. Methods of reducing fat content in the liver or preventing or treating steatosis, NASH or NAFLD in an animal are also provided, the method comprising the step of administering to a patient an amount of a compound of Formula I, II, III, VIII, a prodrug thereof, or a pharmaceutically acceptable salt or co-crystal thereof. In one embodiment the compound is in an active form. In another embodiment, the compound is a prodrug. In another embodiment, the compound of Formula I, II, III, or VIII or a prodrug thereof comprises a stereocenter. In another embodiment, the compound is administered as a racemic mixture. In another embodiment, the compound is administered as an enantiomerically enriched mixture. In another embodiment, the compound is administered as a diastereomeric mixture. In yet another embodiment the compound is administered as an individual stereoisomer. Methods of weight reduction or prevention of weight gain in an animal are also provided, the method comprising the step of administering to a patient an amount of a compound of Formula I, II, III, or VIII, a prodrug of these, or a pharmaceutically acceptable salt or co-crystal thereof. In one embodiment the compound is in an active form. In another embodiment, the compound is a prodrug. In another embodiment, the compound of Formula I, II, III, or VIII or a prodrug thereof comprises a stereocenter. In another embodiment, the compound is administered as a racemic mixture. In another embodiment, the compound is administered as an enantiomerically enriched mixture. In another embodiment, the compound is administered as a diastereomeric mixture. In yet another embodiment the compound is administered as an individual stereoisomer.

Methods of prevention or treatment of obesity in an animal are also provided, the method comprising the step of administering to a patient an amount of a compound of Formula I, II, III, or VIII, a prodrug thereof, or a pharmaceutically acceptable salt or co-crystal of these. In one embodiment the compound is in an active form. In another embodiment, the compound is a prodrug. In another embodiment, the compound of Formula I, II, III, or VIII or a prodrug thereof comprises a stereocenter. In another embodiment, the compound is administered as a racemic mixture. In another embodiment, the compound is administered as an enantiomerically enriched mixture. In another embodiment, the compound is administered as a diastereomeric mixture. In yet another embodiment the compound is administered as an individual stereoisomer. Methods of prevention or treatment of coronary heart disease in an animal are also provided, the method comprising the step of administering to a patient an amount of a compound of Formula I, II, III, or VIII, a prodrug thereof, or a pharmaceutically acceptable salt or co-crystal thereof. In one embodiment the compound is in an active form. In another embodiment, the compound is a prodrug. In another embodiment, the compound of Formula I, II, III, or VIII or a prodrug thereof comprises a stereocenter. In another embodiment, the compound is administered as a racemic mixture. In another embodiment, the compound is administered as an enantiomerically enriched mixture. In another embodiment, the compound is administered as a diastereomeric mixture. In yet another embodiment the compound is administered as an individual stereoisomer. Methods of maintaining or improving glycemic control are also provided in an animal that is treated with a T3 mimetic, the method comprising the step of administering to a patient an amount of a compound of Formula I, II, III, or VIII, a prodrug thereof, or a pharmaceutically acceptable salt or co-crystal thereof. In one embodiment the compound is in an active form. In another embodiment, the compound is a prodrug. In another embodiment, the compound of Formula I, II, III, or VIII or a prodrug thereof comprises a stereocenter. In another embodiment, the compound is administered as a racemic mixture. In another embodiment, the compound is administered as an enantiomerically enriched mixture. In another embodiment, the compound is administered as a diastereomeric mixture. In yet another embodiment the compound is administered as an individual stereoisomer. In one embodiment the glycerin control is maintained after the animal is treated for at least 14 days with the compound. In another embodiment, glycerin control is better for 28 days in an animal treated with the compound. Methods of decreasing blood glucose levels in an animal are also provided, the method comprising the step of administering to a patient an amount of a compound of Formula I, II, III, or VIII, a prodrug thereof, or a pharmaceutically acceptable salt or co-crystal thereof. In one embodiment the compound is in an active form. In another embodiment, the compound is a prodrug. In another embodiment, the compound of Formula I, II, III, or VIII or a prodrug thereof comprises a stereocenter. In another embodiment, the compound is administered as a racemic mixture. In another embodiment, the compound is administered as an enantiomerically enriched mixture. In another embodiment, the compound is administered as a diastereomeric mixture. In yet another embodiment the compound is administered as an individual stereoisomer. Also provided are methods of prevention or treatment of diabetes, insulin resistance, metabolic syndrome X or glucose intolerance in an animal, the method comprising the step of administering to a patient an amount of a compound of Formula I, II, III, ú VIII, a prodrug thereof, or a pharmaceutically acceptable salt or co-crystal thereof. In one embodiment the compound is in an active form. In another embodiment, the compound is a prodrug. In another embodiment, the compound of Formula I, II, III, or VIII or a prodrug thereof comprises a stereocenter. In another embodiment, the compound is administered as a racemic mixture. In another embodiment, the compound is administered as an enantiomerically enriched mixture. In another embodiment, the compound is administered as a diastereomeric mixture. In yet another embodiment the compound is administered as an individual stereoisomer. Methods of prevention or treatment of altered energy expenditure in an animal are also provided, the method comprising the step of administering to a patient an amount of a compound of Formula I, II, III, or VIII, a prodrug thereof , or a pharmaceutically acceptable salt or co-crystal thereof. In one embodiment the compound is in an active form. In another embodiment, the compound is a prodrug. In another embodiment, the compound of Formula I, II, III, or HIV or a prodrug thereof comprises a stereocenter. In another embodiment, the compound is administered as a racemic mixture. In another embodiment, the compound is administered as an enantiomerically enriched mixture. In another embodiment, the compound is administered as a diastereomeric mixture. In yet another embodiment the compound is administered as an individual stereoisomer. Methods of preventing or treating a liver disease sensitive to modulation of T3-sensitive genes in an animal are also provided, the method comprising the step of administering to a patient an amount of a compound of Formula I, II, III , VIII, a prodrug thereof, or a pharmaceutically acceptable salt or co-crystal thereof. In one embodiment the compound is in an active form. In another embodiment, the compound is a prodrug. In another embodiment, the compound of Formula I, II, III, or VIII or a prodrug thereof comprises a stereocenter. In another embodiment, the compound is administered as a racemic mixture. In another embodiment, the compound is administered as an enantiomerically enriched mixture. In another embodiment, the compound is administered as a diastereomeric mixture. In yet another embodiment the compound is administered as an individual stereoisomer. Methods of prevention or treatment of thyroid disease, thyroid cancer, depression, glaucoma, cardiac arrhythmias, cardiac injury, or osteoporosis in an animal are also provided, the method comprising the step of administering to a patient an amount of a compound of the invention. Formula I, II, III, VIII, or a pharmaceutically acceptable salt or co-crystal thereof. In one embodiment the compound is in an active form. In another embodiment, the compound is a prodrug. In another embodiment, the compound of Formula I, II, III, or VIII or a prodrug thereof comprises a stereocenter. In another embodiment, the compound is administered as a racemic mixture. In another embodiment, the compound is administered as an enantiomerically enriched mixture. In another embodiment, the compound is administered as a diastereomeric mixture. In yet another embodiment the compound is administered as an individual stereoisomer.

Methods of increasing mitochondrial biogenesis in an animal are also provided, the method comprising the step of administering to a patient an amount of a compound of Formula I, II, III, or VIII, a prodrug thereof, or a pharmaceutically acceptable salt or co-crystal of these. In one embodiment the compound is in an active form. In another embodiment, the compound is a prodrug. In another embodiment, the compound of Formula I, II, III, or VIII or a prodrug thereof comprises a stereocenter. In another embodiment, the compound is administered as a racemic mixture. In another embodiment, the compound is administered as an enantiomerically enriched mixture. In another embodiment, the compound is administered as a diastereomeric mixture. In yet another embodiment the compound is administered as an individual stereoisomer. Also provided are methods of increasing the expression of PGC-1, activated protein kinase AMP or nuclear respiratory factor in an animal, the method comprising the step of administering to a patient an amount of a compound of Formula I, II, III, VIII, a prodrug thereof, or a pharmaceutically acceptable salt or co-crystal thereof. In one embodiment the compound is in an active form. In another embodiment, the compound is a prodrug. In another embodiment, the compound of Formula I, II, III, or VIII or a prodrug thereof comprises a stereocenter. In another embodiment, the compound is administered as a racemic mixture. In another embodiment, the compound is administered as an enantiomerically enriched mixture. In another embodiment, the compound is administered as a diastereomeric mixture. In yet another embodiment the compound is administered as an individual stereoisomer. Methods of inhibiting hepatic gluconeogenesis in an animal are also provided, the method comprising the step of administering to a patient an amount of a compound of Formula I, II, III, or VIII, a prodrug thereof, or a salt pharmaceutically acceptable or co-crystal of these. In one embodiment the compound is in an active form. In another embodiment, the compound is a prodrug. In another embodiment, the compound of Formula I, II, III, or VIII or a prodrug thereof comprises a stereocenter. In another embodiment, the compound is administered as a racemic mixture. In another embodiment, the compound is administered as an enantiomerically enriched mixture. In another embodiment, the compound is administered as a diastereomeric mixture. In yet another embodiment the compound is administered as an individual stereoisomer. Also provided are kits for reducing lipid levels, increasing the ratio of HDL to LDL or apoAI to LDL, reducing weight or preventing weight gain, maintaining or improving glycemic control, lowering blood glucose levels , increased mitochondrial biogenesis, increased expression of PGC-1, activated protein kinase AMP or nuclear respiratory factor, inhibition of hepatic glycogenesis, or for the prevention or treatment of a disease or disorder for which a compound of the present invention is effective in prevention or treatment, the kits comprise: a) a pharmaceutical composition comprising a compound of Formula I, II, III, or VIII or a prodrug thereof; and b) at least one container for containing the pharmaceutical composition. Also provided are pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable excipient, carrier or diluent. Also provided are pharmaceutical compositions comprising a first pharmaceutical compound selected from Formula I, Formula II or Formula III or Formula VIII or a prodrug thereof and a second pharmaceutical compound of the same Formula but wherein the first and second pharmaceutical compounds are not they are the same molecules. Also provided are pharmaceutical compositions comprising a first selected pharmaceutical compound of Formula I, Formula II or Formula III or Formula VIII or a prodrug thereof and a second pharmaceutical compound selected from Formula I, Formula II or Formula III or Formula VIII or a prodrug thereof, but wherein the first and second pharmaceutical compounds are not both of the same Formula. Also provided are pharmaceutical compositions comprising a first pharmaceutical compound selected from Formula I, Formula II, Formula III or Formula VIII or a prodrug thereof and a second pharmaceutical compound that is not a selected compound of Formula I, Formula II, Formula III or Formula VIII or a prodrug thereof. Also provided are pharmaceutical compositions comprising a first compound of the present invention and a second compound useful for reducing lipid levels, increasing the ratio of HDL to LDL or apoAI to LDL, reducing weight or preventing weight gain. , maintenance or improvement of glycemic control, decreased blood glucose levels, increased mitochondrial biogenesis, increased expression of PGC-1, activated protein kinase of AMP or nuclear respiratory factor, inhibition of hepatic glycogenesis or for the treatment or prevention of atherosclerosis, hypercholesterolemia, obesity, steatosis, NASH, NAFLD, insulin resistance, diabetes, metabolic syndrome X, glucose intolerance, hyperlipidemia, coronary heart disease, thyroid disease, thyroid cancer, depression, glaucoma, cardiac arrhythmias , cardiac injury, or osteoporosis. In one embodiment, the composition comprising the first and second compounds is a single dose unit. In another embodiment, the dosage unit is in the form of a tablet, hard capsule or soft gel capsule. Also provided are the pharmaceutical compositions of the present invention which have an oral bioavailability of at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70 %, 75% or at least 80%. Kits are also provided for the prevention or treatment of a disease or disorder for which a compound of the present invention is effective in prevention or treatment, the kits comprising: a) a first pharmaceutical composition comprising a compound of Formula I , II, III, VIII or a prodrug of these; b) a second pharmaceutical composition comprising an additional compound useful for the treatment or prevention of a disease or disorder for which a compound of the present invention is effective in prevention or treatment; and c) at least one container for containing the first or second or both first and second pharmaceutical composition. Also provided are kits for reducing lipid levels, increasing the ratio of HDL to LDL or apoAI to LDL, reducing weight or preventing weight gain, maintaining or improving glycemic control, lowering blood glucose levels , increased mitochondrial biogenesis, increased expression of PGC-1, activated protein kinase of AMP or nuclear respiratory factor, inhibition of hepatic glycogenesis or for the treatment or prevention of a disease or disorder selected from the group consisting of atherosclerosis, hypercholesterolemia, obesity, steatosis, NASH, NAFLD, insulin resistance, diabetes, metabolic syndrome X, glucose intolerance, hyperlipidemia, coronary heart disease, thyroid disease, thyroid cancer, depression, glaucoma, cardiac arrhythmias, cardiac injury, and osteoporosis , the kits comprise: a) a first pharmaceutical composition comprising a compound of the Formula I, II, III, VIII or a prodrug of these; b) a second pharmaceutical composition comprising an additional compound useful for reducing lipid levels, increasing the ratio of HDL to LDL or apoAI to LDL, reducing weight or preventing weight gain, maintaining or improving glycemic control, decreased blood glucose levels, increased mitochondrial biogenesis, increased expression of PGC-1, activated protein kinase of AMP or nuclear respiratory factor, inhibition of hepatic glycogenesis or for the treatment or prevention of atherosclerosis, hypercholesterolemia, obesity, steatosis, NASH, NAFLD, insulin resistance, diabetes, metabolic syndrome X, glucose intolerance, hyperlipidemia, coronary heart disease, thyroid disease, thyroid cancer, depression, glaucoma, cardiac arrhythmias, cardiac injury, or osteoporosis. c) at least one container for containing the first or second or both the first and second pharmaceutical compositions. Methods for reducing lipid levels, increasing the ratio of HDL to LDL or apoAI to LDL, reducing weight or preventing weight gain, maintaining or improving glycemic control, decreasing glucose levels are also provided. blood, increased mitochondrial biogenesis, increased expression of PGC-1, activated protein kinase of AMP or nuclear respiratory factor, inhibition of hepatic glycogenesis or for the treatment or prevention of atherosclerosis, hypercholesterolemia, obesity, NASH, NAFLD, resistance insulin, diabetes, metabolic syndrome X, glucose intolerance, hyperlipidemia, coronary heart disease, thyroid disease, thyroid cancer, depression, glaucoma, cardiac arrhythmias, cardiac injury, or osteoporosis methods comprise the step of administration to a patient of a therapeutically effective amount of 1) a first pharmaceutical composition comprising a compound or of Formula I, II, III, or VIII or a prodrug thereof, and 2) a second pharmaceutical composition, wherein the second pharmaceutical composition is any other compound of Formula I, II, III, VIII or a prodrug of these, or is not another compound of Formula I, II, III, or VIII or a prodrug thereof. Methods for reducing lipid levels, increasing the ratio of HDL to LDL or apoAI to LDL, reducing weight or preventing weight gain, maintaining or improving glycemic control, decreasing glucose levels are also provided. blood, increased mitochondrial biogenesis, increased expression of PGC-1, activated protein kinase of AMP or nuclear respiratory factor, inhibition of hepatic glycogenesis or for the treatment or prevention of atherosclerosis, hypercholesterolemia, obesity, NASH, NAFLD, insulin resistance, diabetes, metabolic syndrome X, glucose intolerance, hyperlipidemia , coronary heart disease, thyroid disease, thyroid cancer, depression, glaucoma, cardiac arrhythmias, cardiac injury, or osteoporosis methods comprise the step of administering to a patient a therapeutically effective amount of 1) a first pharmaceutical composition comprising a compound of Formula I, II, III, or VIII or a prodrug thereof and 2) a second pharmaceutical composition that is effective alone for the reduction of lipid levels, increase in the ratio of HDL to LDL or apoAI to LDL, weight reduction or prevention of weight gain, maintenance or improvement of glycemic control, decrease in blood glucose levels blood ucose, increased mitochondrial biogenesis, increased expression of PGC-1, activated protein kinase of AMP or nuclear respiratory factor, inhibition of hepatic glycogenesis or for the treatment or prevention of atherosclerosis, hypercholesterolemia, obesity, NASH, NAFLD , insulin resistance, diabetes, metabolic syndrome X, glucose intolerance, hyperlipidemia, coronary heart disease, thyroid disease, thyroid cancer, depression, glaucoma, cardiac arrhythmias, cardiac injury, or osteoporosis. Also provided is the use of a compound of the present invention for the manufacture of a medicament for the reduction of lipid levels, an increase in the ratio of HDL to LDL or apoAI to LDL, weight reduction or prevention of weight gain, maintenance or improved glycemic control, decreased blood glucose levels, increased mitochondrial biogenesis, increased expression of PGC-1, activated protein kinase of AMP or nuclear respiratory factor, inhibition of hepatic glycogenesis or for treatment or prevention of atherosclerosis, hypercholesterolemia, obesity, NASH, NAFLD, insulin resistance, diabetes, metabolic syndrome X, glucose intolerance, hyperlipidemia, coronary heart disease, thyroid disease, thyroid cancer, depression, glaucoma, cardiac arrhythmias, cardiac injury, or osteoporosis. Compounds that selectively distribute to the liver are also provided. In one embodiment, the compounds are at least 10 times, 25 times, 50 times, 75 times, 100 times, 200 times, 300 times, 400 times, 500 times, 600 times, 700 times, 800 times, 900 times, 1000 times, 2,000 times, 3,000 times, 4,000 times, 5,000 times, 6,000 times, 7,000 times, 8,000 times, 9,000 times, 10,000 times, 20,000 times, 30,000 times, 40,000 times, or 50,000 times greater selectivity. In one embodiment, selectivity for the liver is compared to that of the heart. In another embodiment, the selectivity for the liver is compared with that of the pituitary. In another modality the selectivity for the liver is compared with that of the kidney. Also provided are T3 mimetics comprising a phosphonic acid or prodrug thereof having improved liver selectivity compared to a coponding compound wherein the phosphonic acid is replaced by a carboxylic acid, but wherein the coponding compound is otherwise identical . In one embodiment, the phosphonic acid compound (or prodrug thereof) has at least 10 times, 25 times, 50 times, 75 times, 100 times, 200 times, 300 times, 400 times, 500 times, 600 times, 700 times, 800 times, 900 times, 1,000 times, 2,000 times, 3,000 times, 4,000 times, 5,000 times, 6,000 times, 7,000 times, 8,000 times, 9,000 times, 10,000 times, 20,000 times, 30,000 times, 40,000 times, or 50,000 times greater selectivity for the liver compared to the coponding carboxylic acid compound. In one modality, selectivity is relative to that of the heart. In another modality the selectivity for the liver is relative to that of the kidney. In another embodiment, selectivity for the liver is relative to that of the pituitary. T3 mimetics comprising a phosphonic acid or its production and having a decreased Ki compared to a coponding compound where the phosphonic acid is replaced with a carboxylic acid are also provided., but where the corresponding compound is otherwise identical. In one embodiment, the phosphonic acid compound has at least 2 times, 5 times, 7 times, 10 times, 25 times, or 50 times less Ki than the corresponding carboxylic acid derivative compound (where Ki is measured relative to T3). In another embodiment, the Ki of the phosphonic acid compound is <; 150 nM = 100 nM, < 90nM, < 80nM, < 70nM, < 60nM, < 50nM, < 40nM, < 30nM, relative to T3. For purposes of clarity, it is noted that the binding affinity increases as the numerical value of Ki decreases, that is, there is an inverse relationship between Ki and binding affinity. In another embodiment, the phosphonic acid compound has the same Ki as the corresponding carboxylic acid derivative. In another embodiment, the phosphonic acid compound has a Ki greater than the corresponding carboxylic acid derivative. Also provided are compounds of the present invention that bind at least one thyroid hormone receptor with a Ki of < 100 nM, < 90nM, < 80nM, < 70nM, < 60nM, = 50nM, < 40nM, < 30nM, < 20nM, < lOnM, < 50nM, < InM, = 0.5 nM relative to T3. In one modality the thyroid hormone receptor is TRa. In one embodiment, the thyroid hormone receptor is TRß. Compounds that bind at least one thyroid hormone receptor with a Ki of > 100 nM, > 90nM, > 80nM, > 70nM, = 60nM, > 50nM, > 40nM, > 30nM, > 20nM, > lOnM, > 50nM, > InM, = 0.5 nM relative to T3, but in each case = 150 nM. In one modality the thyroid hormone receptor is TRa. In one embodiment, the thyroid hormone receptor is TRß. In one modality the thyroid hormone receptor is TRal. In one embodiment, the thyroid hormone receptor is TRßl. In one modality the thyroid hormone receptor is TRa2. In one embodiment, the thyroid hormone receptor is TRß2. The novel methods described herein describe the use of phosphonic acid-containing compounds that bind TRs. In one aspect, the novel compounds described below include compounds of Formula I, II, III or VIII. The compounds of the present invention can be used in the methods described herein. Novel Compounds of the Invention The novel compounds of the invention are compounds that contain phosphonic acid that binds and activates thyroid receptors in the liver. The present invention relates to compounds of Formula I, II, III, and VIII, which include stereoisomers and mixtures of stereoisomers thereof, pharmaceutically acceptable salts thereof, co-crystals thereof, and prodrugs thereof (including stereoisomers and mixtures thereof). of stereoisomers thereof), and pharmaceutically acceptable salts and co-crystals of the prodrugs. The compounds of the present invention may be either crystalline, amorphous or a mixture thereof. The compositions comprising a crystalline form of a compound of the present invention may contain only one crystalline form of the compound or more of a crystalline form. For example, the composition may contain two or more different polymorphs. The polymorphs can be two different polymorphs of the free form, two or more polymorphs of different co-crystal forms, two or more polymorphs of different salt forms, a combination of one or more polymorphs of one or more co-crystal forms and one or more polymorphs of the free form, a combination of one or more polymorphs of one or more salt forms and one or more polymorphs of the free form, or a combination of one or more polymorphs of one or more forms of co-morphine. crystal and one or more polymorphs of one or more salt forms. The pharmaceutically acceptable base addition salt of the compounds herein are included in the present invention. The pharmaceutically acceptable base addition salt refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from the addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to: sodium, potassium, lithium, ammonium, calcium, magnesium, zinc, aluminum salts and the like. The preferred inorganic salts are the aluminum salts, sodium, potassium, calcium, and magnesium. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amine, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine , triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, purines, piperazine, pyridine, N-ethylpiperidine , polyamine resins and the like. The pharmaceutically acceptable acid addition salt of the compounds herein having a functional base group (eg, a prodrug whereby the phosphonic acid is protected with a group comprising a functional base group) are also included in the present invention. The pharmaceutically acceptable acid addition salt refers to those salts which maintain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable. These salts were prepared from the addition of an inorganic acid or an organic acid to the free base. Salts derived from inorganic acids include, but are not limited to: acrylate, bromohydrate, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, besylate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphtylate, mesylate, glucoheptonate, lactobionate, lauryl sulphonate, bromide, famarate, pamoate, glucuronate, and iodohydrate, iodide, sulfate, xoxinofoate, and chloride salts.

The compounds of the present invention may be pure or substantially pure or have a purity of at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97 %, 98%, 99% or purity of at least 99.5%. The compounds may also be part of the pharmaceutically acceptable composition. The compounds can also be part of a biological sample material. Thus, cells and tissues comprising a compound of the present invention are included in the present invention. The cells or tissues may be in vivo, ex vivo or in vitro. Examples include liver or liver cells (e.g., hepatocytes), blood, gastric fluid (simulated or current), intestional fluid (simulated or current), and urine. In one aspect the invention relates to a thyromimetic compound containing phosphonic acid of the formula X: (Ar1) -G- (Ar2) -T-X wherein: Ar1 and Ar2 are aryl groups; G is an atom or group of atoms that link Ar1 and Ar2 are aryl groups; through an atom C, S, O, or N simple; T is an atom or group of atoms that bind Ar2 to X through 1-4 contiguous atoms or are absent; X is a -P (O) (OH) 2 or prodrug thereof. In one embodiment the compound has a Ki < 150nM. Another embodiment includes a pharmaceutical composition comprising the compound and at least one excipient. In another embodiment, the pharmaceutical composition has a bioavailability of at least 15%. In another embodiment, the compound is crystalline. In another embodiment, the pharmaceutical composition is a unit dose. In one embodiment, when the compound of formula X is a compound of formula I wherein G is -O-, T is -CH 2 -, R 1 and R 2 are each bromine, R 3 is iso-propyl, R 4 is hydrogen, and R5 is -OH, then X is not P (0) (0H) 2 or P (O) (OCH2CH3) 2. In another embodiment, when the compound of the formula X is a compound of the formula I wherein G is -O-, T is - (CH 2) or-4 ~ r R 1 and R 2 are independently halogen, alkyl of 1 to 3 carbons , and cycloalkyl of 3 to 5 carbons, R3 is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 7 carbons, R4 is hydrogen, and R5 is -OH, then X is not -P (O) (0H) 2 or - P (O) (O-lower alkyl) 2. In another embodiment, when the compound of formula X is a compound of formula I wherein G is -O-, R5 is -NHC (0) Re, -NHS ( = 0)! _ 2Re, -NHC (S) NH (Rh), or -NHC (O) NH (Rh), T is - (CH2) m, -CH = CH-, -0 (CH2)? 2- , or -NH (CH2)? _ 2-, then X is not -P (O) (0H) 2 or -P (0) (OH) NH2. In another embodiment, when the compound of formula X is a compound of formula III wherein G is -0-, T is -NH-CH2-, R1 and R2 are each chloro, R3 is iso-propyl, R4 is hydrogen, R7 is fluorine, and R5 is -OH, then X is not P (O) (OH) 2, P (0) (OH) (0CH3) or P (O) (OCH3) 2. In another embodiment, when the compound of the formula X is a compound of the formula III wherein G is selected from the group consisting of -0-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -C (0) - and -NRb-; T is -A-B- where A is selected from the group consisting of -NRb-, -0-, -CH2- and -S- and B is selected from the group that. consists of a bond and substituted or unsubstituted C? -C3 alkyl; R3 is selected from the group consisting of halogen, trifluoromethyl, substituted or unsubstituted Ci-Cß alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aryloxy, substituted amide, sulfone, sulfonamide and C3-C7 cycloalkyl, wherein the aryl, heteroaryl or cycloalkyl rings are linked or fused to the aromatic; R 4 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R1 and R2 are each independently selected from the group consisting of halogen, substituted or unsubstituted C1-C4 alkyl, and substituted or unsubstituted C3-C5 cycloalkyl; R7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, -0-Cx-C4 alkyl, -SH and -S-C CC4 alkyl; and R5 is selected from the group consisting of hydroxyl, optionally substituted-C1-C6alkyl, and -0C (0) Re; then X is not -P (0) (0H) 2. In another aspect the invention relates to a method for improving liver-to-heart selectivity or to increasing the therapeutic index of a thyromimetic compound of formula Y: (Arx) -G- (Ar2) -T- where: Ar1 and Ar2 are aryl groups; G is an atom or group of atoms that link Ar1 and Ar2 are aryl groups; through an atom C, S, 0, or N simple; T is an atom or group of atoms that bind Ar2 to E through 1-4 contiguous atoms or is absent; E is a functional group or a portion with a pKa < 7.4, is carboxylic acid (COOH) or esters thereof, sulfonic acid, tetrazole, hydroxamic acid, 6-azauracil, thiazolidinedione, acylsulfonamide, or other carboxylic acid substitutes known in the art or a prodrug thereof, or an atom or group of atoms containing a 0 u N that binds the thyroid hormone binding cavity of a TRa or TRβ, but where E is not a -P (0) (0H) 2 or ester thereof; which comprises the step of replacing E with a -P (0) (0H) 2 or prodrug thereof. In one embodiment the compound has a Ki < 150nM. Another embodiment includes a pharmaceutical composition comprising the compound and at least one excipient. In another embodiment, the pharmaceutical composition has a bioavailability of at least 15%. In another embodiment, the compound is crystalline. In another embodiment, the pharmaceutical composition is a unit dose. In one embodiment, when the compound of formula X is a compound of formula I wherein G is -0-, T is -CH2-, R1 and R2 are each bromine, R3 is iso-propyl, R4 is hydrogen, and R5 is -OH, then X is not P (0) (0H) 2 or P (0) (OCH2CH3) 2. In another embodiment, when the compound of the formula X is a compound of the formula I wherein G is -0-, T is - (CH 2) or-4 / 'R 1 and R 2 are independently halogen, alkyl of 1 to 3 carbons, and cycloalkyl of 3 to 5 carbons, R3 is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 7 carbons, R4 is hydrogen, and R5 is -OH, then X is not -P (O) (0H) 2 or -P (0) (0-lower alkyl) 2. In another embodiment, when the compound of formula X is a compound of formula I wherein G is -0-, R5 is -NHC (0) Re, -NHS (= 0)? -2Re, -NHC (S) NH (Rh), or -NHC (0) NH (Rh), T is - (CH2) m-, -CH = CH-, -0 (CH2)? -2-, or -NH (CH2)? -2-, then X is not-P (0) (0H) 2 or -P (0) (0H) NH2. In another embodiment, when the compound of formula X is a compound of formula III wherein G is -0-, T is -NH-CH2-, R1 and R2 are each chloro, R3 is iso-propyl, R4 is hydrogen, R7 is fluorine, and R5 is -OH, then X is not P (0) (OH) 2, P (0) (OH) (0CH3) or P (0) (0CH3) 2. In another embodiment, when the compound of the formula X is a compound of the formula III wherein G is selected from the group consisting of -0-, -S-, -S (= 0) -, -S (= 0) 2 ~, -CH2-, -C (0) - and -NRb-; T is -.

A-B- wherein A is selected from the group consisting of -NRb-, -0-, -CH2- and -S- and B is selected from the group consisting of a bond and substituted or unsubstituted C? -C3 alkyl; R 3 is selected from the group consisting of halogen, trifluoromethyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aryloxy, substituted amide, sulfone, sulfonamide and C 3 -C 7 cycloalkyl, wherein the aryl, heteroaryl or cycloalkyl rings. they are linked or fused to the aromatic; R4 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted Ci-Cß alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R1 and R2 are each independently selected from the group consisting of halogen, substituted or unsubstituted C1-C4 alkyl, and substituted or unsubstituted C3-C5 cycloalkyl; R7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, -O-C1-C4 alkyl, -SH and -S-C1-C4 alkyl; and R5 is selected from the group consisting of hydroxyl, optionally substituted-O-alkyl Cj-Cß, and -OC (0) Re; then X is not -P (O) (0H) 2. In another aspect the invention relates to a method for designating a thyromimetic compound with improved liver-to-heart selectivity or to improve the therapeutic index comprising the steps of: Obtain a formula for a thyromimetic formula Y: (? R1) -G- (J? R2) -T-E where: Ar1 and Ar2 are aryl groups; G is an atom or group of atoms that link Ar1 and Ar2 are aryl groups; through an atom C, S, 0, or N simple; T is an atom or group of atoms that bind Ar2 to E through 1-4 contiguous atoms or is absent; E is a functional group or a portion with a pKa < 7.4, is carboxylic acid (COOH) or esters thereof, sulfonic acid, tetrazole, hydroxamic acid, 6-azauracil, thiazolidinedione, acylsulfonamide, or other carboxylic acid substitute known in the art or a prodrug thereof, or an atom or group of atoms containing a 0 u N that binds to the thyroid hormone binding cavity of a TRa or TRβ, but where E is not a -P (O) (OH) 2 or ester thereof; which comprises the step of replacing E with a -P (O) (OH) or prodrug thereof; and synthesizing a compound of the formula X wherein X is phosphonic acid or prodrug thereof. In one embodiment the compound has a Ki < 150nM. Another embodiment includes a pharmaceutical composition comprising the compound and at least one excipient. In another embodiment, the pharmaceutical composition has a bioavailability of at least 15%. In another embodiment, the compound is crystalline. In another embodiment, the pharmaceutical composition is a unit dose. In one embodiment, when the compound of formula X is a compound of formula I wherein G is -0-, T is -CH2-, R1 and R2 are each bromine, R3 is iso-propyl, R4 is hydrogen, and R5 is -OH, then X is not P (0) (OH) 2 or P (0) (OCH2CH3) 2. In another embodiment, when the compound of the formula X is a compound of the formula I wherein G is -0-, T is - (CH2) or -4- R1 and R2 are independently halogen, alkyl of 1 to 3 carbons, and cycloalkyl of 3 to 5 carbons, R3 is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 7 carbons, R4 is hydrogen, and R5 is -OH, then X is not -P (0) (0H) 2 or -P (0) (0-lower alkyl) 2. In another embodiment, when the compound of formula X is a compound of formula I wherein G is -0-, R5 is -NHC (0) Re, -NHS (= 0)? _ 2Re, -NHC (S) NH (Rh), or -NHC (0) NH (Rh), T is - (CH2) m-, -CH = CH-, -0 (CH2)? 2- , or -NH (CH2)? 2-, then X is not -P (0) (0H) 2 or -P (0) (0H) NH2. In another embodiment, when the compound of formula X is a compound of formula III wherein G is -0-, T is -NH-CH2-, R1 and R2 are each chloro, R3 is iso-propyl, R4 is hydrogen, R7 is fluorine, and R5 is -OH, then X is not P (0) (0H) 2, P (0) (OH) (0CH3) or P (0) (0CH3) 2. In another embodiment, when the compound of the formula X is a compound of the formula III wherein G is selected from the group consisting of -0-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -C (0) - and -NRb-; T is -AB- wherein A is selected from the group consisting of -NRb-, -0-, -CH2- and -S- and B is selected from the group consisting of a bond and substituted or unsubstituted C? -C3 alkyl; R 3 is selected from the group consisting of halogen, trifluoromethyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aryloxy, substituted amide, sulfone, sulfonamide and C 3 -C 7 cycloalkyl, wherein the aryl, heteroaryl or cycloalkyl rings are bonded or fused to the aromatic; R4 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted Ci-Cg alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R1 and R2 are each independently selected from the group consisting of halogen, substituted or unsubstituted C? -C4 alkyl, and substituted or unsubstituted C3-C5 cycloalkyl; R7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, -0-C1-C4 alkyl, -SH and -S-C-C4 alkyl; and R5 is selected from the group consisting of hydroxyl, optionally substituted C6-C6alkyl, and -0C (0) Re; then X is not -P (0) (0H) 2. In one aspect, the present invention relates to compounds of Formula I: where : G is selected from the group consisting of -0-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF-, -C (0) -, -CH (OH) -, -NH-, and -N (C? -C4 alkyl) -; T is selected from the group consisting of - (CRa2) k ~, ~ CRb = CRb- (CRa2) n-, - (CRa2) n-CRb = CRb-, - (CRa2) -CRb = CRb- (CRa2) - , 0 (CRb2) (CRa2) n-, -S (CRb2) (CRa2) n-, -N (Rb) (CRb2) (CRa2) "-, N (Rb) C (0) (CRa2) n-, - (CRa2) nCH (NRbRc) -, -C (0) (CRa2) m-, (CRa2) mC (0) -, - (CRa2) C (0) (CRa2) n-, - (CRa2) nC ( 0) (CRa2) -, and -C (0) NH (CRb2) (CRa2) p-; k is an integer from 0-4, m is an integer from 0-3, n is an integer from 0-2, p is an integer from 0-1, each Ra is independently selected from the group consisting of hydrogen, alkyl C Optionally substituted -C, halogen, -OH, -0-C-C4 optionally substituted alkyl, -0CF3, -S-optionally substituted C1-C4 alkyl, -NRbRc, optionally substituted C2-C4 alkenyl, and C2-C4 alkynyl optionally substituted; with the proviso that when a Ra is linked through 0, S, or N, then the other Ra links to the same C that is a hydrogen, or is linked by means of a carbon atom. Each Rb is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl; Each Rc is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 4 alkyl, -C (0) -alkyl optionally substituted C 1 -C 4, and -C (0) H; R1 and R2 are each independently selected from the group consisting of halogen, optionally substituted C?-C4 alkyl, optionally substituted -S-C 1 -C 3 alkyl, optionally substituted C-C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, -CF 3, -0CF3, -0-C-C3 alkyl optionally substituted, and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -0CF3, cyano, optionally substituted C1-C12 alkyl, optionally substituted C2-C2 alkenyl, optionally substituted C2-C12 alkynyl, - ( CRa2) optionally substituted aryl, - (CRa2) m optionally substituted cycloalkyl, ~ (CRa2) m optionally substituted heterocycloalkyl, -0Rd, -SRd, -S (= 0) Re, -S (= 0) 2Re, -S ( = 0) 2NRfRg, -C (0) NRfRg, -C (0) 0Rh, -C (0) Re, -N (Rb) C (0) Re, -N (Rb) C (0) NRfRg, -N (Rb) S (= 0) 2Re, -N (Rb) S (= 0) 2NRfRg, and -NRfRg; Each Rd is selected from the group consisting of optionally substituted C? ~C? 2 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl, - (CRb 2) n optionally substituted aryl, - (CRb 2) optionally substituted cycloalkyl, - (CRb2) n optionally substituted heterocycloalkyl, and -C (0) NRfRg; Each Re is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2-C2 alkenyl, optionally substituted C2-C12 alkynyl, - (CRa2) n optionally substituted aryl, - (CRa2) n optionally substituted cycloalkyl, and - (CRa2) n optionally substituted heterocycloalkyl; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C?-C? 2 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl, - (CRb 2) n aryl optionally substituted, - (CRb2) n optionally substituted cycloalkyl, and - (CRb2) n optionally substituted heterocycloalkyl, or Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second hetero group selected from the group of O, NRC, and S, wherein the optionally substituted heterocyclic ring can be substituted with 0-4 substituents selected from the group consisting of optionally substituted C? -C alkyl, -ORb, oxo, cyano, -CF3, optionally substituted phenyl, and -C (0) ORh; Each Rh is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2-C2 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted aryl (CRb2) n, - (CRb2) n optionally substituted cycloalkyl, and - (CRb2) n optionally substituted heterocycloalkyl; R5 is selected from the group consisting of -OH, optionally substituted C6-C6alkyl, -OC (0) Re, -OC (0) ORh, -F, -NHC (0) Re, -NHS (= 0) Re , -NHS (= 0) 2Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); X is P (0) YR ^ Y'R11; Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are -0-, R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRZ2, -NRZ-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2-0- C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, nd-alkyl-SSS-alkylhydroxy; when Y and Y 'are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy, and cycloalkylene-C00Ry; when Y is -0- and Y 'is NRV, then R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, CH2 ~ optionally substituted heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRZ2, NRz-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2- 0-C (0) 0Ry, C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (R) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy , and -cycloalkylene-C00Ry; or when Y and Y 'are independently selected from -0- and -NRV-, then R11 and R11 together are -alkyl-S-S-alkyl to form a cyclic group, or together R11 and R11 are the group: wherein: V, W, and W 'are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and 1-alkynyl optionally substituted; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group to the beta and gamma bound position to the Y to the phosphorus; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and W are connected by means of 3-5 additional atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W 'are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or heteroaryl replaced; Z is selected from the group consisting of -CHRz0H, CHRz0C (0) Ry, -CHR20C (S) Ry, -CHR0C (S) 0Ry, -CHRzOC (O) SRy, CHRzOC02Ry, -ORz, -SRZ, -CHR2N3, - CH2aryl, -CH (aryl) OH, CH (CH = CRz2) OH, -CH (C = CRz) OH, -Rz, -NRZ2, -OCORy, -OC02Ry, -SCORy, -SC02Ry, -NHCORz, -NHC02Ry, -CH2NHaril, - (CH2) q-0Rz, and - (CH2) q-SRz; q is an integer of 2 or 3; each Rz is selected from the group consisting of Ry and -H; each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; each Rx is independently selected from the group consisting of -H, and alkyl, or together Rx or Rx form a cyclic alkyl group; each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl. Instead of specifically excluding a specific compound of the present invention, conditions can be used for exclusion purposes. Examples of the independent arrangements of the present invention include the following: a) when G is -0-, T is -CH2-, R1 and R2 are each bromine, R3 is iso propyl, R4 is hydrogen, and d R5 is - OH, then X is not -P (0) (0H) 2 or -P (0) (OCH2CH3) 2; b) V, Z, W, W 'are not all -H; c) when Z is -R2, then at least one of V, W, and W 'are not -H, alkyl, aralkyl, or heterocycloalkyl; d) when G is -0-, T is - (CH2) 0-4-, R1 and R2 are independently halogen, alkyl of 1 to 3 carbons, and cycloalkyl of 3 to 5 carbons, R3 is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 7 carbons, R 4 is hydrogen, and R 5 is OH, then X is not -P (0) (0H) 2 or -P (0) (0 lower alkyl) 2; and e) when G is -0-, R5 is -NHC (0) Re, -NHS (= 0)? -2Re, -NHC (S) NH (Rh), or -NHC (0) NH (Rh), T is - (CH2) m-, -CH = CH-, -0 (CH2)? _ 2-, or -NH (CH2)? -2-, then X is not -P (0) (0H) 2 or -P (0) (0H) NH2. In one aspect, the present invention relates to compounds of Formula I: wherein: G is selected from the group consisting of -0-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF-, -C (0) -, -CH (OH) -, -NH-, and -N (C? -C4 alkyl) -; T is selected from the group consisting of ~ (CRa2) k-, -CRb = CRb- (CRa2) n, - (CRa2) n-CRb = CRb-, - (CRa2) -CRb = CRb- (CRa2) -, 0 (CRb2) (CRa2) n-, -S (CRb2) (CRa2) n-, -N (Rb) (CRb2) (CRa2) n-, N (Rb) C (0) (CRa2) n-, - (CRa2) nCH (NRbRc) -, -C (0) (CRa2) m-, (CRa2) mC (0) -, - (CRa2) C (0) (CRa2) n-, - (CRa2) nC (0) (CRa2) -, and -C (0) NH (CRb2) (CRa2) p -; k is an integer from 0-4; m is an integer from 0-3; n is an integer from 0-2; p is an integer from 0-1; each Ra is independently selected from the group consisting of hydrogen, optionally substituted C1-C4 alkyl, halogen, -OH, -O-optionally substituted L-C4 alkyl, -OCF3, -S-optionally substituted C1-C4 alkyl, -NRbRc, optionally substituted C2 ~ C4 alkenyl, and optionally substituted C2-C4alkynyl; with the proviso that when a Ra is linked through O, S, or N, then the other Ra links to the same C as is a hydrogen, or is linked by means of a carbon atom, each Rb is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl; each Rc is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 4 alkyl, -C (O) - optionally substituted C 1 -C 4 alkyl, and -C (0) H; R1 and R2 are each independently selected from the group consisting of halogen, optionally substituted C3-C4 alkyl, -S-optionally substituted C1-C3 alkyl, optionally substituted C2-C4 alkyl, optionally substituted C2-C4 alkynyl, -CF3, -OCF3, -O-C-C3 alkyl optionally substituted, and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted C? -C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C? 2 alkynyl, (CRa2) optionally substituted maryl, (CR2) optionally substituted mCycloalkyl, (CRa2) optionally substituted -heterocycloalkyl, -ORd, SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRfRg, -C (0) NRfRg, -C (0) ORh, -C (0) Re, -N (Rb) C (0) Re, ~ N (R) C (0) NRfRg, -N (Rb) S ( = 0) 2Re, N (Rb) S (= 0) 2NRfRg, and -NRfRg; Each R is selected from the group consisting of optionally substituted C12-alkyl, optionally substituted C2-C2-alkenyl, optionally substituted C2-C2 alkynyl, optionally substituted (CRb2), optionally substituted (CRb2) n-cycloalkyl, - (CRb2) optionally substituted n-heterocycloalkyl, and C (0) NRfRg; Each Re is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2-C2 alkenyl, optionally substituted C2-C2 alkynyl, optionally substituted - (CRa2) naril, - (CR2) n optionally substituted cycloalkyl , and (CRa2) optionally substituted n-heterocycloalkyl; Rf and R9 are each independently selected from the group consisting of hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C2-C2 alkenyl, optionally substituted C2-C2 alkynyl, optionally substituted (CRb2) naril, - ( CRb2) optionally substituted cycloalkyl, and optionally substituted - (CRb2) nheterocycloalkyl, or Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second hetero group selected from the group of O, NRC, and S, wherein the ring optionally substituted heterocyclic may be substituted with 0-4 substituents selected from the group consisting of optionally substituted C 1 -C 4 alkyl, -0Rb, oxo, cyano, -CF 3, optionally substituted phenyl, and -C (0) ORh; Each Rh is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2-C2 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted (CR2), optionally substituted (CRb2) n-cycloalkyl, and (CRb2) ) optionally substituted n-heterocycloalkyl; R5 is selected from the group consisting of -OH, optionally substituted -Oalkyl C? -C6, -OC (0) Re, -CO (0) ORh, -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2 Re, NHC (= S) NH (Rh), and -NHC (0) NH (Rh); X is PfOlYR ^ 'R11; Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are -0-, R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRz2, -NRZ-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2-0- C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, nd-alkyl-SSS-alkylhydroxy; When Y and Y 'are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy, and cycloalkylene-C00Ry; When Y is -0- and Y 'is NRV, then R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 2OC (O) NRZ2, -NRZ- C (0) -Ry, -C (Rz) 2-OC (0) Ry, -C (Rz) 2 -0-C (0) ORy, -C (Rz) 2OC (O) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-COORy, -C (Rx) 2COORy, - [C (R2) 2] qC (0) SRy , and -cycloalkylene-COORy; or when Y and Y 'are independently selected from -O- and -NRV-, then together R11 and R11 are -alkyl-S-S-alkyl to form a cyclic group, or together R11 and R11 are the group: wherein: V, W, and W 'are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and 1-alkynyl optionally substituted; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group to the beta and gamma bound position to the Y to the phosphorus; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and W are connected by means of 3-5 additional atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W 'are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or heteroaryl replaced; Z is selected from the group consisting of -CHRzOH, CHRzOC (0) Ry, -CHRzOC (S) Ry, -CHRzOC (S) 0RY, -CHRzOC (0) SRy, CHRz0C02Ry, -0Rz, -SRZ, -CHRZN3, - CH2aryl, -CH (aryl) OH, -CH (CH = CRz2) 0H, -CH (C = CRZ) OH, -Rz, -NRZ2, -0C0Ry, -0C02Ry, -SC0Ry, -SC02Ry, -NHC0R2, -NHC02Ry , -CH2NHaril, - (CH2) q-0Rz, and - (CH2) q-SRz; q is an integer of 2 or 3; each Rz is selected from the group consisting of Ry and -H; each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; each R is independently selected from the group consisting of -H, and alkyl, or together Rx or Rx form a cyclic alkyl group; each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the provisions that: a) when G is -0-, T is -CH2-, R1 and R2 are each bromine, R3 is iso-propyl, is hydrogen, and R4 is -OH, then X is not P (O) (OH) 2 or P (O) (OCH 2 CH 3) 2; b) V, Z, W, W 'are not all -H; and c) when Z is -Rz, then at least one of V, W, and W 'are not -H, alkyl, aralkyl, or heterocycloalkyl; . In another aspect, the invention comprises a compound of the formula I: wherein: G is selected from the group consisting of -0-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF-, -C (0) -, -CH (OH) -, -NH-, and -N (C 1 -C 4 alkyl) -; T is selected from the group consisting of - (CRa2) k ~ j _ CRb = CRb- (CRa2) n-, - (CRa2) n-CRb = CRb-, - (CRa2) -CRb = CRb- (CR2) - , (CR, - (CR2) (CRa2) n-, -S (CRb2) (CRa2) n-, -N (Rc) (CRb2) (CRa2) n-, -N (Rb) C (0) (CRa2 ) n-, - (CRa2) nCH (NRbRc) -, -C (O) (CRa2) m-, (CRa2) mC (0) -, - (CRa2) C (0) (CRa2) n-, - ( CRa2) nC (0) (CRa2) -, and -C (0) NH (CRb2) (CRa2) p-; k is an integer from 0-4, m is an integer from 0-3, n is an integer from 0-2; p is an integer from 0-1, each Ra is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl, halogen, -OH, -O-C 4 -C 4 alkyl optionally substituted, 0CF3, -S-optionally substituted C1-C4 alkyl, -NRbRc, optionally substituted C2-C4 alkenyl, and optionally substituted C2-C alkynyl, with the proviso that when one of R is linked to C through 1 of 0, S, or N, then the other Ra links to the same C that is a hydrogen, or is bonded by means of a carbon atom; each Rb is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl; each Rc is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 4 alkyl, -C (0) - optionally substituted C 1 -C alkyl, and -C (0) H; R1 and R2 are each independently selected from the group consisting of halogen, optionally substituted C1-C4 alkyl, -S-optionally substituted C1-C3 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, -CF, -0CF3, -0-C-C3 alkyl optionally substituted, and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -0CF3, cyano, optionally substituted C1-C12 alkyl, optionally substituted C2-Ci2 alkenyl, optionally substituted C2-C12 alkynyl, - (CRa2) optionally substituted maryl, - (CRa2) m optionally substituted cycloalkyl, - (CRa2) optionally substituted metheterocycloalkyl, -0Rd, SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRfR9, -C (0) NRfRg, -C (0) 0Rh, -C (0) Re, -N (Rb) C (0) Re, -N (Rb) C (0) NRfRg, -N (Rb) S ( = 0) 2Re, N (Rb) S (= 0) 2NRfRg, and -NRfRg; Each Rd is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2-C2 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted (CRb2), optionally substituted (CRb2) n-cycloalkyl, (CRb2) optionally substituted n-heterocycloalkyl, and C (0) NRfRg; Each Re is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted (CRa2) naryl, optionally substituted (CRa2) n-cycloalkyl, and (CRa2) nheterocycloalkyl optionally substituted; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted - (CRb2) naril, - (CRb2) n-cycloalkyl optionally substituted, and - (CRb2) optionally substituted n-heterocyclealkyl, or Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second hetero group selected from the group consisting of 0, NRC, and S, wherein the heterocyclic ring optionally substituted may be substituted with 0-4 substituents selected from the group consisting of optionally substituted C1-C4 alkyl, -ORb, oxo, cyano, -CF3, optionally substituted phenyl, and -C (0) ORh; Each Rh is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2-C2 alkenyl, optionally substituted C2-C2 alkynyl, optionally substituted (CRb2) naryl, optionally substituted (CRb2) n-cycloalkyl, and (CRb2) optionally substituted n-heterocycloalkyl; R5 is selected from the group consisting of -OH, optionally substituted C6-C6alkyl, -OC (0) Re, -OC (O) ORh, -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2 Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); X is PIOIYR ^ 'R11; Y and Y 'are each independently selected from the group consisting of -O-, and -NRV-; when Y and Y 'are -O-, R11 linked to -O- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 2OC (O) NRZ2, -NRZ-C (0) -Ry, -C (Rz) 2-OC (0) Ry, -C (Rz) 2-0- C (0) ORy, -C (Rz) 2OC (O) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; When Y and Y 'are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-COORy, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy, and cycloalkylene-C00Ry; When Y is -0- and Y 'is NRV, then R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRZ2, -NRZ-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2 -0-C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy , and -cycloalkylene-C00Ry; or when Y and Y 'are independently selected from -0- and -NR11-, then together R11 and R11 are -alkyl-S-S-alkyl- to form a cyclic group, or together R11 and R11 are the group: wherein: V, W, and W 'are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and 1-alkynyl optionally substituted; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or -aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group to the beta and gamma bound position to the Y to the phosphorus; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and W are connected by means of 3-5 additional atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W 'are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or heteroaryl replaced; Z is selected from the group consisting of -CHRzOH, CHRzOC (0) Ry, -CHOC (S) Ry, -CHRz0C (S) 0Ry, -CHRzOC (O) SRy, CHRzOC02Ry, -OR, -SRZ, -CHRZN3, - CH2aryl, -CH (aryl) OH, CH (CH = CRz2) OH, -CH (C = CRz) OH, -Rz, -NRZ2, -OCORy, -OC02Ry, -SC0Ry, -SC02Ry, -NHC0Rz, -NHC02Ry, -CH2NHaril, - (CH2) q- 0Rz, and - (CH2) q-SRz; q is an integer of 2 or 3; each Rz is selected from the group consisting of Ry and -H; every R? is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; each Rx is independently selected from the group consisting of -H, and alkyl, or together Rx or Rx form a cyclic alkyl group; each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the proviso that when G is -O-, T is -CH2-, R1 and R2 are each bromine, R3 is iso-propyl, R4 is hydrogen, and R5 is -OH, then X is not P (O) (0H) 2 or P (O) (OCH2CH3) 2; and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs. In a second aspect the present invention relates to compounds of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of prodrugs as represented by Formula I: wherein: G is selected from the group consisting of -O-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF-, -C (O) -, -CH (OH) -, -NH-, and -N (C 1 -C 4 alkyl) -; T is selected from the group consisting of -. { Ra2) y-, -CRb = CRb- (CRa2) n-, - (CR2) n-CRb = CRb-, - (CRa2) -CRb = CRb- (CRa2) -, 0 (CRb2) (CRa2) n- , -S (CRb2) (CRa2) n-, -N (Rb) (CRb2) (CRa2) n-, N (Rb) C (0) (CRa2) n-, - (CRa2) nCH (NRbRc) -, -C (O) (CRa2) m-, (CRa2) mC (0) -, - (CRa2) C (0) (CRa2) n-, - (CRa2) nC (0) (CRa2) -, and -C (0) NH (CRb2) (CRa2) p-; k is an integer from 0-4; m is an integer from, 0-3; n is an integer from 0-2; p is an integer from 0-1; each Ra is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl, halogen, -OH, -O-C 1 -C 4 alkyl optionally substituted, -OCF 3, -S-C 1 -C 4 alkyl optionally substituted, -NR b R c, optionally substituted C2-C4 alkenyl, and optionally substituted C2-C alkynyl; with the proviso that when a Ra is linked through 0, S, or N, then the other Ra links to the same C that is a hydrogen, or is linked by means of a carbon atom. each Rb is independently selected from the group consisting of hydrogen and optionally substituted C1-C4 alkyl; each Rc is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl, -C (0) -alternatively substituted C 1 -C 4 alkyl, and -C (0) H; R1 and R2 are each independently selected from the group consisting of halogen, optionally substituted C?-C4 alkyl, optionally substituted -S-C 1 -C 3 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C alkynyl, -CF 3, -OCF3, -O-C1-C3 alkyl optionally substituted, and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted C? -C12 alkyl, optionally substituted C2-C? 2 alkenyl, optionally substituted C2-C? 2 alkynyl , - (CRa2) optionally substituted aryl, (CRa2) optionally substituted cycloalkyl, (CRa2) optionally substituted metheterocycloalkyl, -ORd, SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0 ) 2NRfRg, -C (0) NRfRg, -C (0) ORh, -C (0) Re, -N (Rb) C (0) Re, -N (Rb) C (0) NRfRg, -N (Rb) ) S (= 0) 2Re, N (Rb) S (= 0) 2NRfRg, and -NRfRg; Each Rd is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2 ~ C12 alkenyl, C-C alkynyl? optionally substituted, - (CRb2) optionally substituted naril, (CRb2) optionally substituted n-cycloalkyl, (CRb2) nheterocycloalkyl optionally substituted, and C (0) NRfRg; Each Re is optionally substituted C3-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted - (CRa2), optionally substituted - (CRa2) n-cycloalkyl, and optionally substituted - (CRa2) nheterocycloalkyl; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C? -C? 2 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, - (CRb2) optionally substituted nuclide, - (CRb2 optionally substituted cycloalkyl, and optionally substituted - (CRb2) nheterocycloalkyl, or Rf and Rg together can form an optionally substituted heterocyclic ring, which may contain a second hetero group selected from the group of O, NRC, and S, wherein the heterocyclic ring optionally substituted may be substituted with 0-4 substituents selected from the group consisting of optionally substituted C1-C4 alkyl, -0Rb, oxo, cyano, -CF3, optionally substituted phenyl, and -C (0) ORh; Each Rh is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2 ~ Ci2 alkenyl, optionally substituted CC ?2 alkynyl, optionally substituted (CRb2) naryl, optionally substituted (CRb2) n-cycloalkyl, and (CRb2) nheterocycloalkyl optionally substituted; R5 is selected from the group consisting of -OH, -0-optionally substituted Ca-C6 alkyl, -0C (0) Re, -OC (0) ORh ', -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2 Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); X is PfOlYR ^ 'R11; Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are -0-, R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (R2) 20C (0) NRZ2, -NRZ-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2-0- C (0) 0RY, -C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; When Y and Y 'are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRY, and cycloalkylene-C00Ry; When Y is -0- and Y 'is NRV, then R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRz2, -NRZ-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2 -0-C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-COORy, -C (Rx) 2COOR ?, - [C (Rz) 2] qC (0) SRy, and -cycloalkylene-COORy; or when Y and Y 'are independently selected from -0- and -NRV-, then together R11 and R11 are -alkyl-S-S-alkyl to form a cyclic group, or together R11 and R11 are the group: wherein: V, W, and W 'are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and 1-alkynyl optionally substituted; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group to the beta and gamma bound position to the Y to the phosphorus; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and W are connected by means of 3-5 additional atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W 'are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or heteroaryl replaced; Z is selected from the group consisting of -CHRz0H, CHRz0C (0) Ry, -CHRzOC (S) R ?, -CHRzOC (S) ORy, -CHRzOC (O) SRy, CHRz0C02Ry, -ORz, -SRZ, -CHRZN3, -CH2aryl, -CH (aryl) OH, - CH (CH = CRz2) OH, -CH (C-CRz) OH, -Rz, -NRZ2, -OCORy, -OC02Ry, - SCORy, -SC02Ry, -NHC0R2, - NHC02Ry, -CH2NHaril, - (CH2) q-ORz, and - (CH2) q-SRz; q is an integer of 2 or 3; each Rz is selected from the group consisting of Ry and -H; each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; each Rx is independently selected from the group consisting of -H, and alkyl, or together Rx or R form a cyclic alkyl group; each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the proviso that: a) when G is -O-, T is - (CH2) or -4, R1 and R2 are independently halogen, alkyl of 1 to 3 carbons, and cycloalkyl of 3 to 5 carbons, R3 is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 7 carbons, R 4 is hydrogen, and R 5 is -OH, then X is not -P (O) (OH) 2 or -P (O) (0-lower alkyl) 2 / b) when G is -0-, R5 is -NHC (0) Re, -NHS (= 0)? -2Re, -NHC (S) NH (Rh), or -NHC (0) NH (Rh), T is - (CH2) m, -CH = CH-, -0 (CH2)? -2-, or -NH (CH2)? _ 2-, then X is not -P (0) (0H) 2 or -P (0) (0H) NH2; c) V, Z, W, W 'are not all -H; and d) when Z is -Rz, then at least one of V, W, and W 'is not -H, alkyl, aralkyl, or heterocycloalkyl. In a further aspect, the present invention relates to compounds of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of prodrugs as represented by formula I: wherein: G is selected from the group consisting of -O-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF-, -C (0) -, -CH (OH) -, -NH-, and -N (C? -C4 alkyl) -; T is selected from the group consisting of - (CRa2) k ~, -CRb = CRb- (CR2) n-, - (CRa2) n-CRb = CRb-, - (CRa2) -CRb = CRb- (CRa2) - , 0 (CRb2) (CRa2) n-, -S (CRa2) n-, -N (Rb) (CRb2) (CRa2) n-, N (Rb) C (0) (CRa2) n-, - (CRa2 ) nCH (NRbRc) -, -C (O) (CRa2) m, - (CRa2) mC (O) - (CRa2) C (0) (CRa2) n-, - (CRa2) nC (0) (CRa2) -, and C (0) NH (CRb2) (CRa2) p-; k is an integer from 0-4; m is an integer from 0-3; n is an integer from 0-2; p is an integer from 0-1; Each Ra is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl, halogen, -OH, -O-C 1 -C 4 alkyl optionally substituted, -OCF 3, -S-C 1 -C 4 alkyl optionally substituted, -NR b R c, optionally substituted C2-C4 alkenyl, and optionally substituted C2-C4 alkynyl; with the proviso that when a Ra is linked through 0, S, or N, then the other Ra links to the same C which is a hydrogen, or is linked by means of a carbon atom. Each Rb is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 4 alkyl; Each Rc is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl, -C (0) -alternatively substituted C 1 -C 4 alkyl, and -C (0) H; R1 and R2 are each independently selected from the group consisting of halogen, optionally substituted C1-C alkyl, -S-optionally substituted C1-C3 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, -CF3, - 0CF3, -O-C1-C3 alkyl optionally substituted, and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -0CF3, cyano, optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, C2-C? Alkynyl? optionally substituted, - (CRa2) optionally substituted maryl, - (CR) optionally substituted cycloalkyl, (optionally substituted CR ^ mheterocycloalkyl, -ORd, -SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRfRg, -C (0) NRfRg, -C (0) 0Rh, -C (0) Re, -N (Rb) C (0) Re, -N (R) C (0) NRfRg, N (Rb) S (= 0) 2Re, -N (R) S (= 0) 2NRfRg, and -NRfRg, Each rd is selected from the group consisting of optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 2 alkenyl C2-Ci2 alkynyl optionally substituted, - (CRb2) optionally substituted naryl, - (CRb2) n-cycloalkyl optionally substituted, (CRb2) nheterocycloalkyl optionally substituted, and -C (0) NRfRg; Each Re is optionally substituted C1-C12 alkyl, alkenyl C2-C12 optionally substituted, optionally substituted C2-C2 alkynyl, optionally substituted (CRa2), optionally substituted (CRa2) nylcycloalkyl, and optionally substituted (CRa2) nheterocycloalkyl; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2 ~ C2 alkynyl, optionally substituted (CRb2) naryl, (CRb2) n-cycloalkyl optionally substituted, and (CRb2) nheterocycloalkyl, or Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second heterogroup selected from the group of 0, NRC, and S, wherein the optionally substituted heterocyclic ring may be substituted with 0 -4 substituents selected from the group consisting of optionally substituted C1-C4 alkyl, -ORb, oxo, cyano, -CF3, optionally substituted phenyl, and -C (0) ORh; Each Rh is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2-C2 alkenyl, optionally substituted C2-C2 alkynyl, optionally substituted (CRb2) naryl, optionally substituted - (CRb2) n-cycloalkyl, and - (CR2) optionally substituted n-heterocycloalkyl; R5 is selected from the group consisting of -OH, optionally substituted C6-C6alkyl, -0C (0) Re, -OC (0) ORh ', -F, -NHC (0) Re, -NHS (= 0 ) Re, -NHS (= 0) 2Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); X is P (O) YR ^ Y'R11; Y and Y 'are each independently selected from the group consisting of -O-, and -NRV-; when Y and Y 'are -O-, R11 linked to -O- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (R) 2OC (0) NRZ2, -NRZ-C (0) -Ry, -C (Rz) 2-OC (0) R ?, -C (Rz) 2-0 - (C (0) 0RY, -C (Rz) 20C (0) SRy, alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-S-SS-alkylhydroxy; when Y and Y 'are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-COORy, -C (Rx) 2COORy, - [C (Rz) 2] qC (0) SRy, and cycloalkylene-COORy, when Y is -0- and Y 'is NRV, then R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, CH2-heterocycloalkyl optionally substituted in where the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRZ2, -NR2-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2-0-C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy , and -cycloalkylene-COORy; or when Y and Y 'are independently selected from -0- and -NRV-, then R11 and R11 together are -alkyl-S-S-alkyl to form a cyclic group, or together R11 and R11 are the group: wherein: V, W, and W 'are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and 1-alkynyl optionally substituted; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group to the beta and gamma bound position to the Y to the phosphorus; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and W are connected by means of 3-5 additional atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W 'are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or heteroaryl replaced; Z is selected from the group consisting of -CHRzOH, CHRzOC (0) Ry, -CHRzOC (S) Ry, -CHRzOC (S) ORy, -CHRzOC (O) SRy, CHRzOC02Ry, -ORz, -SRZ, -CHRZN3, - CH2aryl, -CH (aryl) OH, -CH (CH = CRz2) OH, -CH (C-CRZ) OH, -RZ, -NR22, -OCORy, -0C02Ry, -SCORy, -SC02Ry, -NHCORz, -NHC02Ry , -CH2NHaril, - (CH2) q-ORz and - (CH2) q-SRz; q is an integer of 2 or 3; Each Rz is selected from the group consisting of Ry and -H; Each R? is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; Each Rx is independently selected from the group consisting of -H, and alkyl, or together Rx or Rx form a cyclic alkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; With the proviso that: a) V, Z, W, W 'are not all -H; and b) when Z is -Rz, then at least one of V, W, and W 'is not -H, alkyl, aralkyl, or heterocycloalkyl. In another aspect, the invention comprises a compound of the formula I: wherein: G is selected from the group consisting of -O-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF-, -C (O) -, -CH (OH) -, -NH-, and -N (C 1 -C 4 alkyl) -; T is selected from the group consisting of ~ (CRa2) k- / '~ CRb = CRb- (CRa2) n-, - (CRa2) n-CRb = CRb-, - (CRa2) -CR = CRb ~ (CRa2) -, 0 (CRb2) (CRa2) n-, -S (CRb2) (CRa2) n-, -N (Rc) (CRb2) (CRa2) n-, N (Rb) C (0) (CRa2) n-, - (CRa2) nCH (NRRc) -, -C (O) (CRa2] (CRa2) mC (0) -, - (CRa2) C (0) ( CRa2) n-, ~ (CRa2) nC (0) (CRa2) -, and C (0) NH (CRb2) (CRa2) p-; k is an integer from 0-4, m is an integer from 0-3; n is an integer from 0-2; p is an integer from 0-1; Each Ra is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl, halogen, -OH, -O-C 1 -C 4 alkyl optionally substituted, -OCF 3, -S-C 4 -C 4 alkyl optionally substituted, NRbRc, optionally substituted C2-C alkenyl, and optionally substituted C2-C4 alkynyl; with the proviso that when a Ra is linked to C through an atom 0, S, or N, then the other Ra links to the same C that is a hydrogen, or is bonded by means of a carbon atom; Each Rb is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 4 alkyl; Each Rc is independently selected from the group consisting of hydrogen, optionally substituted C1-C alkyl, -C (0) -alternatively substituted C1-C4 alkyl, and -C (0) H; R1 and R2 are each independently selected from the group consisting of halogen, optionally substituted C1-C alkyl, -S-optionally substituted C3-C3 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, -CF3, -OCF3, -O-C1-C3 alkyl optionally substituted, and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -0CF3, cyano, optionally substituted CC ?2 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, - (CRa2) optionally substituted maryl, (CRa2) optionally substituted cycloalkyl, (CRa2) optionally substituted metheterocycloalkyl, -0Rd, SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRfRg, -C ( 0) NRfRg, -C (0) ORh, -C (0) Re, -N (Rb) C (0) Re, -N (Rb) C (0) NRfRg, -N (Rb) S (= 0) 2Re, N (Rb) S (= 0) 2NRfRg, and -NRfRg; Each Rd is selected from the group consisting of optionally substituted CI-CJL2 alkyl, optionally substituted C2-C ?2 alkenyl, optionally substituted C2-C ?2 alkynyl, optionally substituted (CRb) naril, - (CR2) n-optionally substituted cycloalkyl, - (CRb2) optionally substituted n-heterocycloalkyl, and C (0) NRfRg; Each Re is optionally substituted C1-C12 alkyl, optionally substituted C-C12 alkenyl, optionally substituted C2-C2 alkynyl, optionally substituted - (CRa2), optionally substituted - (Cra2) n-cycloalkyl, and optionally substituted - (CRa2) nheterocycloalkyl; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted - (CRb2) naril, - (CRb2) n-cycloalkyl optionally substituted, and - (CRb2) optionally substituted n-heterocyclealkyl, or Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second hetero group selected from the group of 0, NRC, and S, wherein the optionally substituted heterocyclic ring may substituted with 0-4 substituents selected from the group consisting of optionally substituted C1-C4 alkyl, -0Rb, oxo, cyano, -CF3, optionally substituted phenyl, and -C (0) 0Rh; Each Rh is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted CC ?2 alkynyl, optionally substituted - (CRb2) naril, - (CRb2) n optionally substituted cycloalkyl, and (CRb2) ) optionally substituted n-heterocycloalkyl; R5 is selected from the group consisting of -OH, optionally substituted C6-C6alkyl, -OC (0) Re, -0C (0) 0Rh, -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2 Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); X is P (0) YRuY'Ru; Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are -0-, R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NR2, -NRZ-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2-0- C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; when Y and Y 'are ~ NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy, and cycloalkylene-COORy; when Y is -0- and Y 'is NRV, then R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRZ2, -NRZ-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2 -0-C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (R2) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy , and -cycloalkylene-C00Ry; or when Y and Y 'are independently selected from -0- and -NRV-, then together R11 and R11 are -alkyl-S-S-alkyl- to form a cyclic group, or together R11 and R11 are the group: wherein: V, W, and W 'are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and 1-alkynyl optionally substituted; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group to the beta and gamma bound position to the Y to the phosphorus; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and W are connected by means of 3-5 additional atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W 'are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or heteroaryl replaced; Z is selected from the group consisting of -CHRzOH, CHRzOC (0) Ry, -CH0C (S) Ry, -CHRz0C (S) 0Ry, -CHRzOC (O) SRy, CHRzOC02Ry, -OR2, -SRZ, -CHRZN3, -CH2aryl, -CH (aryl) OH, - CH (CH = CR22) 0H, -CH (C = CRz) OH, -Rz, -NRZ2, -OCORy, -OC02R ?, SCOR ?, -SC02Ry, -NHC0R2, -NHC02Ry, -CH2NHaril, - (CH2) q -ORz, and - (CH2) q-SRz; q is an integer of 2 or 3; Each Rz is selected from the group consisting of Ry and -H; Each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; Each Rx is independently selected from the group consisting of -H, and alkyl, or together R and Rx form a cyclic alkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; With the proviso that: a) when G is -O-, T is - (CH2) 0--, R1 and R2 are independently halogen, alkyl of 1 to 3 carbons, and cycloalkyl of 3 to 5 carbons, R3 is alkyl from 1 to 4 carbons or cycloalkyl of 3 to 7 carbons, R 4 is hydrogen, and R 5 is -OH, then X is not -P (O) (OH) 2 or -P (O) (0-lower alkyl) 2; b) when G is -O-, R5 is -NHC (0) Re, -NHS (= 0)? -2Re, -NHC (S) NH (Rh), or -NHC (0) NH (Rh), T is - (CH2) m-, -CH = CH-, -0 (CH2)? _ 2-, or -NH (CH2)? -2-, then X is not -P (0) (0H) 2 or -P (0) (0H) NH2; and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs. In one aspect, G is -0-. In another aspect, G is -CH2-.

In still another aspect, G is selected from the group consisting of -0- and -CH2-. In another aspect, G is -S-. In a further aspect, G is -S (= 0) -. In another aspect, G is -S (= 0) 2-. In a further aspect, G is -CH2-. In another aspect, G is -CF2-. In a further aspect, G is -CHF-. In another aspect, G is -C (0) -. In another aspect, G is -CH (OH) -. In a further aspect, G is -NH-. In another aspect, G is N (C1-C4 alkyl) -. In still another aspect, G is selected from the group consisting of -0-, -S- and -CH2-. In one aspect, T is T is -CH2-. In another aspect, T is - (CH2) or -4 ~ - In another aspect, T is selected from the group consisting of - (CH2) m-, -CH = CH-, -O (CH2)? _2-, and -NH (CH2)? _2-. In still another aspect, T is selected from the group that. consists of - (CRa2) n-, -0 (CRb2) (CRa2) p-, -N (Rc) (CRb2) (CRa2) p-, -S (CR2) (CRa2) p-, -NRb (C0) -, and -CH2CH (NRcRb) -. In another aspect, T is -CH2CH (NH2) -. In another aspect, T is -N (H) C (0) -. In a further aspect, T is -0CH2-. In another aspect, T is -CH2CH2-. In still another aspect, T is -CH2CH (NH2) -. In another aspect, T is -N (H) C (0) -. In a further aspect, T is - (CRa2) k-- In another aspect, T is -CRb = CRb- (CRa2) n-- In a further aspect, T is - (CRa2) n-CRb = CRb-. In another aspect, T is - (CRa2) -CRb = CRb- (CRa2) -. In a further aspect, T is -0 (CRb2) (CRa2) -. In another aspect, T is -S (CRb2) (CRa2) n-- In a further aspect, T is N (RC) (CRb2) (CRa2) n-. In another aspect, T is -N (Rb) C (0) (CRa2) n - In a further aspect, T is - (CRa2) nCH (NRbRc) -. In another aspect, T is -C (0) (CR2) m-. In a further aspect, T is - (CRa2) mC (0) -. In another aspect, T is - (CRa2) C (0) (CRa2) n ~ - In a further aspect, T is - (CRa2) nC (0) (CRa2) -. In still another aspect, T is -C (0) NH (CRb2) (CRa2) P ~. In one aspect k is 0. In a further aspect, k is 1. In a further aspect, k is 2. In a further aspect, k is 3. Still in another aspect, k is 4. In one aspect m is 0. In a further aspect, m is 1. In a further aspect, m is 2. In a further aspect, m is 3. In one aspect n is 0. In a further aspect, n is 1. In a further aspect, n is 2. In one aspect, p is 0. In another aspect, p is 1. In one aspect, each Ra is hydrogen with the proviso that when an R is linked to C through an atom 0, S, or N, then the other Ra links to the same C that is a hydrogen, or is linked by means of a carbon atom. In another aspect, each Ra is optionally substituted C 1 -C 4 alkyl with the proviso that when a Ra is linked to C through a 0, S, or N atom, then the other Ra binds to the same C which is a hydrogen, or it is bonded by means of a carbon atom. In a further aspect, each Ra is halogen with the proviso that when a Ra is linked to C through a 0, S, or N atom, then the other Ra binds to the same C which is a hydrogen, or is bound by half of a carbon atom. In another aspect, each Ra is -OH with the proviso that when a Ra is linked to C through an atom 0, S, or N, then the other Ra links to the same C that is a hydrogen, or is bound by half of a carbon atom. In a further aspect, each Ra is -O-C1-C4 alkyl optionally substituted with the proviso that when one Ra is linked to C through a 0, S, or N atom, then the other Ra binds to the same C as It is a hydrogen, or it is bonded by means of a carbon atom. In another aspect, each Ra is -0CF3 with the proviso that when a Ra is linked to C through an atom 0, S, or N, then the other Ra links to the same C that is a hydrogen, or is bound by half of a carbon atom. In a further aspect, each Ra is -S-C-C4 alkyl optionally substituted with the proviso that when one Ra is linked to C through a 0, S, or N atom, then the other Ra binds to the same C which is a hydrogen, or is bonded by means of a carbon atom. In another aspect, each Ra is -NRbRc with the proviso that when a Ra is linked to C through a 0, S, or N atom, then the other Ra binds to the same C that is a hydrogen, or is bound by half of a carbon atom. In a further aspect, each Ra is optionally substituted C2-C4 alkenyl with the proviso that when one Ra binds to C through a 0, S, or N atom, then the other Ra binds to the same C which is a hydrogen , or it is bonded by means of a carbon atom. In another aspect, each Ra is C2-C4 alkynyl with the proviso that when a Ra is linked to C through a 0, S, or N atom, then the other Ra binds to the same C which is a hydrogen, or bonds by means of a carbon atom. In one aspect, Rb is hydrogen. In a further aspect, Rb is optionally substituted C3-C4 alkyl. In one aspect, Rc is hydrogen. In another aspect, Rc is optionally substituted C1-C4 alkyl. In a further aspect, Rc is -C (0) -C1-C4 alkyl optionally substituted. In still another aspect, Rc is -C (0) H. In one aspect, R1 and R2 are each bromine. In another aspect, R1 and R2 are independently selected from the group consisting of hydrogen, halogen, alkyl of 1 to 3 carbons, and cycloalkyl of 3 to 5 carbons. In another aspect, R1 and R2 are independently halogen, alkyl of 1 to 3 carbons, and cycloalkyl of 3 to 5 carbons. In a further aspect, R1 and R2 are the same and are selected from the group consisting of halogen, C1-C4 alkyl, -CF3, and cyano. In a further aspect, R1 and R2 are different and are selected from the group consisting of halogen, C1-C4 alkyl, -CF3, and cyano. In one aspect, R1 and R2 are each independently selected from the group consisting of halogen, C1-C4 alkyl, -CF3, and cyano. In another aspect, R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl, and cyano. In another aspect, R1 and R2 are each iodo. In one aspect, R1 and R2 are each methyl. In a further aspect, R1 and R2 are each chlorine. In another aspect, R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, and methyl. In a further aspect, R1 and R2 are each halogen. In another aspect, R1 and R2 are each optionally substituted C1-C4 alkyl. In a further aspect, R1 and R2 are each optionally substituted -S-C-C3 alkyl. In another aspect, R1 and R2 are each optionally substituted C2-C4 alkenyl. In a further aspect, R1 and R2 are each optionally substituted C2-C4 alkynyl. In another aspect, R1 and R2 are each -CF3. In a further aspect, R1 and R2 are each -OCF3. In another aspect, R1 and R2 are each -O-C1-C3 alkyl optionally substituted. In a further aspect, R1 and R2 are each cyano. In still another aspect, R3 and R4 are each hydrogen. In another aspect, R3 and R4 are each halogen. In a further aspect, R3 and R4 are each -CF3. In another aspect, R3 and R4 are each -OCF3. In a further aspect, R3 and R4 are each cyano. In another aspect, R3 and R4 are each optionally substituted C? -C12 alkyl. In a further aspect, R3 and R4 are each optionally substituted C2-C2 alkenyl. In another aspect, R3 and R4 are each optionally substituted C2-C12 alkynyl. In a further aspect, R3 and R4 are each - (CRa2) optionally substituted maryl. In another aspect, R3 and R4 are each - (CRa2) optionally substituted cycloalkyl. In a further aspect, R3 and R4 are each - (CRa2) optionally substituted m-heterocycloalkyl. In another aspect, R3 and R4 are each -0Rd. In another aspect, R3 and R4 are each -SR. In a further aspect, R3 and R4 are each -S (= 0) Re. In another aspect, R3 and R4 are each -S (= 0) 2Re. In a further aspect, R3 and R4 are each -S (= 0) 2NRfRg. In another aspect, R3 and R4 are each -C (0) NRfRg. In a further aspect, R3 and R4 are each -C (0) 0Rh. In another aspect, R3 and R4 are each -C (0) Re. In a further aspect, R3 and R4 are each -N (Rb) C (0) Re. In another aspect, R3 and R4 are each -N (Rb) C (0) NRfRg. In a further aspect, R3 and R4 are each -N (Rb) S (= 0) 2Re. In another aspect, R3 and R4 are each -N (Rb) S (= 0) 2NRfRg. In a further aspect, R3 and R4 are each -NRfRg. In one aspect, R4 is selected from the group consisting of hydrogen, halogen, C1-C alkyl, cyano, and CF3. In another aspect, R4 is not hydrogen. In a further aspect, R4 is selected from the group consisting of hydrogen and halogen. In another aspect, R4 is selected from the group consisting of hydrogen and iodine. In a further aspect, R4 is hydrogen. In another aspect, each Rd is optionally substituted C? -C? 2 alkyl. In a further aspect, each Rd is optionally substituted C2-C12 alkenyl. In another aspect, each Rd is optionally substituted C 2 -C 2 alkynyl. In an additional aspect, each Rd is - (CRb2) optionally substituted narile. In another aspect, each Rd is - (CRb2) n-cycloalkyl optionally substituted. In a further aspect, each Rd is optionally substituted (CRb2) nheterocycloalkyl. In another aspect, each Rd is -C (0) NRfRg. In a further aspect, Re is optionally substituted C1-C12 alkyl. In another aspect, Re is optionally substituted alkenyl 2_Ci2. In a further aspect, Re is optionally substituted C2-C12 alkynyl. In another aspect, Re is - (CRa2) optionally substituted narile. In a further aspect, Re is - (CRa2) n-optionally substituted cycloalkyl. In another aspect, Re is - (CRa2) n -heterocycloalkyl optionally substituted. In one aspect, Rf and Rg are each hydrogen. In a further aspect, Rf and Rg are each optionally substituted C? -C12 alkyl. In another aspect, Rf and Rg are each optionally substituted C2-C12 alkenyl. In a further aspect, Rf and Rg are each optionally substituted C2-C2 alkynyl. In a further aspect, Rf and Rg are each - (CRb2) optionally substituted naril. In a further aspect, Rf and Rg are each (CRb2) optionally substituted n-cycloalkyl. In another aspect, Rf and Rg are each (CRb2) nheterocycloalkyl. In a further aspect, Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second heterogroup which is O. In another aspect, Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second heterogroup which is NRC. In another aspect, Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second heterogroup which is S. In one aspect, Rf and Rg together may form an unsubstituted heterocyclic ring, which may contain a second heterogroup. In another aspect, the optionally substituted heterocyclic ring can be substituted with 1 substituent selected from the group consisting of optionally substituted Ca-C4 alkyl, -ORb, oxo, cyano, -CF3, optionally substituted phenyl, and -C (Q) ORh. In a further aspect, the optionally substituted heterocyclic ring may be substituted with 2 substituents selected from the group consisting of optionally substituted C 1 -C 4 alkyl, -OR b, oxo, cyano, -CF 3, optionally substituted phenyl, and -C (0) OR h. In another aspect, the optionally substituted heterocyclic ring can be substituted with 3 substituents selected from the group consisting of optionally substituted C 1 -C 4 alkyl, ORb, oxo, cyano, -CF3, optionally substituted phenyl, and -C (0) ORh. In a further aspect, the optionally substituted heterocyclic ring may be substituted with 4 substituents selected from the group consisting of optionally substituted C 1 -C 4 alkyl, -OR b, oxo, cyano, -FC 3, optionally substituted phenyl, and -C (0) OR h. In a further aspect, Rh is optionally substituted C1-C12 alkyl. In another aspect, it is optionally substituted C2-C12 alkenyl. In a further aspect, Rh is optionally substituted C2-C12 alkynyl. In another aspect, Rh is - (CRb2) optionally substituted naril. In a further aspect, Rh is - (CRb2) n-cycloalkyl optionally substituted. In another aspect, Rh is - (CRb2) n-heterocycloalkyl optionally substituted. In one aspect, R5 is -OH. In another aspect, R5 is selected from the group consisting of -OH, -OC (0) Re, -OC (0) ORh, -F, and -NHC (0) Re. In a further aspect, R5 is selected from the group consisting of -OH and -OC (0) Re. In a further aspect, R 5 is -O-C 1 -C 7 alkyl optionally substituted. In another aspect, R5 is -OC (0) Re. In a further aspect, R5 is -OC (0) ORh. In another aspect, R5 is -F. In another aspect, R5 is -NHC (0) Re. In a further aspect, R5 is -NHS (= 0) Re. In another aspect, R5 is -NHS (= 0) 2Re- In a further aspect, R5 is -NHC (= S) NH (Rh). In another aspect, it is -NHC (O) NH (Rh). In one aspect, R3 is selected from the group consisting of halogen, optionally substituted Ci-Cß alkyl, -CF3, cyano, -C (0) NRfRg, (CRa2) optionally substituted narile, -S02NRfRg, and -S02Re- In another aspect , R3 is iso-propyl. In a further aspect, R3 is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 7 carbons. In yet another aspect, R3 is selected from the group consisting of halogen, optionally substituted Ci-Ce alkyl, optionally substituted -CH2aryl, -CH (OH) optionally substituted aryl, -C (0) -amino, -S (= 0) 2-amido, wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -SÜ2Re wherein Re is selected from the group consisting of phenyl, chlorophenyl, 4-fluorophenyl, and 4-pyridyl. In another aspect, R3 is iodine. In yet another aspect, R3 is selected from the group consisting of iodine, bromine, optionally substituted Ci-Ce alkyl, optionally substituted -CH2aryl, -CH (OH) optionally substituted aryl, -C (0) -amido, -S (= 0) 2-amido, wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-metipiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -S02Re wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, and 4-pyridyl. In one aspect, R3 is --CH (OH) (4-fluorophenyl). In one aspect, X is -P (0) YR ^ Y'R11. In one aspect, X is selected from the group consisting of -P03H2, -P (0) [-OCRz2OC (0) Ry] 2, -P (0) [-0CRz20C (0) 0Ry] 2, -P (0) [-N (H) CRz2C (0) 0Ry] 2, -P (0) [-N (H) CRz2C (0) 0Ry] [-0R11], and -P (0) [- 0CH (V) CH2CH20- ], wherein V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl. In another aspect, it is selected from the group consisting of -P03H2, P (0) [-OCRz2OC (0) Ry] 2, -P (0) [-0CRz20C (0) 0Ry] 2, -P (0) [- OCH2CH2SC (0) Me] 2, -P (0) [-N (H) CRZ2C (0) 0RY] 2, -P (0) [- N (H) CRz2C (0) 0Ry] [-0R11] and - P (0) [-0CH (V) CH2CH20-], wherein V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl. In another aspect, X is selected from the group consisting of -P03H2, -P (0) [-0CRz20C (0) Ry] 2, -P (0) [- OCRz2OC (0) ORy] 2, -P (0) [-Oalq-SC (0) Ry] 2, -P (0) [- N (H) CR22C (0) 0Ry] 2, -P (0) [-N (H) CRz2C (0) 0Ry] [- 0R11] and -P (0) [-OCH (V) CH2CH20-], wherein V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl. In one aspect, X is selected from the group consisting of -P03H2, -P (0) [-0CH20C (0) -t-butyl] 2, -P (0) [-0CH20C (0) 0-i-propyl] 2, P (0) [-N (H) CH ( CH3) C (0) OCH2CH3] 2, -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] 2, -P (0) [-N (H) CH (CH3) C ( 0) OCH2CH3] [3, 4-methylenedioxyphenyl], P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] [3,4-methylenedioxyphenyl], -P (0) [-0-CH2CH2S -C (0) CH3] 2, and -P (0) [-0CH (3-chlorophenyl) CH2CH20-]. In a further aspect, X is selected from the group consisting of -P03H2, -P (0) [-0CH20C (0) -t-butyl] 2, -P (0) [-0CH20C (0) 0-i-propyl ] 2, -P (0) [-N (H) CH (CH3) C (0) OCH2CH3] 2, -P (0) [-N (H) C (CH3) 2C (O) OCH2CH3] 2, - P (O) [-N (H) CH (CH3) C (0) OCH2CH3] [3,4-methylenedioxy-phenyl], -P (0) [-N (H) C (CH3) 2C (0) 0CH2CH3 ] [3, 4-ethylenedioxyphenyl], and -P (0) [-OCH (3-chlorophenyl) CH2CH20-]. In another aspect, X is -P03H2. In still another aspect, X is selected from the group consisting of -P (0) [-0CH20C (0) -t-butyl] 2 and -P (0) [-OCH2OC (0) -i-propyl] 2. In one aspect, X is selected from the group consisting of -P (0) [-OCH2OC (0) 0-ethyl] 2 and -P (0) [-0CH20C (0) 0-i-propyl] 2. In another aspect, X is selected from the group consisting of - P (0) [-N (H) CH (CH3) C (0) OCH2CH3] 2 and -P (0) [- N (H) C (CH3) 2C ( 0) OCH2CH3] 2. In a further aspect, X is -P (0) [-OCH2CH2SC (0) Me] 2. In another aspect, X is selected from the group consisting of -P (0) [-N (H) CH (CH3) C (0) OCH2CH3] [3,4-methylenedioxyphenyl] and -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] [3,4-methylenedioxyphenyl]. In a further aspect, X is selected from the group consisting of -P03H2, -P (0) [-0CRz20C (O) Ry] 2, P (0) [-OCRz2OC (0) ORy] 2, -P (0) [-N (H) CR22C (0) 0Ry] 2, -P (0) [- N (H) CRz2C (0) 0Ry] [-0R11] and -P (0) [-0CH (V) CH2CH20-] , wherein V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl. In another aspect, X is selected from the group consisting of -P03H2, -P (0) [-0CH20C (0) -t-butyl] 2, -P (0) [-OCH2OC (0) 0-i-propyl] 2, -P (0) [-N (H) CH (CH3) C (0) OCH2CH3] 2, -P (0) [- N (H) C (CH3) 2C (0) OCH2CH3] 2, -P (0) [-N (H) CH (CH3) C (O) OCH2CH3] [3,4-methylenedioxyphenyl], -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] [3 , 4-methylenedioxyphenyl], and -P (0) [-0CH (3-chlorophenyl) CH2CH20-]. In another aspect, X is -P (0) YR1: LY 'R11 where Y and Y' are each independently selected from -0- and -NRV-; together R11 and R11 are the group: wherein V, W, and W 'are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and 1-alkynyl optionally replaced; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group to the beta and gamma bound position to the Y to the phosphorus; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and W are connected by means of 3-5 additional atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W 'are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or heteroaryl replaced; Z is selected from the group consisting of -CHRzOH, CHRzOC (0) Ry, -CHRz0C (S) Ry, -CHRzOC (S) 0Ry, -CHRzOC (O) SRy, CHRzOC02Ry, -ORz, -SRZ, -CHRZN3, -CH2aryl, -CH (aryl) OH, -CH (CH = CRz2) OH, -CH (C = CRz) OH, -Rz, -NRZ2, -OCORy, -OC02Ry , -SCOR ?, -SC02Ry, -NHC0Rz, -NHC02R ?, -CH2NHaril, - (CH2) q-0Rz, and - (CH2) q-SRz; q is an integer of 2 or 3; with the proviso that: a) V, Z, W, W 'are not all -H; and b) when Z is -R, then at least one of V, W, and W 'is not -H, alkyl, aralkyl, or heterocycloalkyl; Each Rz is selected from the group consisting of Ry and -H; Each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; and Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl. In one aspect, V is optionally substituted aryl. In another aspect, V is selected from the group consisting of 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 3-fluorophenyl, pyrid-4-yl, pyrid-3-yl and 3,5-dichlorophenyl. In one aspect, the relative stereochemistry between the substituent group V and T in the dioxaphosphonan ring is cis. In another aspect, the cis-dioxaphosphonium ring has a carbon stereochemistry R where V binds. In another aspect, the cis-dioxaphosphonne ring has a S-carbon stereochemistry where V binds. In an aspect R11 is not hydrogen. In a further aspect when G is -O-, T is -CH2-, R1 and R2 are each bromine, R3 is iso-propyl, and R5 is -OH, then R4 is not hydrogen. In another aspect, when G is -O-, T is - (CH2) O- _A R1 and R2 are independently selected from the group consisting of halogen, alkyl of 1 to 3 carbons, and cycloalkyl of 3 to 5 carbons, R3 is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 7 carbons, and R5 is -OH, then R4 is not hydrogen; and wherein when G is -0-, R5 is selected from the group consisting of NHC (0) Re, -NHS (= 0)? - 2R% -NHC (= S) NH (Rh), and -NHC (0) ) NH (Rh), T is selected from the group consisting of - (CH2) m- r -CH = CH-, -0 (CH2)? -2-, and -NH (CH2)? _2-, then R4 does not It is hydrogen. In a further aspect for the compounds of Formula I, G is selected from the group consisting of -0- and -CH2-; T is selected from the group consisting of - (CRa2) n, -0 (CRb2) (CRa2) p-, -N (RC) (CRb2) (CRa2) p-, -S (CRb2) (CRa2) p-, -NRb (C0) -, and CH2CH (NRcRb) -; R1 and R2 are each independently selected from the group consisting of halogen, C? -C4 alkyl, -CF, and cyano; R 4 is selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, cyano and CF 3; R5 is selected from the group consisting of -OH, -0C (0) Re, -0C (0) 0Rh, -F and -NHC (0) Re; R3 is selected from the group consisting of halogen, optionally substituted Ci-Ce alkyl, -CF3, cyano, -C (0) NRfRg, - (CRa2) optionally substituted naril, -S02NRfRg, and -S02Re; and X is selected from the group consisting of -P03H2, -P (0) [-OCRz2OC (0) Ry] 2, -P (0) [-0CRz20C (0) 0Ry] 2, -P (0) [- Oalq -SC (0) Ry] 2, -P (0) [-N (H) CRZ2C (0) 0Ry] 2, -P (0) [- N (H) CRz2C (0) 0Ry] [-0R11] and -P (0) [-0CH (V) CH2CH20-], wherein V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl. In another aspect, G is selected from the group consisting of -0- and -CH2-; T is selected from the group consisting of ~ (CRa2) n, -0 (CRb2) (CRa2) p-, -N (Rc) (CRb2) (CR2) p-, -S (CRb2) (CRa2) P-, -NRb (C0) ~, and -CH2CH (NRcRb) -; R1 and R2 are each independently selected from the group consisting of halogen, C? -C4 alkyl, -CF3, and cyano; R 4 is selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, cyano and CF 3; R5 is selected from the group consisting of -OH, -0C (0) Re, -0C (0) 0Rh, -F and -NHC (0) Re; R3 is selected from the group consisting of halogen, optionally substituted C6-C6 alkyl, -CF3, cyano, -C (0) NRfRg, - (CRa2) optionally substituted naril, -S02NRfRg, and -S02Re; and X is selected from the group consisting of -P03H2, -P (0) [-OCRz2OC (0) Ry] 2, -P (0) [-OCRz2OC (0) ORy] 2, -P (0) [- N (H) CRz2C (0) ORy] 2, -P (0) [-N (H) CRz2C (0) 0Ry] [-0R11] and -P (0) [-OCH (V) CH2CH20-], where V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl. In a further aspect, G is selected from the group consisting of -0- and -CH2-; T is -CH2CH (NH2) -; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl, and cyano; R4 is hydrogen; R5 is selected from the group consisting of -OH and -0C (0) Re; R3 is selected from the group consisting of halogen, optionally substituted Ci-Ce alkyl, optionally substituted -CH2aryl, optionally substituted -CH (OH) aryl, -C (O) -amido wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-metipiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, -S (= 0) 2-amido wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -S02R wherein R is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, and 4-pyridyl, and X is selected from the group consisting of -P03H2, -P (0) [-OCRz2OC (O) Ry] 2, -P (0) [-0CR220C (O) 0Ry] 2, -P (0) [-N (H) CRz2C (0) ORy] 2, -P (0) [ -N (H) CRZ2C (0) 0Ry] [0Re] and -P (0) [-OCR2 (aryl) CH2CH20-]. In another aspect, when G is -0-, T is -CH2-, R1 and R2 are bromine, R3 is iso-propyl, R5 is -OH, and X is selected from the group consisting of -P03H2, -P (0 ) [-0CRz20C (0) Ry] 2, -P (0) [- OCRz2OC (0) ORy] 2, -P (0) [-N (H) CRz2C (0) 0Ry] 2, -P (0) [-N (H) CRz2C (0) 0Ry] [0Re] and -P (0) [-0CRz (aryl) CH2CH20-], then R4 is not hydrogen. In one aspect for the compounds of Formula I, G is -0-; T is -CH2CH (NH2) -; R1 and R2 are each iodo; R4 is selected from the group consisting of hydrogen and iodine; R5 is -OH; and R3 is iodine; and X is selected from the group consisting of -P03H2, -P (0) [-0CRz20C (0) Ry] 2, -P (0) [-0CRz20C (O) 0Ry] 2, - (0) [- N ( H) CRz2C (0) ORy] 2, -P (0) [-N (H) CRZ2C (O) 0Ry] [0Re] and -P (0) [-OCRz (aryl) CH2CH20-]. In another aspect G is -0-; T is -CH2CH (NH2) -; R1 and R2 are each iodo; R4 is selected from the group consisting of hydrogen and iodine; R5 is -OH; R3 is iodine; and X is selected from the group consisting of -P03H2, -P (0) [-OCH2OC (0) -t-butyl] 2, - P (0) [-OCH2OC (0) 0-i-propyl] 2, - P (0) [-N (H) CH (CH3) C (0) 0CH2CH3] 2, - P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] 2, -P (0) [- N (H) CH (CH3) C (0) 0CH2CH3] [3, 4-methylenedioxyphenyl], -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] [3, 4- methylenedioxyphenyl], and -P (0) [-OCH (3-chlorophenyl) CH2CH20-]. In a further aspect for the compounds of formula I, G is selected from the group consisting of -0- and -CH2-; T is -N (H) C (0) -; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl, and cyano; R 4 is selected from the group consisting of hydrogen, iodine, 4-chlorophenyl, and cyclohexyl; W is selected from the group consisting of -OH and -0C (0) Re; R5 is selected from the group consisting of hydrogen, iodine, bromine, optionally substituted Ci-Cg alkyl, optionally substituted -CH2 ryl, optionally substituted -CH (OH) aryl, -C (0) -amido wherein the amido group is selected of the group consisting of phenethylamino, piperidinyl, 4-methylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, -S (= 0) 2-amido wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperizinyl , morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -S02R wherein R is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, and 4-pyridyl; and X is selected from the group consisting of -P03H2, -P (0) [-OCRz2OC (0) Ry] 2, - P (0) [-0CRz20C (0) 0Ry] 2 r -P (0) [-N (H) CR22C (0) 0Ry] 2, -P (0) [- N (H) CRz2C (0) 0Ry] [0Re] and -P (0) [-0CRz (aryl) CH2CH20-]. An additional aspect is when G is -0-; T is -N (H) C (OJ, R1 and R2 are methyl, R4 is hydrogen, R5 is -OH, R3 is -CH (OH) (4-fluorophenyl), and X is selected from the group consisting of -P03H2 , -P (0) [-0CRz20C (0) Ry] 2, -P (0) [- 0CRz20C (0) 0Ry] 2, -P (0) [-N (H) CR22C (0) 0Ry] 2, -P (0) [- N (H) CR22C (0) 0Ry] [0Re] and -P (0) [-0CRz (aryl) CH2CH20-] In a further aspect, G is -0-; T is - N (H) C (0) - R1 and R2 are each methyl, R4 is hydrogen, R5 is -OH, R3 is -CH (OH) (4-fluorophenyl), and X is selected from the group consisting of - P03H2, -P (0) [-0CH20C (0) -t-butyl] 2, -P (0) [- 0CH20C (0) 0-i-propyl] 2, -P (0) [-N (H) CH (CH3) C (0) 0CH2CH3] 2, -P (0) [- N (H) C (CH3) 2C (0) OCH2CH3] 2, -P (0) [-N (H) CH (CH3) C (0) 0CH2CH3] [3, 4-methylenedioxyphenyl], -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] [3,4-methylenedioxyphenyl], and -P (0) [ -0CH (3-chlorophenyl) CH2CH20-] In a further aspect G is selected from the group consisting of -0- and -CH2-, T is -0CH2-, R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine , methyl, and cyano; R 4 is selected from the group consisting of hydrogen, iodine, 4-chlorophenyl, and cyclohexyl; R5 is selected from the group consisting of -OH and -OC (0) Re; R3 is selected from the group consisting of hydrogen, iodine, bromine, optionally substituted lower alkyl, -CH2aryl optionally substituted, -CH (OH) optionally substituted aryl, -C (0) -amido wherein the amido group is selected from the group consists of phenethylamino, piperidinyl, 4-methylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, -S (= 0) 2-amido wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -S02R wherein R is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, and 4-pyridyl; and X is selected from the group consisting of -P03H2, -P (0) [-0CRz20C (0) Ry] 2, -P (0) [-0CRz20C (0) 0Ry] 2, P (0) [-N ( H) CRZ2C (0) 0Ry] 2, -P (0) [-N (H) CRz2C (0) 0Ry] [0Re] and -P (0) [-0CRZ (aryl) CH2CH20-]. - In another aspect G is -CH2-; T is -0CH2-; R1 and R2 are each methyl; R4 is hydrogen; R5 is -OH; R3 is iso-propyl; and X is selected from the group consisting of -P03H2, -P (0) [-0CRz20C (0) Ry] 2, -P (0) [-0CR20C (0) 0Ry] 2, -P (0) [-N (H) CRZ2C (0) 0Ry] 2, -P (0) [-N (H) CRz2C (0) 0Ry] [0Re] and -P (0) [-0CRz (aryl) CH2CH20-]. In another aspect, G is -CH2-; T is -0CH-; R1 and R2 are each methyl; R4 is hydrogen; R5 is -OH; R3 is isopropyl; and X is selected from the group consisting of -P03H2, - P (0) [-OCH2OC (0) -t-butyl] 2, -P (0) [-OCH2OC (0) Oi-propyl] 2, P (0 ) [-N (H) CH (CH3) C (0) OCH2CH3] 2, -P (0) [-N (H) C (CH3) 2C (0) 0CH2CH3] 2, -P (0) [-N (H) CH (CH3) C (0) OCH2CH3] [3,4-methylenedioxyphenyl], P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] [3,4-methylenedioxyphenyl], and P (0) [-OCH (3-chlorophenyl) CH2CH20-]. In a further aspect, G is selected from the group consisting of -0- and -CH-; T is -CH2-; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl, and cyano; R 4 is selected from the group consisting of hydrogen, iodine, 4-chlorophenyl, and cyclohexyl; R5 is selected from the group consisting of -OH and -0C (0) Re; R3 is selected from the group consisting of hydrogen, iodine, bromine, optionally substituted lower alkyl, -CH optionally substituted aryl, -CH (OH) optionally substituted aryl, -C (0) -amido wherein the amido group is selected from the group consists of phenethylamino, piperidinyl, 4-methylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, -S (= 0) 2-amido wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -S02R wherein R is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, and 4-pyridyl; and X is selected from the group consisting of -P03H2, -P (0) [-0CRz20C (0) Ry] 2, P (O) [-OCRz2OC (O) 0Ry] 2, -P (O) [-N ( H) CR 2C (O) 0R y] 2, -P (O) [- N (H) CRz 2 C (0) ORy] [0Re] and -P (0) [-OCRz (aryl) CH 2 CH 20-]. In further aspects, when G is -0-, T is -CH2-, R1 and R2 are each bromine, R3 is iso-propyl, R5 is -OH; and X is selected from the group consisting of -P03H2, -P (0) [-OCRz2OC (0) Ry] 2, -P (0) [-0CRz20C (0) 0Ry] 2 -P (0) [-N ( H) CRZ2C (0) 0Ry] 2, -P (0) [-N (H) CRZ2C (0) 0Ry] [0Re] and -P (0) [-0CR2 (aryl) CH2CH20-], then R4 is not hydrogen. In another aspect, G is -0-; T is -CH2-; R1 and R2 are each chlorine; R4 is hydrogen; R5 is -OH; R3 is i-propyl; and X is selected from the group consisting of -P03H2, -P (0) [-OCRz2OC (0) Ry] 2, -P (0) [-0CRz20C (0) 0Ry] 2, -P (0) [- N (H) CRz2C (0) ORy] 2, -P (0) [-N (H) CRZ2C (0) 0Ry] [0Re] and -P (0) [-0CRz (aryl) CH2CH20-]. In another aspect, G is -0-; T is -CH2-; R1 and R2 are each chlorine; R4 is hydrogen; R5 is -OH; R3 is i-propyl; and X is selected from the group consisting of -P03H2, -P (0) [-0CH20C (0) -t-butyl] 2, -P (0) [-OCH2OC (0) 0-i-propyl] 2, - P (0) [- N (H) CH (CH3) C (O) OCH2CH3] 2, -P (O) [-N (H) C (CH3) 2C (0) 0CH2CH3] 2, P (0) [ -N (H) CH (CH 3) C (0) OCH 2 CH 3] [3,4-methylenedioxyphenyl], -P (0) [-N (H) C (CH 3) 2C (0) OCH 2 CH 3] [3, 4- methylenedioxyphenyl], and -P (0) [-OCH (3-chlorophenyl) CH2CH20-]. In additional aspects for the compounds of the formula I, G is selected from the group consisting of -0- and -CH2-; T is -CH2CH2-; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl, and cyano; R 4 is selected from the group consisting of hydrogen, iodine, 4-chlorophenyl, and cyclohexyl; R5 is selected from the group consisting of -OH and -OC (0) Re; R3 is selected from the group consisting of hydrogen, iodine, bromine, optionally substituted lower alkyl, -CH2aryl optionally substituted, -CH (OH) optionally substituted aryl, -C (0) -amido wherein the amido group is selected from the group consists of phenethylamino, piperidinyl, 4-methylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, -S (= 0) 2-amido wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -SO2R wherein R is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, and 4-pyridyl; and X is selected from the group consisting of -P03H2, _P (0) [-0CR220C (0) Ry] 2, -P (0) [-0CRz20C (0) 0Ry] 2, -P (0) [- N ( H) CRz2C (0) 0Ry] 2, -P (0) [-N (H) CRZ2C (0) 0RY] [0Re] and -P (0) [-OCRz (aryl) CH2CH20-]. In a further aspect, G is -0-; T is -CH2CH2 ~; R1 and R2 are each chlorine; R4 is hydrogen; R5 is -OH; R3 is isopropyl; and X is selected from the group consisting of -P03H2, -P (0) [-0CR220C (0) Ry] 2, -P (0) [-0CR220C (0) 0Ry] 2, -P (0) [- N (H) CRz2C (0) ORy] 2, -P (0) [-N (H) CRz2C (0) 0Ry] [0Re] and -P (0) [-OCRz (aryl) CH2CH20-]. In another aspect, G is -0-; T is -CH2CH2-; R1 and R2 are each chlorine; R4 is hydrogen; R5 is -OH; R3 is iso-propyl; and X is selected from the group consisting of -P03H2, -P (0) [-OCH2OC (0) -t-butyl] 2, -P (0) [-0CH20C (0) Oi-propyl] 2, -P ( 0) [-N (H) CH (CH3) C (0) 0CH2CH3] 2, -P (0) [-N (H) C (CH3) C (0) OCH2CH3] 2, P (0) [-N (H) CH (CH3) C (0) 0CH2CH3] [3,4-methylenedioxyphenyl], -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] [3,4-methylenedioxyphenyl] , and -P (0) [- OCH (3-chlorophenyl) CH2CH20-]. In a further aspect, G is -CH2-; T is -0CH2-; R1 and R2 are each methyl; R4 is hydrogen; R5 is -OH; R3 is iso-propyl; and X is -P03H2. In a further aspect, G is -CH2-; T is -0CH2-; R1 and R2 are each methyl; R4 is hydrogen; R5 is -OH; R3 is iso-propyl; and X is selected from the group consisting of -P (0) [-0CH20C (0) -t-butyl] 2 and -P (0) [-0CH20C (0) -i-propyl] 2. In another aspect, G is -CH2-; T is -0CH2-; R1 and R2 are each methyl; R4 is hydrogen; R5 is -OH; R3 is iso-propyl; and X is selected from the group consisting of -P (0) [-0CH20C (O) 0-ethyl] 2 and -P (0) [-0CH20C (0) 0-i-propyl] - In a further aspect, G is -CH2-; T is -OCH2-; R1 and R2 are each methyl; R4 is hydrogen; R5 is -OH; R3 is iso-propyl; and X is selected from the group consisting of -P (0) [~N (H) CH (CH3) C (0) OCH2CH3] 2 and -P (0) [- N (H) C (CH3) 2C (0 ) 0CH2CH3] 2. In additional aspects, G is -CH2-; T is -0CH2-; R1 and R2 are methyl; R4 is hydrogen; R5 is -OH; R3 is iso-propyl; and X is -P (0) [~ 0CH2CH2SC (0) Me] 2, or X is -P (0) [-N (H) C (CH3) C (0) OCH2CH3] [3,4-methylenedioxyphenyl], or X is -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] [3,4-methylenedioxyphenyl]. In another aspect, G is -0-, T is - (CH2) or -4 ~, R1 and R2 are independently selected from the group consisting of hydrogen, halogen, alkyl of 1 to 3 carbons, and cycloalkyl of 3 to 5 carbons , R3 is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 7 carbons, and R5 is -OH, then R4 is not hydrogen; and wherein when G is -0-, R5 is selected from the group consisting of NHC (0) Re, -NHS (= 0)? 2Re, -NHC (S) NH (Rh), and -NHC (0) NH (Rh), T is selected from the group consisting of - (CH2) m-, -CH = CH-, -0 (CH2)? -2-, and -NH (CH2)? -2 ~, then R4 is not hydrogen. In a further aspect, G is -CH2-; T is -0CH2-; R1 and R2 are each methyl; R4 is hydrogen; R5 is -OH; R3 is isopropyl; and X is -P (0) YR1: LY 'R11; wherein Y and Y 'are each independently selected from -0- and -NR11-; together R11 and R11 are the group: wherein: V, W, and W 'are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and 1-alkynyl optionally substituted; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group to the beta and gamma bound position to the Y to the phosphorus; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and W are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W 'are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or heteroaryl replaced; Z is selected from the group consisting of -CHRzOH, -CHRzOC (0.) Ry, -CHRzOC (S) Ry, -CHRzOC (S) ORy, -CHRz0C (O) SRy, -CHRz0C02Ry, -0RZ, -SRZ, - CHR2N3, -CH2aryl, -CH (aryl) OH, -CH (CH = CRZ2) OH, -CH (G = CRz) OH, -Rz, -NRZ2, -OCORy, -OC? 2Ry, -SC0Ry, -SC02Ry, -NHC0R2, -NHC02Ry, -CH2NHaril, - (CH2) q-ORz, and - (CH2) q-SRz; q is an integer of 2 or 3; with the proviso that: a) V, Z, W, W 'are not all -H; and b) when Z is -Rz, then at least one of V, W, and W0 are not -H, alkyl, aralkyl, or heterocycloalkyl; Each Rz is selected from the group consisting of Ry and -H; Each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; Each Rx is independently selected from the group consisting of -H, and alkyl, or together Rx or Rx form a cyclic alkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl. In an additional aspect V is aryl. In a further aspect Z is hydrogen, W is hydrogen, and W 'is hydrogen. In a further aspect, V is 3-chlorofenyl, 4-chlorophenyl, 3-bromofenyl, 3-f luorofenyl, pyrid-4-yl, pyrid-3-yl or 3,5-dichlorofenyl. In a further aspect the relative stereochemistry between the substituents on the dioxaf osphuran ring is cis. In another aspect, each Ra is independently selected from the group consisting of hydrogen, optionally substituted C?-C2 alkyl, halogen, -OH, -O-C?-C opcional optionally substituted alkyl, -OCF 3, -S-C alquilo-alkyl C2 optionally substituted, -NR1 ^ 0, optionally substituted C2 alkenyl, and optionally substituted C2-alkynyl; Each Rb is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 2 alkyl; Each Rc is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl, and optionally substituted -C (O) -alkyl C 2 -C 2, -C (0) H; Each Rd is selected from the group consisting of optionally substituted C6-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted (CRb2) nfenyl, optionally substituted monocyclic - (CR2) nheteroaryl, - (CRb2) n C3-Cs optionally substituted cycloalkyl, - (CRb2) n-C4-C5 heterocycloalkyl optionally substituted, and -C (0) NRfRg; Each Re is selected from the group consisting of optionally substituted Ci-Cß alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, - (CRb2) nphenyl optionally substituted, (CRb2) n-heteroaryl optionally substituted monocyclic, - (CRb2 ) optionally substituted C3-C6-cycloalkyl, optionally substituted C4-C5 (C2-C5) n-heterocycloalkyl; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted Ci-Cß alkyl, optionally substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl optionally substituted, - (CRb 2) nphenyl optionally substituted, - (CRb 2) n-heteroaryl monocyclic optionally substituted, optionally substituted C3-C6- (CRb2) n-cycloalkyl, optionally substituted C4-Cs- (CRb2) n-heterocycloalkyl, or Rf and Rg together can form an optionally substituted heterocyclic ring, which may contain a selected second hetero group from the group of O, NRb, and S, wherein the optionally substituted heterocyclic ring can be substituted with 0-2 substituents selected from the group consisting of optionally substituted C? -C2 alkyl, -ORb, oxo, cyano, -CF3, phenyl optionally substituted, and -C (0) 0Rh; Each Rh is optionally substituted Ci-Cie alkyl, optionally substituted C2-C16 alkenyl, optionally substituted C2-Ci6 alkynyl, - (CRb2) nphenyl optionally substituted, - (CRb2) optionally substituted monocyclic n-heteroaryl, - (CRb2) n-C3-C6 cycloalkyl optionally substituted, - (CRb2) optionally substituted C4-C5-heterocycloalkyl. In a further aspect, each Ra is independently selected from the group consisting of hydrogen, methyl, fluorine, chlorine, -OH, -0-CH3, -OCF3, -SCH3, -NHCH3, -N (CH3) 2; Each Rb is independently selected from the group consisting of hydrogen, and methyl; Each Rc is independently selected from the group consisting of hydrogen, methyl, -C (0) CH3, -C (0) H; Each Rd is selected from the group consisting of optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, - (CH 2) nphenyl optionally substituted, - (CH 2) n-heteroaryl optionally substituted monocyclic, - (CH 2 C3-C6 optionally substituted n-cycloalkyl, optionally substituted C4-C5- (CH2) n-heterocycloalkyl, and -C (0) NRfRg; Each Re is selected from the group consisting of optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, (CH2) optionally substituted n-phenyl, - (CH2) n-monoalkyl optionally substituted, - (CH2) n-cycloalkyl C3-C6 optionally substituted, optionally substituted C4-C5- (CH2) n -heterocycloalkyl; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C alkenyl, optionally substituted C2-C4 alkynyl, - (CH2) nphenyl optionally substituted, - (CH2) n-heteroaryl monocyclic optionally substituted, optionally substituted C3-C6- (CH2) n-cycloalkyl, optionally substituted C4-C5- (CH2) n-heterocycloalkyl, or Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a selected second hetero group from the group of O, NRb, and S, wherein the optionally substituted heterocyclic ring can be substituted with 0-2 substituents selected from the group consisting of optionally substituted methyl, -ORb, oxo, cyano, -CF3, optionally substituted phenyl, and - C (0) 0Rh; Each Rh is optionally substituted C1-C alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, - (CH2) nphenyl optionally substituted, - (CH2) n-heteroaryl optionally substituted monocyclic, - (CH2) n-cycloalkyl C3- Optionally substituted Cβ, optionally substituted C 4 -C 5 - (CH 2) n-heterocycloalkyl. Each of the individual spaces of the compounds of Formula I may be generated by making all the permutations above may be specifically established for inclusion or may be specifically excluded from the present invention.

In another aspect, the invention relates to compounds of Formula II, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of prodrugs as represented by formula II: wherein: A is selected from the group consisting of -NR1-, -O-, and -S-; B is selected from the group consisting of -CRb-, and -N-; R1 is selected from the group consisting of hydrogen, -C (O) C1-C4 alkyl, C1-C4 alkyl, and C1-C4 aryl; . R b is selected from the group consisting of hydrogen and optionally substituted C 1 -C 4 alkyl; G is selected from the group consisting of -O-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF-, -C (O) -, -CH (OH) -, -NH-, and -N (C 1 -C 4 alkyl) -; D is selected from the group consisting of a bond, - (CRa2) -, and -C (O) -; Each Ra is independently selected from the group consisting of hydrogen, optionally substituted C1-C4 alkyl, halogen, -OH, optionally substituted 0-C2-C4 alkyl, -OCF3, -S-optionally substituted C-C4 alkyl, -NRbRc , optionally substituted C-C4 alkenyl, and optionally substituted C-C4 alkynyl; with the proviso that when a Ra is linked to C through an atom 0, S, or N, then the other Ra links to the same C that is a hydrogen, or is bonded by means of a carbon atom; R1 and R2 are each independently selected from the group consisting of halogen, optionally substituted C1-C4 alkyl, -S-optionally substituted C-C3 alkyl, optionally substituted C2-C alkenyl, optionally substituted C2-C4 alkynyl, -CF3, -0CF3, -O-C1-C3 alkyl optionally substituted, and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted C1-C12 alkyl, optionally substituted C2-C2 alkenyl, optionally substituted C2-C12 alkynyl, - ( CRa2) optionally substituted maryl, - (CRa2) optionally substituted cycloalkyl, (CRa2) mheterocycloalkyl optionally substituted, -0Rd, SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRfRg, -C (0) NRfRg, -C (0) ORh, -C (0) Re, -N (Rb) C (0) Re, -N (Rb) C (0) NRfRg, -N (Rb) S ( = 0) 2Re, N (Rb) S (= 0) 2NRfRg, and -NRfRb; Each Rd is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted CC ?2 alkynyl, optionally substituted (CRb2) naryl, (CRb2) n optionally substituted cycloalkyl, (CRb2) nheterocycloalkyl optionally replaced, and -C (0) NRfRg; Each Re is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2-C2 alkenyl, optionally substituted C2-C alkynyl, optionally substituted (CRa2), optionally substituted (CRa2) nCycloalkyl, and (CRa2) ) optionally substituted n-heterocycloalkyl; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, optionally substituted C2-C? 2 alkynyl, optionally substituted (CRb2) naryl, - (CRb2) optionally substituted n-cycloalkyl, and - (CRb2) n-heterocycloalkyl optionally substituted, or Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second hetero group selected from the group consisting of O, NRC, and S, wherein the optionally substituted heterocyclic ring can be substituted with 0-4 substituents selected from the group consisting of optionally substituted C? -C4 alkyl, -ORb, oxo, cyano, -CF3, optionally substituted phenyl, and -C (0) ORh; Each Rh is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2-C2 alkenyl, optionally substituted C2-C2 alkynyl, optionally substituted (CR2), optionally substituted (CRb2) nCycloalkyl, and ( CRb2) optionally substituted n-heterocycloalkyl; R5 is selected from the group consisting of -OH, -0-C-C6 alkyl optionally substituted, -0C (0) Re, -0C (0) 0Rh, -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2 Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); X is P (0)? RuY'Ru; Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are -0-, R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (R) 20C (0) NR2, -NRZ-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2-0- C (0) 0RY, -C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; when Y and Y 'are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy, and cycloalkylene-COORy; when Y is -O- and Y 'is NRV, then R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRZ2, -NRz-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz2) - 0-C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (R2) 2] qC (0) SRy , and -cycloalkylene-C00Ry; or when Y and Y 'are independently selected from -0- and -NR11-, then together R11 and R11 are -alkyl-S-S-alkyl to form a cyclic group, or together R11 and R11 are the group: wherein: V, W, and W 'are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and 1-alkynyl optionally substituted; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group to the beta and gamma bound position to the Y to the phosphorus; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and W are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W 'are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or heteroaryl replaced; Z is selected from the group consisting of -CHR20H, CHRzOC (0) Ry, -CHRzOC (S) Ry, -CHRzOC (S) ORy, -CHR20C (O) SRy, CHRzOC02R ?, -0RZ, -SRz, -CHRN3, -CH2aryl, -CH (aryl) OH, -CH (CH = CRZ2) 0H, -CH (G = CRz) OH, -Rz, -NRZ2, -OCORy, -OC02Ry, -SCORy, -SC02R ?, -NHC0Rz, -NHC02Ry, -CH2NHaril, - (CH2) q-ORz, and - (CH2) q-SRz; q is an integer of 2 or 3; Each Rz is selected from the group consisting of Ry and -H; Each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; Each Rx is independently selected from the group consisting of -H, and alkyl, or together Rx or Rx form a cyclic alkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the proviso that: a) V, Z, W, and W 'are not all -H; and b) when Z is -Rz, then at least one of V, W, and W 'is not -H, alkyl, aralkyl, or heterocycloalkyl. In another aspect, G is selected from the group consisting of -0- and -CH2-. In one aspect, G is -0-. In another aspect, G is -S-. In another aspect, G is -S (= 0) -. In a further aspect, G is -S (= 0) 2-. In another aspect, G is -CH2-. In a further aspect, G is -CF2-. In another aspect, G is -CHF-. In a further aspect, G is -C (0) -. In another aspect, G is - CH (OH) -. In another aspect, G is -NH-. In a further aspect, G is -N (C1-C4 alkyl) -. In a further aspect, D is selected from the group consisting of a bond and -CH2-. In another aspect D is a link. In an additional aspect D is - (CRa2) -. In another aspect D is -C (0) -. Still in another aspect A is selected from -NH-, -NMe-, -0-, and -S-. In one aspect, A is -NR1-. In another aspect, A is -0-, In a further aspect, A is -S-. In a further aspect, B is selected from -CH2-, CMe-, and -N-. In another aspect, B is -CRb-. In a further aspect, B is-N-. In one aspect, R1 is hydrogen, -C (0) C -C4 alkyl. In another aspect, R 1 is C 1 -C 4 alkyl. In a further aspect, R1 is aryl C? -C4.

In one aspect, Rb is hydrogen. In another aspect, R b is optionally substituted C 1 -C 4 alkyl. In another aspect, Ra is hydrogen with the proviso that when a Ra binds to C through a 0, S, or N atom, then the other Ra binds to the same C that is a hydrogen, or binds by means of a carbon atom. In a further aspect, Ra is optionally substituted C-C4 alkyl with the proviso that when a Ra is linked to C through a 0, S, or N atom, then the other Ra binds to the same C which is a hydrogen, or it is bonded by means of a carbon atom. In another aspect, Ra is halogen with the proviso that when a Ra binds to C through a 0, S, or N atom, then the other Ra binds to the same C that is a hydrogen, or binds by means of a carbon atom. In a further aspect, Ra is -OH with the proviso that when a Ra is linked to C through an atom 0, S, or N, then the other Ra binds to the same C which is a hydrogen, or is bound by half of a carbon atom. In another aspect, R is -0-C C-C4 alkyl optionally substituted with the proviso that when one R is linked to C through a 0, S, or N atom, then the other Ra binds to the same C which is a hydrogen, or it is bonded by means of a carbon atom. In another aspect, Ra is -0CF3 with the proviso that when a Ra is linked to C through an atom 0, S, or N, then the other Ra binds to the same C that is a hydrogen, or binds by means of of a carbon atom. In a further aspect, Ra is -S-C?-C4 alkyl optionally substituted with the proviso that when a Ra is linked to C through a 0, S, or N atom, then the other Ra binds to the same C as It is a hydrogen, or it is bonded by means of a carbon atom. In another aspect, Ra is -NRbRc with the proviso that when an R is linked to C through an atom 0, S, or N, then the other Ra binds to the same C that is a hydrogen, or binds by means of of a carbon atom. An additional aspect, Ra is C2-C4 alkenyl optionally substituted with the proviso that when a Ra is linked to C through a 0, S, or N atom, then the other Ra binds to the same C which is a hydrogen, or it is bonded by means of a carbon atom. In another aspect, Ra is optionally substituted C2-C4 alkynyl with the proviso that when a Ra is linked to C through a 0, S, or N atom, then the other Ra binds to the same C which is a hydrogen, or it is bonded by means of a carbon atom. In one aspect, R1 and R2 are the same and are selected from the group consisting of halogen, C? -C4 alkyl, -CF3, and cyano. In another aspect, R1 and R2 are different and are selected from the group consisting of halogen, C? -C4 alkyl, -CF3, and cyano. In a further aspect, R1 and R2 are each halogen. In another aspect, R1 and R2 are each optionally substituted C? -C4 alkyl. In a further aspect, R1 and R2 are each optionally substituted -S-C-C3 alkyl. In another aspect, R1 and R2 are each optionally substituted C2-C4 alkenyl. In a further aspect, R1 and R2 are each optionally substituted C2-C4 alkynyl. In another aspect, R1 and R2 are each -CF3. In a further aspect, R1 and R2 are each -0CF3. In another aspect, R1 and R2 are each optionally substituted-C-C3-O-alkyl. In a further aspect, R1 and R2 are each cyano. In still another aspect, R3 and R4 are each hydrogen. In another aspect, R3 and R4 are each halogen. In a further aspect, R3 and R4 are each -CF3. In another aspect, R3 and R4 are each -0CF3. In a further aspect, R3 and R4 are each cyano. In another aspect, R3 and R4 are each optionally substituted C? -C12 alkyl. In a further aspect, R3 and R4 are each optionally substituted C2-C2 alkenyl. In another aspect, R3 and R4 are each optionally substituted C2-C12 alkynyl. In a further aspect, R3 and R4 are each - (CRa2) optionally substituted maryl. In another aspect, R3 and R4 are each - (CRa2) optionally substituted cycloalkyl. In a further aspect, R3 and R4 are each - (CR2) optionally substituted m-heterocycloalkyl. In another aspect, R3 and R4 are each -0Rd. In another aspect, R3 and R4 are each -SRd. In a further aspect, R3 and R4 are each -S (= 0) Re. In another aspect, R3 and R4 are each -S (= 0) 2Re. In a further aspect, R3 and R4 are each -S (= 0) 2NRfRg. In another aspect, R3 and R4 are each -C (0) NRfRg. In a further aspect, R3 and R4 are each -C (0) ORh. In another aspect, R3 and R4 are each -C (0) Re. In a further aspect, R3 and R4 are each -N (Rb) C (0) Re. In another aspect, R3 and R4 are each -N (Rb) C (0) NRfRg. In a further aspect, R3 and R4 are each -N (Rb) S (= 0) 2Re. In another aspect, R3 and R4 are each -N (Rb) S (= 0) 2NRfRg. In a further aspect, R3 and R4 are each -NRfRg. In a further aspect, R 4 is selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, cyano and CF 3. In a further aspect, R3 is selected from the group consisting of halogen, optionally substituted C6-C6 alkyl, -CF3, cyano, -C (0) NRfRg, - (CRa) optionally substituted naril, -S02NRfRg, and -S02Re. In another aspect, each Rd is optionally substituted C? -C? 2 alkyl. In a further aspect, each Rd is optionally substituted C2-C12 alkenyl. In another aspect, each Rd is optionally substituted C2-C12 alkynyl. In a further aspect, each Rd is optionally substituted (CRb2) naril. In another aspect, each Rd is - (CRb2) n-cycloalkyl optionally substituted. In an additional aspect, each Rd is(CRb2) optionally substituted n-heterocycloalkyl. In another aspect, each Rd is -C (0) NRfRg. In a further aspect, Re is optionally substituted C? -C? 2 alkyl. In another aspect, Re is optionally substituted C2-C1 alkenyl. In a further aspect, Re is optionally substituted C2-C12 alkynyl. In another aspect, Re is - (CRa2) optionally substituted narile. In a further aspect, Re is - (CRa2) nCycloalkyl optionally substituted. In another aspect, Re is - (CRb2) n -heterocycloalkyl optionally substituted. In one aspect, Rf and Rg are each hydrogen. In a further aspect, Rf and Rg are each optionally substituted C? -C? 2 alkyl. In another aspect, Rf and Rg are each optionally substituted C2-C12 alkenyl. In a further aspect, Rf and Rg are each optionally substituted C2-C12 alkynyl. In a further aspect, Rf and Rg are each - (CRb2) optionally substituted naril. In a further aspect, Rf and Rg are each (CRb2) optionally substituted n-cycloalkyl. In another aspect, Rf and Rg are each - (CRb2) n -heterocycloalkyl optionally substituted. In a further aspect, Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second heterogroup which is O. In another aspect, Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second heterogroup which is NRC. In another aspect, Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second heterogroup which is S. In one aspect, Rf and Rg together may form an unsubstituted heterocyclic ring, which may contain a second heterogroup. In another aspect, the optionally substituted heterocyclic ring may be substituted with 1 substituent selected from the group consisting of optionally substituted C 1 -C 4 alkyl, -0Rb, oxo, cyano, -CF 3, optionally substituted phenyl, and -C (0) ORh. In a further aspect, the optionally substituted heterocyclic ring can be substituted with 2 substituents selected from the group consisting of optionally substituted C-C4 alkyl, -ORb, oxo, cyano, -CF3, optionally substituted phenyl, and -C (0) ORh. In another aspect, the optionally substituted heterocyclic ring may be substituted with 3 substituents selected from the group consisting of optionally substituted C 1 -C 4 alkyl, -OR b, oxo, cyano, -CF 3, optionally substituted phenyl, and -C (0) OR h. In a further aspect, the optionally substituted heterocyclic ring can be substituted with 4 substituents selected from the group consisting of optionally substituted C? -C alkyl, -ORb, oxo, cyano, -CF3, optionally substituted phenyl, and -C (0) ORh . In a further aspect, Rh is optionally substituted C 1 -C 1 alkyl. In another aspect, Rh • is optionally substituted C2-C12 alkenyl. In a further aspect, Rh is optionally substituted C 2 -C 2 alkynyl. In another aspect, Rh is - (CRb2) optionally substituted naril. In a further aspect, Rh is - (CRb2) n-cycloalkyl optionally substituted. In another aspect, Rh is - (CRb2) nheterocycloalkyl. In another aspect, R5 is selected from the group consisting of -OH, -OC (0) Re, -OC (0) ORh, -F, and -NHC (0) Re. In a further aspect, R5 is optionally substituted -O-alkyl Ci-Ce. In another aspect, R5 is -OC (0) Re. In a further aspect, R5 is -OC (0) ORh. In another aspect, R5 is -F. In another aspect, R5 is -NHC (0) Re. In a further aspect, R5 is -NHS (= 0) Re. In another aspect, R5 is -NHS (= 0) 2Re. In a further aspect, R5 is -NHC (= S) NH (Rh). In another aspect, R5 is -NHC (O) NH (Rh). In a further aspect, X is selected from the group consisting of -P03H2, -P (O) [-OCR2OC (O) Ry] 2, -P (0) [-OCRz2OC (0) ORy] 2, -P (O ) [-N (H) CRZ2C (O) ORy] 2, -P (0) [-N (H) CRz2C (0) 0Ry] [-OR11], and -P (0) [-0CH (V) CH2CH20 -], wherein V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl. In one aspect, G is selected from the group consisting of -O- and -CH2-; D is selected from the group consisting of a bond and -CH2-; A is selected from the group consisting of -NH-, -NMe-, -0-, and -S-; B is selected from the group consisting of -CH-, -CMe-, and -N-; R1 and R2 are each independently selected from the group consisting of halogen, -C1-C4 alkyl, -CF3, and cyano; R 4 is selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, cyano and CF 3; R5 is selected from the group consisting of -OH, -CO (0) Re, -OC (0) ORh, -F, and -NHC (0) Re; R3 is selected from the group consisting of halogen, optionally substituted C6-C6 alkyl, -CF3, cyano, -C (0) NRfRg, - (CRa2) optionally substituted naril, -S02NRfRg, and -S02Re; and X is selected from the group consisting of -P03H2, -P (O) [-OCRz2OC (O) Ry] 2, -P (O) [-OCRz2OC (O) ORy] 2, -P (O) [-N (H) CRZ2C (O) ORy] 2, -P (O) [-N (H) CRz2C (0) ORy] [-OR11] and -P (O) [-OCH (V) CH2CH20-], wherein V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl. In another aspect, G is selected from the group consisting of -O- and -CH2; D is selected from the group consisting of a bond and -CH2-; A is selected from the group consisting of -NH-, -NMe-, -O-, and -S-; B is selected from the group consisting of -CH-, -CMe- and -N-; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl, and cyano; R4 is selected from the group consisting of hydrogen and halogen; R5 is selected from the group consisting of -OH and -OC (0) Re; and R3 is selected from the group consisting of halogen, optionally substituted C?-Cg alkyl, optionally substituted -CH2aryl, optionally substituted -CH (OH) aryl, -C (O) -amido, -S (= 0) 2-amido , wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -S02Re wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, -fluorophenyl, and 4-pyridyl. Still in another aspect, G is -0-; D is a link; A is selected from the group consisting of -NH- and -NMe-; B is selected from the group consisting of -CH- and -CMe-; R1 and R2 are each bromine; R4 is selected from the group consisting of hydrogen and iodine; R5 is -OH; and R3 is isopropyl. In another aspect, G is -0-; D is a link; A is selected from the group consisting of -NH- and -NMe-; B is selected from the group consisting of -CH- and -CMe-; R1 and R2 are each bromine; R4 is selected from the group consisting of hydrogen and iodine; R5 is -OH; R3 is isopropyl, and X is selected from the group consisting of -P03H2, -P (O) [-OCH2OC (0) -t-butyl] 2, -P (O) [-OCH2OC (0) 0-i-propyl ] 2, -P (O) [-N (H) CH (CH3) C (O) OCH2CH3] 2, -P (O) [-N (H) C (CH3) 2C (O) OCH2CH3] 2, P (O) [-N (H) CH (CH3) C (O) OCH2CH3] [3,4-methylenedioxyphenyl], -P (0) [-N (H) C (CH3) 2C (0) 0CH2CH3] [3 , 4-methylenedioxyphenyl], and -P (0) [-OCH (3-chlorophenyl) CH2CH20-]. In a further aspect, G is -0-; D is a link; A is -0-; B is selected from the group consisting of -CH- and -CMe-; R1 and R2 are each bromine; R4 is selected from the group consisting of hydrogen and iodine; R5 is -OH; and R3 is isopropyl. In another aspect, G is -0-; D is a link; A is -0-; B is selected from the group consisting of -CH- and -CMe-; R1 and R2 are each bromine; R4 is selected from the group consisting of hydrogen and iodine; R5 is -OH; R3 is isopropyl, X is selected from the group consisting of -P03H2, -P (O) [-OCH2OC (O) -t-butyl] 2, -P (0) [-OCH2OC (0) 0-i-propyl] 2, -P (0) [-N (H) CH (CH3) C (0) OCH2CH3] 2, -P (0) [-N (H) C (CH3) 2C (0) 0CH2CH3] 2, -P (0) [- N (H) CH (CH3) C (0) OCH2CH3] [3,4-methylenedioxyphenyl], -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] [3 , 4-methylenedioxyphenyl], and -P (0) [-OCH (3-chlorophenyl) CH2CH20-]. In a further aspect, X is -P03H. Each of the individual spaces of the compounds of Formula II which can be generated by making all the permutations above can be specifically established for inclusion or can be specifically excluded from the present invention. In another aspect, the invention relates to compounds of Formula III, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of prodrugs as represented by formula III: wherein: G is selected from the group consisting of -0-, ~ S-, - S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF-, -C (0) -, -CH (OH) -, -NH-, and -N (C 1 -C 4 alkyl) -; T is selected from the group consisting of - (CRa2) k-, -CRb = CRb- (CRa2) n, - (CRa2) n-CRb = CRb-, - - (CRa2) -CRb = CRb- (CR2) - , 0 (CRb2) (CRa2) n-, -S (CRb2) (CRa2) n-, -N (Rc) (CRb2) (CRa2) n-, N (Rb) C (0) (CRa2) n-, - (CRa2) nCH (NRbRc) -, -C (O) (CRa2) m-, (CRa2) mC (0) -, - (CRa2) C (0) (CRa2) n-, - (CRa2) nCO) (CRa2) -, and -C (0) NH (CRb2) (CRa2) p-; k is an integer from 0-4, m is an integer from 0-3, n is an integer from 0-2, p is an integer from 0-1; Each Ra is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl, halogen, -OH, -O-C 1 -C 4 alkyl optionally substituted, -OCF 3, -S-optionally substituted C 1 -C 4 alkyl, -NRbRc optionally substituted C2-C alkenyl, and optionally substituted C2-C4 alkynyl; with the proviso that when a Ra is linked to C through an atom O, S, or N, then the other Ra links to the same C that is a hydrogen, or is bonded by means of a carbon atom; Each Rb is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 4 alkyl; . Each Rc is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 4 alkyl, -C (0) -C 1 -C 4 alkyl optionally substituted, and ~ C (0) H; R1 and R2 are each independently selected from the group consisting of halogen, optionally substituted C1-C4 alkyl, -S-optionally substituted C-C3 alkyl, optionally substituted C2-C alkenyl, optionally substituted C2-C4 alkynyl, -CF3, -0CF3, -O-C-C3 alkyl optionally substituted, and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, C2-C? Alkynyl? optionally substituted, - (CRa2) optionally substituted maryl, (CRa) optionally substituted cycloalkyl, - (CRa2) optionally substituted -heterocycloalkyl, -0R, SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NHfRg, -C (0) NRfRg, -C (0) ORh, -C (0) Re, -N ( Rb) C (0) Re, -N (Rb) C (0) NRfRg, -N (Rb) S (= 0) 2Re, N (Rb) S (= 0) 2NRfRg, and -NRfRg; Each Rd is selected from the group consisting of optionally substituted C 2 -C 12 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl, optionally substituted - (CR 2) naryl, - (CR 2) n cycloalkyl optionally substituted, - (CRb2) n-heterocycloalkyl optionally substituted, and C (0) NRfRg; Each Re is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C2 alkynyl, optionally substituted (CRa2), optionally substituted (CRb2) nCycloalkyl, and (CRa2) ) optionally substituted n-heterocycloalkyl; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C? -C? 2 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C? 2 alkynyl, optionally substituted - (CRb2) naril, - (CRb2) optionally substituted cycloalkyl, and optionally substituted - (CRb2) nheterocycloalkyl, or Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second hetero group selected from the group consisting of O, NRC, and S, in wherein the optionally substituted heterocyclic ring can be substituted with 0-4 substituents selected from the group consisting of optionally substituted Cx-C4 alkyl, -OR, oxo, cyano, -CF3, optionally substituted phenyl, and -C (0) ORh; Each Rh is selected from the group consisting of optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, optionally substituted C2-C? 2 alkynyl, - (CRb2) optionally substituted naril, - (CRb2) n-cycloalkyl optionally substituted, and - (CRb2) nheterocycloalkyl optionally substituted; R5 is selected from the group consisting of -OH, optionally substituted C6-C6alkyl, -OC (0) Re, -OC (0) ORh, -F, -NHC (0) Re, -NHS (= 0) Re , -NHS (= 0) 2Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); R7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, -O-C1-C4 alkyl, -SH and -S-C1-C4 alkylX is P (0) YR ^ Y'R11; Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are -0-, R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRZ2, -NRZ-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2-0- C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; when Y and Y 'are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, ~ [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy, and cycloalkylene-COORy; when Y is -0- and Y 'is NRV, then R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRz2, -NR2-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2 -0-C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rz) 2C00Ry, - [C (R2) 2] qC (0) SRy and -cycloalkylene-C00Ry; or when Y and Y 'are independently selected from -0- and -NRV-, then together R11 and R11 are -alkyl-S-S-alkyl to form a cyclic group, or together R11 and R11 are the group: wherein: V, W, and W 'are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and 1-alkynyl optionally substituted; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group to the beta and gamma bound position to the Y to the phosphorus; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and W are connected by means of 3-5 additional atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W 'are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or heteroaryl replaced; Z is selected from the group consisting of -CHR20H, CHRzOC (0) Ry, -CHRzOC (S) Ry, -CHRzOC (S) ORy, -CHR20C (O) SRy, CHRzOC02Ry, -0RZ, -SRZ, -CHRZN3, - CH2aryl, -CH (aryl) OH, -CH (CH = CRz2) OH, -CH (C = CR2) OH, -R2, -NRZ2, -OCORy, -OC02Ry, -SCORy, -SC02Ry, -NHC0R2, -NHC02Ry , -CH2NHaril, - (CH2) q-0R2, and - (CH2) q-SR2; q is an integer of 2 or 3; Each Rz is selected from the group consisting of Ry and -H; Each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; Each Rx is independently selected from the group consisting of -H, and alkyl, or together W and W form a cyclic alkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the proviso that: a) when G is -O-, T is -NH-CH2-, R1 and R2 are each chlorine, R3 is iso-propyl, R4 is hydrogen, R7 is fluorine, and R5 is -OH , then X is not P (0) (OH) 2, P (O) (OH) (OCH3) or P (O) (OCH3) 2; b) V, Z, W, and W 'are not all -H; and c) when Z is -R2, then at least one of V, W, and W 'is not -H, alkyl, aralkyl, or heterocycloalkyl. In a further aspect, the invention relates to compounds of Formula III, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of prodrugs as represented by formula III: wherein: G is selected from the group consisting of -0-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF-, -C (0) -, -CH (OH) -, -NH-, and -N (C? -C4 alkyl) -; T is selected from the group consisting of - (CRa2) k-, -CRb = CRb- (CRa2) n, - (CRa2) n-CRb = CRb-, - (CRa2) -CRb = CRb- (CR2) -, 0 (CRb2) (CRa2) n-, -S (CRb2) (CRa2) n-, -N (Rc) (CRb2) (CRa2) n ~, N (Rb) C (0) (CRa2) n-, - (CRa2) nCH (NRRc) -, -C (O) (CRa2) m-, (CRa2) mC (0) -, - (CRa2) C (0) (CRa2) n-, - (CRa2) nC (0 ) (CRa2) -, and -C (0) NH (CRb2) (Ra2) p-; k is an integer from 0-4; m is an integer from 0-3; n is an integer from 0-2; p is an integer from 0-1; Each Ra is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl, halogen, -OH, -O-optionally substituted C 1 -C 4 alkyl, -OCF 3, -S-optionally substituted C 1 -C 4 alkyl, -NRbRc optionally substituted C2-C alkenyl, and optionally substituted C2-C4 alkynyl; with the proviso that when a Ra is linked to C through an atom O, S, or N, then the other Ra links to the same C that is a hydrogen, or is bonded by means of a carbon atom; Each Rb is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 4 alkyl; Each Rc is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl, -C (O) - optionally substituted Ci-C 4 alkyl, and -C (0) H; R1 and R2 are each independently selected from the group consisting of halogen, optionally substituted C1-C4 alkyl, -S-optionally substituted Cx-C3 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, -CF3, - OCF3, -O-C-C3 alkyl optionally substituted, and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, C2-C? Alkynyl? optionally substituted, - (CRa2) optionally substituted maryl, - (CRa2) optionally substituted cycloalkyl, (CRa2) mheterocycloalkyl optionally substituted, -0Rd, SRd, -S (= 0) Re, -S (= 0) 2Re, -S ( = 0) 2NRfRg, -C (0) NRfRg, -C (0) ORh, -C (0) Re, -N (Rb) C (0) Re, -N (Rb) C (0) NRfRg, -N (Rb) S (= 0) 2Re, N (Rb) S (= 0) 2NRfRg, and -NRfRg; Each Rd is selected from the group consisting of optionally substituted C? -C? 2 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted (CRb2) naryl, - (CRb2) n optionally substituted cycloalkyl, ( CRb2) optionally substituted n-heterocycloalkyl, and -C (0) NRfRg; Each Re is optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted (CR2) naryl, optionally substituted - (CRb2) n-cycloalkyl, and - (CRb2) optionally substituted n-heterocyclealkyl; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C2-C2 alkenyl, C2-C alkynyl? optionally substituted, - (CRb2) optionally substituted naril, - (CRb2) n-optionally substituted cycloalkyl, and - (CRb2) n-heterocycloalkyl optionally substituted, or Rf and Rg together can form an optionally substituted heterocyclic ring, which may contain a second heterogroup selected from the group of 0, NRC, and S, wherein the optionally substituted heterocyclic ring can be substituted with 0-4 substituents selected from the group consisting of optionally substituted C? -C alkyl, -0Rb, oxo, cyano, -CF3, optionally substituted phenyl , and -C (0) 0Rh; Each Rh is selected from the group consisting of optionally substituted C? -Ca2 alkyl, optionally substituted C2-C? 2 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted (CRb2) naryl, - (CRb2) n optionally substituted cycloalkyl, and (CRb2) nheterocycloalkyl; R5 is selected from the group consisting of -OH, optionally substituted C6-C6alkyl, -OC (0) Re, -OC (0) ORh, -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2 Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); R7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, -O-C C-C4 alkyl, -SH and -S-C?-C4 alkyl; X is P (0) YR ^ Y'R11; Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are -0-, R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, heterocycloalkyl optionally. substituted, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (R2) 20C (0) NR22, -NRZ-C (0) -Ry, -C (Rz) 2- 0C (0) Ry, -C (Rz) 2-0-C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and - alkyl-SSS-alkylhydroxy; When Y and Y 'are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy, and cycloalkylene-C00Ry; When Y is -0- and Y 'is NRV, then R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRZ2, -NRZ-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2 -0-C (0) 0Ry, -C (R2) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NR- is independently selected from the group consisting of -H, - [C (R2) 2] q-C00Ry, - C (Rx) 2COORy, - [C (Rz) 2] qC (0) SRy , and -cycloalkylene-COORy; or when Y and Y 'are independently selected from -0- and then R11 and R11 together are -alkyl-S-S-alkyl to form a cyclic group, or together R11 and R11 are the group: wherein: V, W, and W 'are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and 1-alkynyl optionally substituted; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group to the beta and gamma bound position to the Y to the phosphorus; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and W are connected by means of 3-5 additional atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W 'are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or heteroaryl replaced; Z is selected from the group consisting of -CHRzOH, CHR20C (0) Ry, -CHR2OC (S) Ry, -CHRz0C (S) 0Ry, -CHROC (O) SRy, CHRz0C02Ry, -ORz, -SRZ, -CHRZN3, - CH2aryl, -CH (aryl) OH, CH (CH = CRz2) OH, -CH (C = CR2) OH, -R2, -NRZ2, -0C0Ry, -OC02Ry, -SCORy, - SC02Ry, -NHC0R2, -NHC02Ry, -CH2NHaril, - (CH2) q-ORz, and - (CH2) q-SRz; q is an integer of 2 or 3; Each Ra is selected from the group consisting of Ry and -H; Each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; Each Rx is independently selected from the group consisting of -H, and alkyl, or together Rx or Rx form a cyclic alkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the proviso that: a) when G is selected from the group consisting of -O-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -C (O ) - and -NRb-; T is -AB- wherein A is selected from the group consisting of -R-, -O-, -CH2- and -S- and B is selected from the group consisting of a bond and substituted or unsubstituted C?-C3 alkyl; R3 is selected from the group consisting of halogen, trifluoromethyl, substituted or unsubstituted C3-C6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aryloxy, substituted amide, sulfone, sulfonamide and C3-C7 cycloalkyl, wherein the aryl, heteroaryl or cycloalkyl rings are bonded or fused to the aromatic; R 4 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R1 and R2 are each independently selected from the group consisting of halogen, substituted or unsubstituted C1-C4 alkyl, and substituted or unsubstituted C3-C5 cycloalkyl; R7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, -O-C1-C4 alkyl, -SH and -S-C1-C4 alkyl; and R5 is selected from the group consisting of hydroxyl, optionally substituted Ci-C3alkyl, and -OC (0) Re; then X is not -P (O) (0H) 2; b) V, Z, W, and W 'are not all -H; and c) when Z is -Rz, then at least one of V, W, and W 'is not -H, alkyl, aralkyl, or heterocycloalkyl. In another aspect, when G is -O-, T is -NH-CH2-, R1 and R2 are each chlorine, R3 is iso-propyl, R7 is fluoro and R4 is -OH, then R4 is not hydrogen. In a further aspect, when G is selected from the group consisting of oxygen, sulfur, sulfoxide, sulfonyl, -CH2-, -C (O) - and -NRb-; T is -A-B- wherein A is selected from the group consisting of -NRb-, -O-, -CH2- and -S- and B is selected from the group consisting of a bond and substituted or unsubstituted C1-C3 alkyl; R3 is selected from the group consisting of halogen, trifluoromethyl, substituted or unsubstituted C6-C6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aryloxy, substituted amide, sulfone, sulfonamide and C3-C7 cycloalkyl, wherein the aryl, heteroaryl or cycloalkyl rings are bonded or fused to the aromatic; R4 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted Ci-Cß alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R1 and R2 are each independently selected from the group consisting of halogen, substituted or unsubstituted C1-C4 alkyl, and substituted and unsubstituted C3-C5 cycloalkyl; and R7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, -O-C1-C4 alkyl, -SH and -S-C1-C4 alkyl; then R5 is not hydroxyl, optionally substituted C6-C6alkyl, or -0C (0) Re. In one aspect, G is selected from the group consisting of -O- and -CH2-. In a further aspect, G is -O-. In another aspect, G is -S-. In a further aspect, G is -S (= 0) -. In another aspect, G is -S (= 0) 2-. In a further aspect, G is -CH2-. In another aspect, G is -CF2-. In a further aspect, G is -CHF-. In another aspect, G is -C (O) -. In another aspect, G is -CH (OH) -. In a further aspect, G is -NH-. In another aspect, G is -N (C1-C4 alkyl) -. In another aspect, T is selected from the group consisting of - (CRa2) n-, -0 (CRb2) (CRa2) p-, -N (Rc) (CRb2) (CRa2) p-, S (CRb2) (CRa2) ) p-, -NRb (C0) -, and -CH2CH (NRcR) -. In an additional aspect, T is - (CRa2) -. In another aspect, T is -CRb = CRb- (CRa2) n. In a further aspect, T is - (CRa2) n-CRb = CR-. In another aspect, T is - (CRa2) -CRb = CRb- (CRa2) -. In a further aspect, T is -O (CRb2) (CRa2) n-. In another aspect, T is -S (CRb2) (CRa2) n-- In a further aspect, T is N (RC) (CRb2) (CRa2) n-. In another aspect, T is -N (Rb) C (0) (CRa2) n - In a further aspect, T is - (CRa2) nCH (NRbRc) -. In another aspect, T is -C (O) (CRa2) m_- In a further aspect, T is - (CRa2) mC (0) -. In another aspect, T is - (CRa2) C (O) (CRa2) n-. In a further aspect, T is - (CRa2) nC (O) (CRa2) -. In still another aspect, T is -C (O) NH (CRb2) (CRa2) p-. In one aspect, k is 0. In a further aspect, k is -1. In a further aspect, k is 2. In a further aspect, k is 3. Still in another aspect, k is 4. In one aspect m is 0. In a further aspect, m is 1. In a further aspect, m is 2. In a further aspect, m is 3. In one aspect n is 0. In a further aspect, n is 1. In a further aspect, n is 2. In one aspect, p is 0. In another aspect, p is 1. In one aspect, each Ra is hydrogen with the proviso that when a Ra is bonded to C through an O, S, or N atom, then the other Ra binds to the same C that is a hydrogen, or binds by means of a carbon atom. In another aspect, each Ra is optionally substituted C 1 -C 4 alkyl with the proviso that when one Ra is linked to C through an O, S, or N atom, then the other Ra links to the same C which is a hydrogen, or it is bonded by means of a carbon atom.

In a further aspect, each Ra is halogen with the proviso that when a Ra is linked to C through a 0, S, or N atom, then the other Ra binds to the same C which is a hydrogen, or is bound by half of a carbon atom. In another aspect, each Ra is -OH with the proviso that when a Ra is linked to C through an atom 0, S, or N, then the other Ra links to the same C that is a hydrogen, or is bound by half of a carbon atom. In a further aspect, each Ra is -O-C1-C4 alkyl optionally substituted with the proviso that when one Ra is linked to C through a 0, S, or N atom, then the other Ra binds to the same C as It is a hydrogen, or it is bonded by means of a carbon atom. In another aspect, each Ra is -0CF3 with the proviso that when a Ra is linked to C through an atom O, S, or N, then the other Ra links to the same C that is a hydrogen, or is bound by half of a carbon atom. In a further aspect, each Ra is -S-C1-C4 alkyl optionally substituted with the proviso that when a Ra is linked to C through a 0, S, or N atom, then the other Ra binds to the same C as it is a hydrogen, or it is bonded by means of a carbon atom. In another aspect, each Ra is -NRbRc with the proviso that when one Ra is linked to C through a 0, S, or N atom, then the other R links to the same C that is a hydrogen, or is bound by half of a carbon atom. In a further aspect, each Ra is optionally substituted C2-C4 alkenyl with the proviso that when one Ra binds to C through a 0, S, or N atom, then the other Ra binds to the same C which is a hydrogen , or it is bonded by means of a carbon atom. In another aspect, each Ra is optionally substituted C2-C4 alkynyl with the proviso that when a Ra is linked to C through a 0, S, or N atom, then the other Ra binds to the same C which is a hydrogen, or it is bonded by means of a carbon atom. In one aspect, Rb is hydrogen. In a further aspect, R b is optionally substituted C 1 -C 4 alkyl. In one aspect, Rc is hydrogen. In another aspect, Rc is optionally substituted C1-C4 alkyl. In a further aspect, Rc is -C (0) -alkyl C? -C optionally substituted. In still another aspect, Rc is -C (0) H. In a further aspect, R 1 and R 2 are the same and are selected from the group consisting of halogen, C 1 -C 4 alkyl, -CF 3, and cyano. In still another aspect, R1 and R2 are different and are selected from the group consisting of halogen, C1-C4 alkyl, -CF3, and cyano. In a further aspect, R1 and R2 are each halogen. In another aspect, R1 and R2 are each optionally substituted C1-C4 alkyl. In a further aspect, R1 and R2 are each -S-optionally substituted C1-C3 alkyl. In another aspect, R1 and R2 are each optionally substituted C2-C4 alkenyl. In a further aspect, R1 and R2 are each optionally substituted C2-C alkynyl. In another aspect, R1 and R2 are each -CF3. In a further aspect, R1 and R2 are each -OCF3. In another aspect, R1 and R2 are each -O-C1-C3 alkyl optionally substituted. In a further aspect, R1 and R2 are each cyano. In still another aspect, R3 and R4 are each hydrogen. In another aspect, R3 and R4 are each halogen. In a further aspect, R3 and R4 are each -CF3. In another aspect, R3 and R4 are each -OCF3. In a further aspect, R3 and R4 are each cyano. In another aspect, R3 and R4 are each optionally substituted C1-C12 alkyl. In a further aspect, R3 and R4 are each optionally substituted C2-C2 alkenyl. In another aspect, R3 and R4 are each optionally substituted C2-C2 alkynyl. In a further aspect, R3 and R4 are each - (CRa2) optionally substituted maryl. In another aspect, R3 and R4 are each - (CRa2) optionally substituted cycloalkyl. In a further aspect, R3 and R4 are each - (CRa2) optionally substituted m-heterocycloalkyl. In another aspect, R3 and R4 are each -ORd. In another aspect, R3 and R4 are each -SRd. In a further aspect, R3 and R4 are each -S (= 0) Re. In another aspect, R3 and R4 are each -S (= 0) 2Re- In a further aspect, R3 and R4 are each -S (= 0) 2NRfRg. In another aspect, R3 and R4 are each -C (0) NRfRg. In a further aspect, R3 and R4 are each -C (0) 0Rh. In another aspect, R3 and R4 are each -C (0) Re. In a further aspect, R3 and R4 are each -N (Rb) C (0) Rc. In another aspect, R3 and R4 are each -N (Rb) C (O) NRfRg. In a further aspect, R3 and R4 are each -N (Rb) S (= 0) 2Re. In another aspect, R3 and R4 are each -N (Rb) S (= 0) 2NRfRg. In a further aspect, R3 and R4 are each -NRfRg. In another aspect, R4 is selected from the group consisting of hydrogen, halogen, C? -C alkyl, cyano, and CF3. In a further aspect, R3 is selected from the group consisting of halogen, optionally substituted C6-C6 alkyl, -CF3, cyano, -C (0) NRfRg, - (CRa2) optionally substituted naril, -S02NRfRg, and -S02Re. In another aspect, each Rd is optionally substituted C? -C? 2 alkyl. In a further aspect, each Rd is optionally substituted C2-C12 alkenyl. In another aspect, each Rd is optionally substituted C 2 -C 2 alkynyl. In a further aspect, each Rd is optionally substituted (CRb2) naril. In another aspect, each Rd is - (CRb2) n-cycloalkyl optionally substituted. In a further aspect, each Rd is optionally substituted (CRb2) nheterocycloalkyl. In another aspect, each Rd is -C (0) NRfRg. In a further aspect, Re is optionally substituted C? -C? 2 alkyl. In another aspect, Re is optionally substituted C2_C? 2 alkenyl. In a further aspect, Re is optionally substituted C 2 -C 2 alkynyl. In another aspect, Re is - (CRa2) optionally substituted narile. In a further aspect, Re is - (CRa2) nCycloalkyl optionally substituted. In another aspect, Re is - (CRa2) n -heterocycloalkyl optionally substituted. In one aspect, Rf and Rg are each hydrogen. In a further aspect, Rf and Rg are each optionally substituted C1-C12 alkyl. In another aspect, R f and R g are each optionally substituted C 2 -C 2 alkenyl. In a further aspect, Rf and Rg are each optionally substituted C2-C12 alkynyl. In a further aspect, Rf and Rg are each - (CRb2) optionally substituted naril. In a further aspect, Rf and Rg are each - (CRb2) n-cycloalkyl optionally substituted. In another aspect, Rf and Rg are each - (CRb2) n -heterocycloalkyl optionally substituted. In a further aspect, Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second heterogroup which is O. In another aspect, Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second heterogroup which is NRC. In another aspect, Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second heterogroup which is S. In one aspect, Rf and Rg together may form an unsubstituted heterocyclic ring, which may contain a second heterogroup. In another aspect, the optionally substituted heterocyclic ring may be substituted with 1 substituent selected from the group consisting of optionally substituted C 1 -C 4 alkyl, -0Rb, oxo, cyano, -FC 3, optionally substituted phenyl, and -C (0) ORh. In a further aspect, the optionally substituted heterocyclic ring can be substituted with 2 substituents selected from the group consisting of optionally substituted C1-C alkyl, -0Rb, oxo, cyano, -CF3, optionally substituted phenyl, and -C (0) ORh. In another aspect, the optionally substituted heterocyclic ring can be substituted with 3 substituents selected from the group consisting of optionally substituted C 1 -C 4 alkyl, -OR b, oxo, cyano, -CF 3, optionally substituted phenyl, and -C (0) OR h. In a further aspect, the optionally substituted heterocyclic ring can be substituted with 4 substituents selected from the group consisting of optionally substituted C 1 -C 4 alkyl, -ORb, oxo, cyano, -CF3, optionally substituted phenyl, and -C (0) ORh. In a further aspect, Rh is optionally substituted C 1 -C 1 alkyl. In another aspect, Rh is optionally substituted C 2 -C 2 alkenyl. In a further aspect, Rh is optionally substituted C 2 -C 2 alkynyl. In another aspect, Rh is - (CRb2) optionally substituted naril. In a further aspect, Rh is - (CRb2) nCycloalkyl optionally substituted. In another aspect, it is optionally substituted - (CRb2) nheterocycloalkyl.

In one aspect, R5 is selected from the group consisting of -OH, -OC (0) Re, -OC (0) ORh, -F, and -NHC (0) Re. In a further aspect, R5 is -O-alkyl Ci-C? optionally substituted. In another aspect, R5 is -OC (0) Re. In a further aspect, R5 is -OC (0) ORh. In another aspect, R5 is -F. In another aspect, R5 is -NHC (0) Re. In a further aspect, R5 is -NHS (= 0) Re. In another aspect, R5 is -NHS (= 0) 2Re. In a further aspect, R5 is -NHC (= S) NH (Rh). In another aspect, R5 is -NHC (0) NH (Rh). In one aspect, X is selected from the group consisting of -P03H2, -P (0) [-OCRz2OC (0) Ry] 2, -P (0) [-0CRz20C (0) 0Ry] 2, -P (0) [~ N (H) CRz2C (0) ORy] 2, -P (0) [-N (H) CRz2C (0) 0Ry] [-0R11], and -P (0) [- OCH (V) CH2CH2O- ], wherein V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl. In another aspect, R7 is selected from the group consisting of hydrogen, fluorine, chlorine, amino, hydroxyl, and -0-CH3. In one aspect, G is selected from the group consisting of-0- and -HC2-; T is selected from the group consisting of - (CRa2) n-, -0 (CRb2) (CRa2) p-, -N (RC) (CRb2) (CRa2) p-, -S (CRb2) (CRa2) p- , -NRb (C0) -, and -CH2CH (NRcR) -; R1 and R2 are each independently selected from the group consisting of halogen, C1-C4 alkyl, -CF3, and cyano; R 4 is selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, cyano and CF 3; R5 is selected from the group consisting of -OH, -0C (0) Re, -OC (0) ORh, -F, and -NHC (0) Re; R3 is selected from the group consisting of halogen, optionally substituted Ci-C3 alkyl, -CF3, cyano, -C (0) NRfRg, - (CRa2) optionally substituted naril, -S02NRfRg, and -S02Re; R7 is selected from the group consisting of hydrogen, fluorine, chlorine, amino, hydroxyl, and -0-CH3; and X is selected from the group consisting of -P03H2, -P (0) [-OCRz2OC (0) Ry] 2, -P (0) [- 0CRz20C (0) 0Ry] 2, -P (0) [-N (H) CRZ2C (0) 0Ry] 2, -P (0) [-N (H) CR22C (0) 0Ry] [-0R11] and -P (0) [-0CH (V) CH2CH20-], where V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl. In a further aspect, when G is -0-, T is -CH2-, R1 and R2 are chlorine, R3 is iso-propyl, R7 is fluorine, and R5 is -OH, then R4 is not hydrogen. In another aspect, when G is selected from the group consisting of -0- and -CH2-; T is -AB- wherein A is selected from the group consisting of -NRb-, -0-, -CH2- and -S- and B is selected from the group consisting of a bond and substituted or unsubstituted C? -C3 alkyl; R3 is selected from the group consisting of halogen, trifluoromethyl, substituted or unsubstituted Ci-Cß alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aryloxy, substituted amide, sulfone, sulfonamide and C3-C7 cycloalkyl, wherein the aryl, heteroaryl or cycloalkyl rings are linked or fused to the aromatic; R 4 is selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted C 1 -C 4 alkyl; R1 and R2 are each independently selected from the group consisting of halogen and substituted or unsubstituted C1-C4 alkyl; and R7 is selected from the group consisting of hydrogen, fluorine, chlorine, amino, hydroxyl, and -0-CH3; then R5 is not hydroxy, optionally substituted C6-C6alkyl, or -OC (0) Re. In a further aspect, T is -N (H) C (0) -; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl, and cyano; R4 is selected from the group consisting of hydrogen and iodine; R5 is selected from the group consisting of -OH and -0C (0) Re; R3 is selected from the group consisting of iodine, bromine, optionally substituted Ci-Ce alkyl, optionally substituted -CH2aryl, -CH (OH) optionally substituted aryl, -C (O) -amido, -S (= 0) 2-amido , wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -S02Re wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, -fluorophenyl, and 4-pyridyl; and R7 is selected from the group consisting of hydrogen and fluoro. In a further aspect, T is -N (H) C (0) -; G is -0-; R1 and R2 are each chlorine; R4 is hydrogen; R5 is -OH; R3 is isopropyl; and R7 is fluoro. In a further aspect, T is -N (H) C (0) -; G is -0-; R1 and R2 are each chlorine; R4 is hydrogen; R5 is -OH; R3 is -isopropyl; R7 is fluoro; X is selected from the group consisting of -P03H2, -P (O) [-OCH2OC (O) -t-butyl] 2, -P (O) [-OCH2OC (0) Oi-propyl] 2, -P (0 ) [-N (H) CH (CH3) C (0) OCH2CH3] 2, -P (0) [-N (H) C (CH3) 2C (0) 0CH2CH3] 2 -P (0) [-N ( H) CH (CH3) C (0) 0CH2CH3] [3,4-methylenedioxyphenyl], -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] [3,4-methylenedioxyphenyl], and -P (0) [-0CH (3-chlorophenyl) CH2CH20-]. In another aspect, T is -OCH2-; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl, and cyano; R4 is selected from the group consisting of hydrogen and iodine; R5 is selected from the group consisting of -OH, and -0C (0) Re; R3 is selected from the group consisting of iodine, bromine, optionally substituted Ci-Ce alkyl, optionally substituted -CH2aryl, optionally substituted -CH (OH) aryl, -C (0) -amido, -S (= 0) 2-amido , wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -S02Re wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, -fluorophenyl, and 4-pyridyl; and R7 is selected from the group consisting of hydrogen and fluoro. In another aspect, T is -0CH2-; G is -0-; R1 and R2 are each chlorine; R4 is hydrogen; R5 is -OH; R3 is iso-propyl; and R7 is fluoro. In another aspect, T is -OCH2-; G is -0-; R1 and R2 are each chlorine; R4 is hydrogen; R5 is -OH; R3 is iso-propyl; R7 is fluoro; and X is selected from the group consisting of -P03H2, -P (0) [-OCH2OC (0) -t-butyl] 2, -P (0) [-OCH2OC (0) O-i-propyl] 2, P (0) [-N (H) CH (CH3) C (0) OCH2CH3] 2, -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] 2, -P (0) [-N (H) CH (CH3) C (0) OCH2CH3] [3,4-methylenedioxyphenyl], P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] [3,4-methylenedioxyphenyl] ], and P (0) [-OCH (3-chlorophenyl) CH2CH20-]. In a further aspect, T is -CH2-; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl, and cyano; R4 is selected from the group consisting of hydrogen and iodine; R5 is selected from the group consisting of -OH, and -0C (0) Re; R 3 is selected from the group consisting of iodine, bromine, optionally substituted C 1 -C 7 alkyl, optionally substituted -CH 2 aryl, optionally substituted -CH (OH) aryl, -C (0) -amido, -S (= 0) 2-amido wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -S02Re wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, 4- fluorophenyl, and 4-pyridyl; and R7 is selected from the group consisting of hydrogen and fluoro. In a further aspect, T is -CH2-; G is -0-; R1 and R2 are each chlorine; R4 is hydrogen; R5 is -OH; R3 is i-propyl; and R7 is fluoro. In a further aspect, T is -CH2-; G is -0-; R1 and R2 are each chlorine; R4 is hydrogen; R5 is -OH; R3 is i-propyl; R7 is fluoro; and X is selected from the group consisting of -P03H2, -P (0) [-OCH2OC (0) -t-butyl] 2, -P (0) [-0CH20C (0) 0-i-propyl] 2, - P (0) [-N (H) CH (CH3) C (0) OCH2CH3] 2, -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] 2, -P (0) [-N (H) CH (CH3) C (0) OCH2CH3] [3,4-methylenedioxyphenyl], -P (0) [-N (H) C (CH3) 2C (0) 0CH2CH3] [3, 4- ethylenedioxyphenyl], and -P (0) [-0CH (3-chlorophenyl) CH2CH20-]. In a further aspect, T is -CH2CH2-; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl, and cyano; R4 is selected from the group consisting of hydrogen and iodine; R5 is selected from the group consisting of -OH and -0C (0) Re; R 3 is selected from the group consisting of iodine, bromine, optionally substituted C 1 -C 6 alkyl, optionally substituted -CH 2 aryl, optionally substituted -CH (OH) aryl, -C (0) -amido, -S (= 0) 2- amido, wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -S02Re wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, and 4-pyridyl; and R7 is selected from the group consisting of hydrogen and fluoro. In another aspect, T is -CH2CH2-; G is -0-; R1 and R2 are each chlorine; R4 is hydrogen; R5 is -OH; R3 is iso-propyl; and R7 is fluoro. In another aspect, T is -CH2CH-; G is -0-; R1 and R are each chlorine; R4 is hydrogen; R5 is -OH; R3 is iso-propyl; R7 is fluoro; and X is selected from the group consisting of -P03H2, -P (0) [-OCH2OC (0) -t-butyl] 2, -P (0) [-OCH2OC (0) 0-i-propyl] 2, ~ P (0) [-N (H) CH (CH3) C (0) 0CH2CH3] 2, -P (0) [-N (H) C (CH3) 2C (0) 0CH2CH3] 2, -P (0) [-N (H) CH (CH3) C (0) OCH2CH3] [3,4-methylenedioxyphenyl], -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] [3,4- ethylenedioxyphenyl], and -P (0) [-0CH (3-chlorophenyl) CH2CH20-]. In another aspect, T is -NHCH2-; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl, and cyano; R4 is selected from the group consisting of hydrogen and iodine; R5 is selected from the group consisting of -OH, and -0C (0) Re; R 3 is selected from the group consisting of iodine, bromine, optionally substituted C 1 -C 7 alkyl, optionally substituted -CH 2 aryl, optionally substituted -CH (OH) aryl, -C (0) -amido, -S (= 0) 2-amido , wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -S02Re wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, -fluorophenyl, and 4-pyridyl; and R7 is selected from the group consisting of hydrogen and fluoro. In still another aspect, T is -NHCH2-; G is -0-; R1 and R2 are each chlorine; R 4 is selected from the group consisting of hydrogen and iodine R 5 is -OH; R3 is iso-propyl; and R7 is fluoro. In another aspect, T is -NHCH2-; G is -0-; R1 and R2 are each bromine; R 4 is selected from the group consisting of hydrogen and iodine R 5 is -OH; R3 is iso-propyl; and R7 is fluoro.

In another aspect, T is -NHCH2-; G is -0-; R1 and R2 are each bromine; R 4 is selected from the group consisting of hydrogen and iodine R 5 is -OH; R3 is iso-propyl; R7 is fluoro; and X is selected from the group consisting of -P03H2, -P (O) [-OCH2OC (O) -t-butyl] 2, -P (O) [-OCH2OC (0) 0-i-propyl] 2, - P (O) [- N (H) CH (CH3) C (O) OCH2CH3] 2, -P (O) [-N (H) C (CH3) 2C (O) OCH2CH3] 2, P (O) [-N (H) CH (CH3) C (O) OCH2CH3] [3, 4-methylenedioxyphenyl], -P (O) [-N (H) C (CH3) 2C (O) OCH2CH3] [ 3, 4-methylenedioxyphenyl], and -P (0) [-OCH (3-chlorophenyl) CH2CH20-]. In a further aspect, X is -P03H. In a further aspect of the invention, the invention relates to compounds of Formula VIII: Formula VIII wherein: G is selected from the group consisting of -O-, -S-, S (= 0) -, -S (= 0) 2-, -Se-, -CH2-, -CF2-, - CHF-, -C (0) -, -CH (OH) -, -CH (CX-C4 alkyl) -, -CH (C1-C4 alkoxy) -, -C (= CH2) -, -NH-, and -N (C1-C4 alkyl) -; T is selected from the group consisting of - (CRa2) k- -CRb = CRb- (CRa2) n-, - (CRa2) n-CRb = CRb-, - (CRa2) ~ CRb = CRb- (CRa2) - , 0 (CRb2) (CRa2) n ~, -S (CRb2) (CRa2) n-, -N (Rc) (CRb2) (CRa2) n-, N (R) C (0) (CRa2) n-, - (CRa2) nCH (NRbRc) -, -C (0) (CRa2) m-, (CRa2) mC (0) -, - (CRa2) C (0) (CRa2) n-, - (CRa2) nC ( 0) (CRa2) -, and -C (0) NH (CRb2) (CRa2) p-; k is an integer from 0-4; m is an integer from 0-3; n is an integer from 0-2; p is an integer from 0-1; Each R is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl, halogen, -OH, -O-C 1 -C 4 alkyl optionally substituted, -OCF 3, -S-C 4 -C 4 alkyl optionally substituted, -NR b R c optionally substituted C2-C4 alkenyl, and optionally substituted C2-C4 alkynyl; with the proviso that when a Ra is linked to C through an atom O, S, or N, then the other Ra links to the same C that is a hydrogen, or is bonded by means of a carbon atom; Each Rb is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 4 alkyl; Each Rc is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 4 alkyl, -C (0) -alternatively substituted C 1 -C 4 alkyl, and -C (0) H; R1, R2, R6, R7, R8, and R9 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted C1-C4 alkyl, -S-optionally substituted C1-C3 alkyl, optionally substituted C2-C4 alkenyl, C2-C4 alkynyl optionally substituted, -CF3, -OCF3, -O-C-C3 alkyl optionally substituted, and cyano; with the proviso that at least one of R1 and R2 are not hydrogen; or R6 and T are taken together, together with the carbons and are bonded to form a ring of 5 to 6 atoms, 0 to 2 heteroatoms independently selected from -NR1-, -0-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have been separated by at least one carbon atom; and X is linked to this ring by a direct bond to a carbon in the ring, or by linking - (CRa2) ~ to a carbon in the ring or to a nitrogen in the ring; R1 is selected from the group consisting of hydrogen, -C (O) C1-C4 alkyl, -C1-C4 alkyl, and aryl CL-C; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted C1-C12 alkyl, optionally substituted CC2 alkenyl, optionally substituted C2-C2 alkynyl, - ( CRa2) optionally substituted maryl, (CRa2) optionally substituted cycloalkyl, (CRa2) mheterocycloalkyl optionally substituted, -0Rd, SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRfRg, - C (0) NRfRg, -C (0) 0Rh, -C (0) Re, -N (Rb) C (0) Re, -N (R) C (0) NRfRg, -N (Rb) S (= 0) 2Re, N (Rb) S (= 0) 2NRfRg, and -NRfRg; Each Rd is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2-C2 alkenyl, optionally substituted C2-C2 alkynyl, optionally substituted (CRb2) naryl, - (CRb2) n optionally substituted cycloalkyl , - (CRb2) nheterocycloalkyl optionally substituted, and C (0) NRfRg; Each Re is selected from the group consisting of optionally substituted C? -Ci2 alkyl, optionally substituted C2-C1 alkenyl, optionally substituted C2-C? 2 alkynyl, optionally substituted (CRa2), optionally substituted (CRa2) nCycloalkyl, and - (CRa2) optionally substituted n-heterocycloalkyl; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C2-CX2 alkenyl, optionally substituted C2-C2 alkynyl, optionally substituted - (CRb2) naril, - (CRb2) optionally substituted cycloalkyl, and optionally substituted - (CRb2) nheterocycloalkyl, or Rf and Rg together can form an optionally substituted heterocyclic ring, the heterocyclic ring can contain a second hetero group within the ring selected from the group consisting of 0, NRC, and S, wherein the optionally substituted heterocyclic ring can be substituted with 0-4 substituents selected from the group consisting of optionally substituted C 1 -C 4 alkyl, -0Rb, oxo, cyano, -CF 3, optionally substituted phenyl, and -C (0) ORh; Each Rh is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2-C2 alkenyl, optionally substituted C2-C2 alkynyl2, optionally substituted (CRb2) naryl, (CRb2) n optionally substituted cycloalkyl, and (CRb2) optionally substituted n-heterocycloalkyl; R5 is selected from the group consisting of -OH, Optionally substituted C?-C6alkyl, -OC (0) Re, -OC (0) ORh, -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); X is PfOjYR ^ 'R11; Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are -0-, R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (R2) 20C (0) NR22 / -NR2-C (0) -Ry, -C (R2) 2-0C (0) Ry, -C (Rz) 2-0- C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; when Y and Y 'are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy, and cycloalkylene-C00Ry; when Y is -0- and Y 'is NRV, then R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRZ2, -NRZ-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2 -0-C (0) 0Ry, -C (RZ) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, - C (Rx) 2COORy, - [C (R) 2] qC (0) SRy , and -cycloalkylene-COORy; or when Y and Y 'are independently selected from -0- and -NRV-, then together R11 and R11 are -alkyl-S-S-alkyl to form a cyclic group, or together R11 and R11 are the group: wherein: V, W, and W 'are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and 1-alkynyl optionally substituted; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are three atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group to the beta and gamma bound position to the Y to the phosphorus; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms which are three atoms of a Y bond to phosphorus; or together Z and W are connected by means of 3-5 additional atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W 'are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or heteroaryl replaced; Z is selected from the group consisting of -CHR20H, CHR20C (0) Ry, -CHRzOC (S) Ry, -CHR20C (S) ORy, -CHRzOC (O) SRy, CHR20C02Ry, -ORz, -SRZ, -CHRZN3, - CH2aryl, -CH (aryl) OH, -CH (CH = CRZ2) 0H, -CH (C = CRZ2) OH, -RZ, -NRZ2, -OCORy, -OC02Ry, - SCORy, -SC02Ry, -NHCORz, -NHC02Ry , -CH2NHaril, - (CH2) q-ORz, and - (CH2) q-SRz; q is an integer of 2 or 3; Each Rz is selected from the group consisting of Ry and -H; Each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; Each Rx is independently selected from the group consisting of -H, and alkyl, or together Rx or Rx form a cyclic alkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl. with the proviso that: a) V, Z, W, and W 'are not all -H; and b) when Z is -Rz, then at least one of V, W, and W 'are not -H, alkyl, aralkyl, or heterocycloalkyl. In one aspect, when G is -O-, T is -CH2-, R1 and R2 are each bromine, R3 is iso-propyl, R4 is hydrogen, and R5 is -OH, then X is not P (O) ( 0H) 2 or P (0) (OCH2CH3) 2. In another aspect, when G is -O-, T is - (CH2) or -4 ~, R1 and R2 are independently halogen, alkyl of 1 to 3 carbons, and cycloalkyl of 3 to 5 carbons, R3 is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 7 carbons, R 4 is hydrogen, and R 5 is -OH, then X is not -P (O) (OH) 2 or -P (O) (O lower alkyl) 2. In a further aspect , when G is -O-, R5 is -NHC (0) Re, -NHS (= 0)? -2Re, -NHC (S) NH (Rh), or -NHC (0) NH (Rh), T is ~ (CH2) m-, -CH = CH-, -0 (CH2)? -2-, or -NH (CH2)? -2-, then X is not -P (0) (0H) 2 or -P (0) (0H) NH2. In one aspect, G is selected from the group consisting of -0- and -CH2-. In a further aspect, G is -0-. In another aspect, G is -S-. In a further aspect, G is -S (= 0) -. In another aspect, G is -S (= 0) 2-- In a further aspect, G is -CH-. In another aspect, G is -CF2-. In a further aspect, G is -CHF-. In another aspect, G is -C (0) -. In another aspect, G is -CH (OH) -. In a further aspect, G is -NH-. In another aspect, G is -N (C1-C4 alkyl) -. Still in another aspect, G is -Se-. In another aspect, G is -CH (C 1 -C 4 alkyl) -. In another aspect, G is -CH (C 1 -C 4 alkoxy) -. In another aspect, G is -C (= CH2) -, In another aspect, T is selected from the group consisting of - (CRa2) n-, -0 (CRb2) (CRa2) P-, -N (Rc) ( CRb2) (CRa2) p-, S (CRb2) (CRa2) p-, -NR (C0) -, and -CH2CH (NRcRb) -. In a further aspect, T is - (CRa2) k-. In another aspect, T is -CRb = CR- (CRa2) n-. In a further aspect, T is - (CRa2) n-CR = CRb-. In another aspect, T is - (CRa2) -CRb = CRb- (CRa2) -. In a further aspect, T is -0 (CRb2) (CRa2) n. In another aspect, T is -S (CRb2) (CRa2) n-- In a further aspect, T is N (RC) (CRb2) (CR2) -. In another aspect, T is -N (Rb) C (0) (CRa2) n. In a further aspect, T is - (CRa2) nCH (NRbRc) -. In another aspect, T is -C (0) (CR2) m-- In a further aspect, T is - (CRa2) mC (0) - In another aspect, T is - (CRa2) C (0) (CRa2) n-. In a further aspect, T is - (CRa2) nC (0) (CRa2) -. In still another aspect, T is -C (0) NH (CRb2) (CRa2) p-. In one aspect k is 0. In a further aspect, k is 1. In a further aspect, k is 2. In a further aspect, k is 3. Still in another aspect, k is 4. In one aspect m is 0. In a further aspect, m is 1. In a further aspect, m is 2. In a further aspect, m is 3. In one aspect n is 0. In a further aspect, n is 1. In a further aspect, n is 2. In one aspect, p is 0. In another aspect, p is 1. In one aspect, each R is hydrogen with the proviso that when a Ra is linked to C through an atom O, S, or N, then the other Ra links to the same C that is a hydrogen, or is linked by means of a carbon atom. In another aspect, each Ra is optionally substituted C 1 -C alkyl with the proviso that when one R is linked to C through an O, S, or N atom, then the other Ra binds to the same C which is a hydrogen, or it is bonded by means of a carbon atom. In a further aspect, each Ra is halogen with the proviso that when a Ra is linked to C through an O, S, or N atom, then the other Ra binds to the same C which is a hydrogen, or is bound by half of a carbon atom. In another aspect, each Ra is -OH with the proviso that when a Ra is linked to C through an atom O, S, or N, then the other Ra links to the same C that is a hydrogen, or is linked by means of a carbon atom. In a further aspect, each R is -O-C1-C4 alkyl optionally substituted with the proviso that when a Ra is linked to C through a 0, S, or N atom, then the other Ra binds to the same C as It is a hydrogen, or it is bonded by means of a carbon atom. In another aspect, each Ra is -0CF3 with the proviso that when a Ra is linked to C through an atom 0, S, or N, then the other Ra links to the same C that is a hydrogen, or is bound by half of a carbon atom. In a further aspect, each Ra is -S-C-C4 alkyl optionally substituted with the proviso that when a Ra is linked to C through an O, S, or N atom, then the other R binds to the same C which is a hydrogen, or is bonded by means of a carbon atom. In another aspect, each Ra is -NRbRc with the proviso that when one R is linked to C through an atom 0, S, or N, then the other Ra links to the same C that is a hydrogen, or is bound by half of a carbon atom. In a further aspect, each Ra is alkenyl CC optionally substituted with the proviso that when a Ra is linked to C through a 0, S, or N atom, then the other Ra binds to the same C which is a hydrogen, or it is bonded by means of a carbon atom. In another aspect, each R is optionally substituted C2-C4 alkynyl with the proviso that when a Ra is linked to C through a 0, S, or N atom, then the other Ra binds to the same C which is a hydrogen, or it is bonded by means of a carbon atom. In one aspect, Rb is hydrogen. In a further aspect, R b is optionally substituted C 1 -C 4 alkyl. In one aspect, Rc is hydrogen. In another aspect, Rc is optionally substituted C1-C4 alkyl. In a further aspect, Rc is -C (0) -C1-C4 alkyl optionally substituted. In still another aspect, Rc is -C (0) H. In a further aspect, R1 and R2 are the same and are selected from the group consisting of halogen, C1-C4 alkyl, -CF3, and cyano. In still another aspect, R1 and R2 are different and are selected from the group consisting of halogen, C1-C4 alkyl, -CF3, and cyano. In a further aspect, R1 and R2 are each halogen. In another aspect, R1, R2, R6, R7, R8, and R9 are each optionally substituted C1-C4 alkyl. In a further aspect, R1, R2, R6, R7, R8, and R9 are each -S-optionally substituted C1-C3 alkyl. In another aspect, R1, R2, R6, R7, R8, and R9 are each optionally substituted C2-C4 alkenyl. In a further aspect, R1, R2, R6, R7, R8, and R9 are each optionally substituted C2-C alkynyl. In another aspect, R1, R2, Rd, R7, R8, and R9 are each -CF3. In a further aspect, R1, R2, R6, R7, R8, and R9 are each -0CF3. In another aspect, R1, R2, R6, R7, R8, and R9 are each optionally substituted-C-C3 alkyl. In a further aspect, R1, R2, R6, R7, R8, and R9 are each cyano.

In one aspect, R6 and T are taken together, together with the carbons which are bonded to form a ring of 5 to 6 atoms containing 0 to 2 unsaturations and 0 to 2 heteroatoms independently selected from -NR1-, -0-, and -S- with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have been separated by at least one carbon atom; and X is linked to this ring for either a carbon or nitrogen by either - (CRa2) - or -C (0) - or a bond if X is bonded directly to a carbon atom. In one aspect, R6 and T are taken together, together with the carbons which are bonded to form a ring of 5 to 6 atoms containing 0 unsaturations. In another aspect, R6 and T are taken together, together with the carbons that are bonded to form a ring of 5 to 6 atoms containing 1 unsaturation. R6 and T are taken together, together with the carbons that are bonded to form a ring of 5 to 6 atoms containing 2 unsaturations. In one aspect, 0 to 2 heteroatoms are -NR1-. In another aspect, 0 to 2 heteroatoms are -0-. In another aspect, 0 to 2 heteroatoms are -S-. In one aspect, R1 is hydrogen. In another aspect, R1 is -C (0) C1-C4 alkyl. In another aspect, R 1 is C 1 -C 4 alkyl. In a further aspect, R1 is C1-C4 aryl. In still another aspect, R3 and R4 are each hydrogen. In another aspect, R3 and R4 are each halogen. In a further aspect, R3 and R4 are each -CF3. In another aspect, R3 and R4 are each -0CF3. In a further aspect, R3 and R4 are each cyano. In another aspect, R3 and R4 are each optionally substituted C1-C12 alkyl. In a further aspect, R3 and R4 are each optionally substituted C2-C2 alkenyl. In another aspect, R3 and R4 are each optionally substituted C2-Ci2 alkynyl. In a further aspect, R3 and R4 are each - (CRa2) optionally substituted maryl. In another aspect, R3 and R4 are each - (CRa2) optionally substituted cycloalkyl. In a further aspect, R3 and R4 are each - (CRa2) optionally substituted m-heterocycloalkyl. In another aspect, R3 and R4 are each_-ORd. In another aspect, R3 and R4 are each -SRd. In a further aspect, R3 and R4 are each -S (= 0) Re. In another aspect, R3 and R4 are each -S (= 0) 2Re. In a further aspect, R3 and R4 are each -S (= 0) 2NRfRg. In another aspect, R3 and R4 are each -C (0) NRfRg. In a further aspect, R3 and R4 are each -C (0) 0R. In another aspect, R3 and R4 are each -C (0) Re. In a further aspect, R3 and R4 are each -N (Rb) C (0) Re. In another aspect, R3 and R4 are each -N (R) C (0) NRfRg. In a further aspect, R3 and R4 are each -N (Rb) S (= 0) 2Re. In another aspect, R3 and R4 are each -N (Rb) S (= 0) 2NRfRg. In a further aspect, R3 and R4 are each -NRfRg. In another aspect, R 4 is selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, cyano and CF 3. In a further aspect, R3 is selected from the group consisting of halogen, optionally substituted C6-C6 alkyl, -CF3, cyano, -C (0) NRfRg, - (CRa2) optionally substituted naril, -S02NRfRg, and -S02Re. In another aspect, each Rd is optionally substituted C? -C? 2 alkyl. In a further aspect, each Rd is optionally substituted C 2 -C 2 alkenyl. In another aspect, each Rd is optionally substituted -C-C 2 alkynyl. In a further aspect, each Rd is optionally substituted (CRb2) naril. In another aspect, each Rd is - (CRb2) n-cycloalkyl optionally substituted. In a further aspect, each Rd is - (CRb2) n-heterocycloalkyl optionally substituted. In another aspect, each Rd is -C (0) NRfRg. In a further aspect, Re is optionally substituted C 1 -C 12 alkyl. In another aspect, Re is optionally substituted C 2 -C 2 alkenyl. In a further aspect, Re is optionally substituted C2-C2alkyl2. In another aspect, Re is - (CRa2) optionally substituted narile. In a further aspect, Re is - (CRa2) n-optionally substituted cycloalkyl. In another aspect, Re is - (CRa2) n-heterocycloalkyl optionally substituted. In one aspect, Rf and Rg are each hydrogen. In a further aspect, Rf and Rg are each optionally substituted C? -C12 alkyl. In another aspect, R f and R g are each optionally substituted C 2 -C 2 alkenyl. In a further aspect, Rf and Rg are each optionally substituted C2-C2 alkynyl. In a further aspect, Rf and Rg are each - (CRb2) optionally substituted naril. In a further aspect, Rf and Rg are each (CR2) optionally substituted n-cycloalkyl. In another aspect, Rf and Rg are each optionally substituted (C2-C2) n-heterocycloalkyl. In a further aspect, Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second heterogroup which is O. In another aspect, Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second heterogroup which is NRC. In another aspect, Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second heterogroup which is S. In one aspect, Rf and Rg together may form an unsubstituted heterocyclic ring, which may contain a second heterogroup. In another aspect, the optionally substituted heterocyclic ring may be substituted with 1 substituent selected from the group consisting of optionally substituted C 1 -C 4 alkyl, -OR b, oxo, cyano, -CF 3, optionally substituted phenyl, and -C (0) OR h. In a further aspect, the optionally substituted heterocyclic ring can be substituted with 2 substituents selected from the group consisting of optionally substituted C? -C alkyl, -ORb, oxo, cyano, -CF3, optionally substituted phenyl, and -C (O) Oh. In another aspect, the optionally substituted heterocyclic ring may be substituted with 3 substituents selected from the group consisting of optionally substituted C 1 -C 4 alkyl, -0R, oxo, cyano, -CF 3, optionally substituted phenyl, and ~ C (0) 0Rh. In a further aspect, the optionally substituted heterocyclic ring may be substituted with 4 substituents selected from the group consisting of optionally substituted C 1 -C 4 alkyl, -0Rb, oxo, cyano, -CF 3, optionally substituted phenyl, and -C (0) 0Rh. In a further aspect, Rh is optionally substituted C 1 -C 12 alkyl. In another aspect, Rh is optionally substituted C 2 -C 2 alkenyl. In a further aspect, Rh is optionally substituted C 2 -C 2 alkynyl. In another aspect, Rh is - (CRb2) optionally substituted naril. In a further aspect, Rh is - (CRb2) n-cycloalkyl optionally substituted. In another aspect, it is optionally substituted - (CRb2) nheterocycloalkyl. In one aspect, R5 is selected from the group consisting of -OH, -OC (0) Re, -OC (0) ORh, -F, and -NHC (0) Re. In a further aspect, R5 is -O-C6-C6 alkyl optionally substituted. In another aspect, R5 is -0C (0) Re. In a further aspect, R5 is -OC (0) ORh. In another aspect, R5 is -F. In another aspect, R5 is -NHC (0) Re. In a further aspect, R5 is -NHS (= 0) Re, In another aspect, R5 is -NHS (= 0) 2Re. In a further aspect, R5 is -NHC (= S) NH (Rh). In another aspect, R5 is -NHC (0) NH (Rh). Each of the individual spaces of the compounds of Formula III can be generated by making all the above permutations can be specifically established for inclusion or can specifically be excluded from the present invention. In a further aspect, this invention relates to Formula I, II, III, or VIII wherein X is P (0) YR1: lY 'R11. In one aspect, Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-. In another aspect, Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are -0-, R11 linked to -0- is -H, alkyl. In another aspect, Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are -0-, R11 linked to -0- is optionally substituted aryl. In another aspect, Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are -0-, R11 linked to -0- is optionally substituted heterocycloalkyl. In a further aspect, Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are -0-, R11 linked to -0- is optionally substituted CH2-heterocycloalkyl. In one aspect, the cyclic portion contains a carbonate or thiocarbonate. In another aspect, the cyclic moiety contains optionally substituted alkylaryl. In another aspect, the cyclic portion contains a -C (R2) 20C (0) NR22. In another aspect, the cyclic portion contains -NR2-C (0) -Ry. In another aspect, the cyclic portion contains -C (RZ) 2-0C (0) Ry. In another aspect, the cyclic portion contains -C (RZ) 2-0-C (0) 0Ry. In a further aspect, the cyclic portion contains -C (Rz) 20C (0) SRy. In another aspect, the cyclic portion contains -alkyl-S-C (0) Ry. In another aspect, the cyclic portion contains -alkyl-S-S-alkylhydroxy. In a further aspect, the cyclic portion contains -alkyl-S-S-alkylhydroxy. Still in another aspect, Y and Y 'are -NRV-. In another aspect, when Y and Y 'are -NRV-, then R11 linked to -NRV- is -H. In a further aspect, when Y and Y 'are -NRV-, then R11 linked to -NRV- is - [C (Rz) 2] q-C00Ry. In another aspect, when Y and Y 'are -NRV-, then R11 linked to -NRV- is -C (Rx) 2C00Ry. In a further aspect, when Y and Y 'are -NRV-, then R11 linked to -NRV- is - [C (Rz) 2] q-C (0) SRy. In another aspect, when Y and Y 'are -NRV-, then R11 linked to -NRV- is -cycloalkylene-C00Ry. In one aspect, Y is -0- and Y 'is NRV. In another aspect, when Y is -0- and Y 'is NRV, then R11 linked to -0- is -H. In a further aspect, when Y is -0- and Y 'is NRV, then R11 linked to -0- is alkyl. In another aspect, when Y is -0- and Y 'is NRV, then R11 linked to -0- is optionally substituted aryl. In a further aspect, when Y is -0- and Y 'is NRV, then R linked to -0- is optionally substituted heterocycloalkyl. In another aspect, when Y is -0- and Y 'is NRV, then R11 linked to -0- is optionally substituted CH2-heterocycloalkyl. In one aspect, the cyclic portion contains a carbonate or thiocarbonate. In another aspect, the cyclic moiety contains optionally substituted alkylaryl. In another aspect, the cyclic portion contains -C (Rz) 20C (0) NRZ2. In another aspect, the cyclic portion contains -NRZ-C (0) -Ry. In another aspect, the cyclic portion contains -C (RZ) 2-0C (0) Ry. In another aspect, the cyclic portion contains -C (R) 2-0-C (0) 0Ry. In a further aspect, the cyclic portion contains C (R2) 20C (0) SRy. In another aspect, the cyclic portion contains -alkyl-S-C (0) Ry. In another aspect, the cyclic portion contains -alkyl-S-S-alkylhydroxy. In a further aspect, the cyclic portion contains -alkyl-S-S-alkylhydroxy. In another aspect, when Y is -0- and Y 'is NRV, and R11 linked to -NRV- is -H. In a further aspect, when Y is -0- and Y 'is NRV, and R11 linked to -NRV- is - [C (Rz) 2] q-C00Ry. In another aspect, when Y is -0- and Y 'is NRV, and R11 linked to -NRC- is -C (Rx) C00Ry. In a further aspect, when Y is -0-e Y 'is NRV, and R11 linked to -NRV- is - [C (Rz) 2] q-C (0) SRy. In another aspect, when Y is -0- and Y 'is NRV, and R11 linked to -NRV- is -cycloalkylene-C00Ry.

In another aspect, Y and Y 'are independently selected from -0- and -NRV-, then together R11 and R11 are-alkyl-S-S-alkyl to form a cyclic group. In one aspect, Y and Y 'are independently selected from -0- e -NRV- and together R11 and R11 are the group: In a further aspect, V is hydrogen. In another aspect, V is optionally substituted alkyl. In a further aspect, V is optionally substituted aralkyl. In another aspect, V is heterocycloalkyl. In another aspect, V is aryl. In a further aspect, V is substituted aryl. In another aspect, V is heteroaryl. In a further aspect, V is substituted heteroaryl. In another aspect, V is optionally substituted 1-alkenyl. In a further aspect, V is optionally substituted 1-alkynyl. In a further aspect, W is hydrogen. In another aspect, W is optionally substituted alkyl. In a further aspect, W is optionally substituted aralkyl. In another aspect, W is heterocycloalkyl. In another aspect, W is aryl. In a further aspect, W is substituted aryl. In another aspect, W is heteroaryl. In a further aspect, W is substituted heteroaryl. In another aspect, W is optionally substituted 1-alkenyl. In a further aspect, W is optionally substituted 1-alkynyl. In a further aspect, W 'is hydrogen. In another aspect, W 'is optionally substituted alkyl. In a further aspect, W 'is optionally substituted aralkyl. In another aspect, W 'is heterocycloalkyl. In another aspect, W 'is aryl. In a further aspect, W 'is substituted aryl. In another aspect, W 'is heteroaryl. In a further aspect, W 'is substituted heteroaryl. In another aspect, W is optionally substituted 1-alkenyl. In a further aspect, W 'is optionally substituted 1-alkynyl. In one aspect, together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon. In one aspect, the ring is substituted with hydroxyl bonded to a carbon atom which are 3 atoms of both Y groups bonded to the phosphorus. In another aspect, the ring is substituted with acyloxy linked to a carbon atom which are 3 atoms of both Y groups bonded to the phosphorus. In a further aspect, the ring is substituted with alkylthiocarbonyloxy linked to a carbon atom which are 3 atoms of both Y groups linked to the phosphorus. In another aspect, the ring is substituted with alkoxycarbonyloxy linked to a carbon atom which are 3 atoms of both groups Y bonded to phosphorus. In a further aspect, the ring is substituted with aryloxycarbonyloxy linked to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus. In yet another aspect, together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group at the position beta and gamma linked to Y to phosphorus. In a further aspect, together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent. In one aspect, the substituent is hydroxyl which is bonded to one of the carbon atoms which are 3 atoms of a Y bond to the phosphorus. In another aspect, the substituent is acyloxy which is bonded to one of the carbon atoms which are 3 atoms of a Y bond to the phosphorus. In another aspect, the substituent is alkoxycarbonyloxy which is bonded to one of the carbon atoms which are 3 atoms of a Y bond to the phosphorus. In another aspect, the substituent is alkylthiocarbonyloxy which is bonded to one of the carbon atoms which are 3 atoms of a Y bond to the phosphorus. In another aspect, the substituent is aryloxycarbonyloxy which is bonded to one of the carbon atoms which are 3 atoms of a Y bond to the phosphorus. In another aspect, Z and W together are connected by means of 3-5 additional atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl. In yet another aspect, together W and W 'are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl. In one aspect, Z is -CHRzOH. In another aspect, Z is -CHR2OC (0) Ry. In a further aspect, Z is -CHROC (S) Ry. In another aspect, Z is -CHROC (S) 0Ry. In a further aspect, Z is -CHR20C (0) SRy. In another aspect, Z is -CHRzOC02Ry. In a further aspect, Z is -ORz. In another aspect, Z is -SRZ. In a further aspect, Z is -CHRZN3. In another aspect, Z is -CH2aryl. In a further aspect, Z is -CH (aryl) OH. In another aspect, Z is -CH (CH = CRZ2) OH. In another aspect, Z is -CH (C = CRZ) OH. In a further aspect, Z is -Rz. In another aspect, Z is -NRZ2 In a further aspect, Z is -OCORy. In another aspect, Z is -0C02Ry. In a further aspect, Z is -SCORy. In another aspect, Z is -SC02Ry. In a further aspect, Z is -NHCORz. In another aspect, Z is -NHC02Ry. In a further aspect, Z is -CH2NHaril. In another aspect, Z is -CH2) q-ORz. In a further aspect, Z is - (CH2) q-SRz. In an aspect R11 is not hydrogen. In one aspect, q is 2. In a further aspect, q is 3. In one aspect, Ry is alkyl. In another aspect, Ry is aril. In a further aspect, Ry is heterocycloalkyl. In another aspect, Ry is aralkyl. In one aspect, Rx is -H. In another aspect, Rx is alkyl. In still another aspect, together Rx and Rx form a cyclic alkyl group. In one aspect, Rv is -H. In another aspect, Rv is lower alkyl. In another aspect, Rv is acyloxyalkyl. In another aspect, Rv is alkoxycarbonyloxyalkyl. In another aspect, Rv is lower acyl. In one aspect, the present invention excludes through unsubstituted lower alkyl diesters of X when X is P03H2, for example, where X is -P (0) (OCH2CH3) 2. SPECIFIC COMPOUNDS In one aspect the following compounds are included in the invention but the compounds are not limited to those illustrative compounds. The compounds are shown without description of stereochemistry since the compounds are biologically active as the diastereomeric mixture or as a simple stereoisomer. The compounds named in Table 2 are designated by numbers assigned to the variables of formulas V-VII using the following convention: V ^ V ^ .V4.

Formula V Formula VI Formula VII Variable VI: 1) -P (O) (OH) 2 2) -P (O) [0-CH2OC (0) C (CH3) 3] 2 3) -P (O) [0-CH2OC (0 ) CH (CH3) 2] 2 4) -P (0) [0-CH2OC (0) OCH2CH3] 2 5) -P (O) [NH-CH (CH3) C (0) OCH2CH3] 2 6) -P (0) [NH-C (CH3) 2C (0) OCH2CH3] 2 7) -P (0) (OC6H5) 2 8) -P (0) (0-CH (3-chlorophenyl) CH2CH2-0) 9) -P (0) (0-CH (4-pyridyl) CH2CH2-0) Variable V2: 1) -CH2- 2) -0CH2-3) -CH2-CH2-4) -NHCH2- 5) -NH ( CO) - 6) -CH2-CH (NH2) - (R-configuration) 7) -CH2-CH (NH2) - (S-configuration) 8) -CH = CH- (trans) 9) -nuil Variable V3 : 1) -Ometyl 2) iodine 3) bromo 4) chloro 5) fluoro 6) methyl 7) trifluoromethyl 8) cyano 9) -OCF3 Variable V4: 1) iodine 2) CH (CH3) 2 3) C6Haa 4) C6H5 5 ) -C (0) NHC6Hu 6) -CH (OH) (4-fluorophenyl) 7) -S02 (4-fluorophenyl) 8) -S02 (N-piperazinyl) 9) bromo In another aspect, the additional compounds are listed in Table 2 using Formula V, VI or VII. For example, compound 1.3.6.7 of Formula V represents the compound of Formula V wherein V1 is 1, that is, of group V1 is 1, that is, of the group -P (O) (OH) 2; V2 is 3, that is, of the group -CH2-CH2-; V3 is 6, that is, of the methyl group; and V4 is 7, that is, of the group -SO2 (4-fluorophenyl).

TABLE 2 l.Ll.l 1.1.1.2 1.1.1.3 1114 1115 1116 1117 j I * JLo 1119 115.1 i «J. 1.1.2.3? * Jr ** ^ # t 112.5 112.6 1.12.7 112.8 112.9 113.1 1135 1. 1.3.3 1.1.3.4 1.1.3.5 113.6 113.7 113.8 113.9 11.41 14A2 1,1,43 1. L4.4 t.1.4.5 1.1.4.6 1.14.7 1.14.8 1.14.9 1151 115.2 1.153 1.1.5.4 1. 1.5.5 1.1.5.6 1.1.5.7 115.8 1.15.9 1.1.6.1 116.2 11.6.3 1.16.4 1165 1. 1.6.6 1.1.6.7 1.1.6,8 116.9 117.? 117.2 1173 117.4 117.5 117.6 117. 7 1.1.7.8 Ll.7.9 1.18.1 L #? Qrd * 1.1.8.3 118.4 118.5 1.1.8.6 118.7 U.8 U.8.9 1.1.9.1 1.1A2 119.3 119.4 119.5 11.9.6 119.7 119.8 l .9.9 1.2.1.1 12,12 1,2,13. 4 Li &i? . t 12.16 121.7 12.1.8 12.1.9 1-2.2.1 1255 12.2.3 1.2.2.4 1555 12.2, $ 12.2.9 1231 1535 1.2.3.3 1.2.3.4 123.5 1.2.3.6 A- * • & ** - * / 123.8 123.9 15.41 12.45 1. 2.43 1.2.4.4 1.2.4.5 12.4.6 12.4.7 124.8 15.4.9 123.1 12.5.2 12.53 1. 2.5.4 1.2.5.5 1.2.5.6 123.7 12.5.8 12.5.9 L5.61 12.62 12.63 12.6.4 1.2.6.5 1.2.6.6 1.2.6.7 12.6.8 12.6.9 1.2.7.1 12.7.2 12.73 12.7.4 12.7.5 1. 2.7.6 12.7.7 1.2.7.8 12.7.9 12.8.1 1.2.0-2 12.83 12.8.4 12.8.5 15.8.6 1. 2.8.7 1.2.8.8 1.2.8.9 12.9.1 12.9.2 1 * £ »«? #? 12.9.4 12.9.6 12.9.7 1. 2.9.8 1.3.1.1 1.3.12 1313 13.1.4 13.15 13.16 13.17 131.8 1. 31.9 13.2.1 1322 1.353 13.2.4 13.2.5 13.2.6 13.2.7 13.2.S 13.2.9 1. 3.3.1 1.3.3.2 1.3.33 133.4 133.5 13.3.6 1.3.3.7 133.8 133.9 13.4.1 1. 3.4.2 1.3.4.3 13.4.5 13.4.6 13.4.7 13.48 13.4.9 13.51 13.55 1.3.5.3 13.5.4 1.3.5.5 13.S.6 13.5.7 13.5.8 J * -3 * -_? 13.6.1 1.3.6.2 13.63 1. 3,6,4 1.3.6.5 1.3.6.6 13.6.7 13.6.8 13.6.9 13.71 13.7.2 1.3.73 13.7.4 1. 3.7.7 1.3.7.6 1.3.7.7 13.7.8 13.7.9 13.8.1 13.8.2 13.8.3 13.8.4 13.8.5 1. 3.8.6 1.3.8.7 1.3.8.8 13.8.9 13.9.1 1.3.95 13.93 13.9.4 13.9.5 13.9.6 1. 3.9.7 13.9.8 13.9 S 1.4 Ll 14.12 1.413 14.14 * 4T '* -. * W? L4L6 141.7 1. 4.1.8 1.4.1.9 1.4.2J 1.4.2.2 14.23 142.4 14.2.5 145.6 142.7 1? 2 1. # . 9.5 15.9.6 15.9.7 15.9.8 15.9.9 16.11 1615 16.13 161.4 16.15 16. 1.6 161.7 16.18 16.19 165.1 16.2.2 16.23 16.2.4 165.5 16.2.6 16. 2.7 1.65.8 16.2.9 163.1 163.2 1.6.33 1.6.3.4 16.35 16.3.6 1.6.3.7 163.8 163.9 16.41 16.42 16.4.3 16.4.4 16.45 16.46 16.47 1.6.48 16. 4.9 16.5.1 16.5.2 16.53 165.4 16.5.5 16.5.6 16.5.7 165.8 1.65.9 1. 6.61 16.65 16.63 16.6.4 16.6.5 l.6.6 16-6.7 16.6.8 1.6.6.9 1.6.71 16. 72 1.6.7.3 16.7.4 16.7.5 16.7.6 1 .7.7 16.7.8 1.6.7.9 1.6.8.1 1.6.8.2 16.83 1.6.8.4 1.6.85 16.8.6 16.8.7 16.8.8 ldS9 16, 91 16.9.2 16.9.3 Table 2 - (-continuation 16. 9.4 16.95 16.9.6 16.9.7 16.9.S 165.9 1.7.1.1 17.1.2 17.13 1.7.14 1715 17.16 1.71.7 17.18 17.19 1.75.1 1.7.23 175.4 1.75.5 175. 6 17.2.7 175.8 1.7.2.9 17.31 1.7.3.2 173.3 17.3.4 173.5 173.6 173. 7 173.8 173.9 17.41 17.45 1743 17.4.4 t.7.45 17.4.6 1.7.47 17. 4S 17.4.9 1751 17.55 175.3 175.4 1.75.5 175.6 175.7 1.75.8 175. 9 1.7.6.1 17.6.2 17.63 17.6.4 17.65 1.7.6.6 17.6.7 17.6.8 17.65 17.7.1 17.7.2 1.7.7.3 17.7.4 17.75 17.7.6 1.7.7.7 1.7.7.8 17.7.9 17.8.1 17.8.2 17.83 1.7.8.4 17.85 17.8.6 1.7.8.7 17.8.8 1.7.85 1751 1755 17. 9.3 17.9.4 17.95 17.9.6 17.9.7 17.9.8 1.7.9.9 1.8.11 18.12 18.13 18.14 1815 1.8.16 18.17 18.18 181.9 1.85.1 18.2.2 18.23 185.4 18. 25 185.6 185.7 185.8 18.2.9 1831 1835 183.3 183.4 1835 18. 3.6 183.7 1.8.3.8 183.9 1.8.4.1 18.4.2 18.43 18.4.4 18.45 18.4.6 18.4.7 18.48 1SA9 1851 1855 1853 18.5.4 1855 185.6 185.7 1. 85.8 185.9 18.61 18.65 18.63 18.6.4 18.6.5 18.6.6 18.6.7 18.6.8 18. 6.9 18.71 18.75 18.73 1.8.7.4 18.75 18.7.6 18.7.7 18.7.8 18.75 IS.8.1 18.8.2 LS.83 18.8.4 1.8.8.5 1.8.8.6 1.8.8.7 1.8.8.8 18.8.9 1.8.91 18. 95 18.9.3 18.94 18.95 18.9.6 185.7 1.8.9.8 18.9.9 19.11 1.9.15 1913 19.14 1915 191-6 191.7 191.8 15.1.9 195.1 1955 1553 19. 2.4 19.2.5 * -,? *, * & * .0 19.2,7 195.8 193.1 193.2 1933 193.4 1935 193.6 153.7 193.8 193.9 19.41 1.9.42 1.9.43 19.44 1.9.45 19.4.6 19.47 15.48 19.49 19.51 1955 1953 195.4 1555 195.6 195. 7 195.8 1.95.9 19.61 19.6.2 15.63 19.6.4 19.6.5 19.6.6 15.6.7 19.6.8 19.6.9 1.9.74 19.7.2 19.73 19.7.4 15.75 19.7.6 19.7.7 19.7.8 19. 7.9 19.8.1 19.85 19.83 1.9.S4 19.85 15.8.6 15.8.7 19.8.8 15.85 1. 951 1.9.9.2 15.93 19.9.4 19.9.5 1.95.6 1J.9.7 19.9.8 19.9.9 2.1.1.1 21. 15 2.113 2.114 2.115 2.1.16 2.117 2.1.1.8 2.119 2.151 215.2 2. 1.23 2.12.4 21.25 2.15.6 2.12.7 2.15.8 21.2.9 2.13.1 2.13.2 2.133 213.4 2135 2.13.6 2.13.7 2.13.8 213.9 2.141 2.1.42 2.143 21.44 2,145 2.1,46 2.1,4,7 2.L4S 2.1.4,9 2.13.1 2.1.5,2 2.153 2.15.4 2155 2.1.5.6 2.15.7 215.8 2.15.9 2.16.1 2.165 21.63 2.1.6.4 2.165 21.6.6 21. 6.7. 2.16.8 2.16.9 2.175 2.175 2.173 2.175 21.7.6 21.7.7 2. 17.8 2.17.9 2.18.2 2.183 21.8.4 2.185 21.8.6 2.18.7 2.18.8 2. 1S.9 2.191 £ * - *. + 6 * 2,194 2155 2.19.6 2.19.7 2.19.8 2.15.9 2. 2.11 2515 25.13 251.4 2.2.15 251.6 25.17 25.18 2515 255.1 . 25 255 255,4 2555 2 255,7 255,8 255,9 2531 2232. 2533 253.4 253.6 2.23.7 2.23.8 253.9 2.2.41 25.45 25.43 . 4.4 2.2.45 25.46 2.2.47 2.2.4.8 2.251 2555 2.253 255.4 2. 2.5.5?,?, «? 0 2.2.5.8 * £, * & ** $ **? i ,, > * v * 2.2.6.2 2.2.6.3 2.2.6.4 25.65 .6.6 25.6.7 25.6.8 25.6.9 25.71 25.75 25.7.4 25.7.5 25.7.6 . 7.7 25.7.8 25.7.9 25.81 2.2.85 25.83 2.2.8.4 2.2.85 25.8.6 25.8.7 . 8.8 2.2.8.9 25.91 2.2.95 2.2.93 25.9.4 25.95 2.2.9.6 2.2.9.7 25.9.8 . 9-9 23.11 23-15 23.14) 2315 23.16 231.7 23.18 23.15 2351 J *, J.? F * $ 2,354 * -i ** 3 f fj -4 ^ * 3 ^ * 0 235.7 235.8 2355 2331 ¿? Tf < -233.3 2,335 233.6 233.7 233.8 23.41 23.43 23.4.4 23.45 2.3.4.6 234.7 23.4.8 23.4.9 235.1 23.5.2 235.3 235. 4 235.6 235.7 235.8 235.9 23.61 23.6.2 23.63 23.6.4 23. 65 2.3.6.6 23.6.7 23.6.8 23.65 23.71 23.75 53.73 23.7.4 2.3.7.5 23.7.6 23.7.7 23.7.8 23.7.9 23.81 23.8.2 23.83 2.3.8.4 23.85 23.8.6 Table 2 - < continuation 23. 8.7 23.8.8 23.85 23.9.1 23.95 235.3 23.9.4 2355 23.9.6 235.7 235. 8 23.95 2.411 24.1.2 2.413 2.414 2.415 241.6 2.418 2. 419 24.2.1 2.4.2.3 2.454 24.2.5 24.2.6 2.4.2.7 2.42.8 2.4.2.9 2431 2.43.2 2433 243.4 2.43.5 2.43.6 2.43.7 2.43.8 2.43.9 24.41 2. 445 24.43 2.4.4.4 2.445 24.4.6 244.7 2.4.4.8 2.445 2.451 24.53 2. 453 2.45.4 2455 2.45.6 2.45.7 245.8 245.9 2.461 2.4.6.2 2.463 2. 4.6.4 2.4.6.5 2A6S 2.4.6.7 2.4.6.8 2.4.6.9 24.71 24.73 2.4.7.4 24. 75 2.47.6 24.7.7 24.7.8 2.475 24.81 2.485 24.83 2.4.8.4 2.4.85 2. 48.6 2.4.8.7 2.4.8.8 2.4S.9 2.4.9.1 2.4.95 2.493 2.49.4 2455 2.45.6 2.4.9.7 2.49.8 2.45.9 25.11 25.12 25.13 2.51.4 25.15 2.5.16 251.7 . 18 25.19 2551 -f¿ «» - &&> > - £ 2554 2555 25.2.6 25.2.7 25.2.8 2555 25.31 2535 253.3 253.4 2535 2.53.6 253.7 253.8 2535 . 41 2545 2.5.43 2.5.44 25.45 25.46 25.47 2.5.4.8 &** ?? rt? 2551 2555 2553 2554 2555 255.6 25.5.7 255.8 £ • ', •? ** J * C * 25.61 25.63 . 63 25.6.4 25.65 25.6.6 25.6.7 2.5.6.8 2.5.65 < ? »D * / *? 2.5.7.4 2.5.75 2.5.7.6 2.5.7.7 2.5.7.8 25.75 2.5.8.1 2.5.8.2 2.5.8.3 25.8.4 2.5.8.5 25.8.6 25.8.7 25.8.8 25.85 2551 25.95 255.3 25.9.4 255.5 255. 6 255.7 255.8 25.95 2.6.11 2.615 2.413 2.6.14 2.6.15 2.61.6 2. 6.17 2.6.18 2.651 2.6.2.2 2.654 2.655 2.65.6 2.65.7 2.6.2.8 2.6.25 2.631 2.63.2 2.6.33 2.634 2.635 2.63.6 2.63.7 2.63.8 2. 635 2,641 2.6.45 2.6.43 2.6.4.4 2.6.45 2.6.46 2.6.4.7 2.6.4.8 2.6.45 2,651 2.65.2 2,653 2.6.5.4 2.65.5 2.65.6 2.6.5.7 2.65.8 2.6.5.9 2.6.61 2. 6.65 2.6.63 2.6.6.4 2.6.65 2.6.6.6 2.6.6.7 2.6.6.8 2.6.6.9 2.6.71 2.6.75 2.6.73 2.6.74 2.6.75 2.6.7.6 2.6.7.7 2.6.7.8 2.6.75 2.6.81 2.6.8.2 2.6.83 2. 6.84 2.6.85 2.6.8.6 2.6.S.7 2.6.8.8 2.6.8.9 2 .9.1 2-6.9.2 2,, 93 2.654 2. 6.95 2.65.6 2.6.9.7 2.65.8 2.655 2.7.11 2.715 2.7.13 2.7.14 2.715 2. 7.16 2.71.7 2.7.18 2.71.9 2.75.1 2.755 2.75.3 2.7.24 2.755 2.75.6 2. 75.7 2.7.25 2.731 2.735 2.733 2.734 2.735 2.73.6 2.73.7 2. 7.3.8 2 .3.9 2.7.42 2.7.4.3 2.7.44 2.7.4.5 2.7.46 2.7.4.7 2.74,8 2. 7.49 2.75.1 2.755 2.753 2.754 2.755 2.7.5.6 2.75.7 2.75.8 2.73.9 2. 7.61 2.7.6.2 2.7.63 2.7.6.4 2.7.65 2.7.6.6 2.7.6.7 2.7.6.8 2.7.6.9 2.7.71 2.7.75 2.7.73 2.7.74 2.7.75 2.7.7.6 2.7.7.7 2.7.7.8 2.7.75 2.7.8.1 2.7.8.2 2.7,83 2.7.8.4 2.7.85 2.7.8.6 2.7.8.7 2.7.8.8 2.7.8.9 2.7.91 2.755 2.753 2. 7.9.4 2.755 2.75.6 2.75.7 2.75.8 2.755 2.8.11 2.815 2.813 2.814 2. 8.15 2A 6 2.81 * 7 2.8.18 2.815 2.8.2.1 2.8.2.2 2.8.23 2.8.2.4 2.855 2. 8.2.2 2.85.7 2.85.8 2.8.2.9 2.831 2.835 2.833 2.83.4 2.835 2.83.6 2.83.7 2.83.8 2.835 2A41 2.845 2.843 2.8.4.4 2.845 2.8.4.6 2.8.4.7 2. 8.48 2.8.49 2.8.51, or, 5, 2.8.5.3 2.S.5.4 2.8.5.5 2.8.5.6 2.8.5.7 2.8.5.8 2. 85.9 2.8.6.1 2.8.65 2.8.63 2.8.64 2.8.65 2.8.6.6 2.8.6.7 2.8.6.8 2.8.65 2. S.71 2.8.75 2.8.73 2.8.7.4 2.8.75 2.8.7.6 2.8.7.7 2.8.7.8 2.8.7.9 2.8.81 2. 8.8.2 2.8.83 2.8.S4 2.S.85 2.8.8.6 2.8.8.7 2.8.8.8 2.8.85 2.8.9.1 2.8.95 2. 8.9.3 2.8.94 2.8.95 2.8.9.6 2.85.7 2.85.8 2 # 9 »1« I 251.2 25.13 2. # 355. 6 33.5.7 3.25.8 335.9 33.61 33.63 3.2.63 3.2.64 33.65 35.6.6 .6.7 33.6.8 3.2.6.9 3.2.7.1 33.73 3.2.74 3.2.7.5 3.2.7.6 3.2.7.7 .7.8 33.75 33.81 3.2.83 3.2.83 33.8.4 3.2.85 33.8.6 33.8.7 33.8.8 .85 3351 335.2 3.253 3354 3.25.5 3.25.6 3.25.7 35.9.8 3355 33. 1.1 33.12 3.313 3314 3315 3.31.6 33.1.7 331.8 33.1.9 3331 3334 3335 3.33.6 333.7 33.2.8 333.9 3.331 333.2 3. 3.3.3 3.3.3.4 3.33.5 3.33.6 3.3.3.7 33.3.S 333.9 33.41 33.45 334.3 354. 4 33.45 33.4.6 33.4.7 33.4.8 3345 3351 3352 3353 335.4 3555 33.5.6 335.7 335.8 33.6.1 33.63 33.64 33.65 33. 6.6 33.6.7 33.6.8 33.65 33.71 33.7.2 33.73 33.7.4 33.75 3.3.7.6 33. 7.7 33.7.8 33.75 33.8.1 3.3.8.2 3.3.83 33.84 33.8.5 3.3.8.6 33.8,7 33. 8.8 33.8.9 3351 3353 3.35.3 33.94 3355 33.9.6 33.9.7 335.8 3.3.9.9 34.11 3413 3414 34.15 3.416 3.41.7 3.4.18 3415 3451 34.25 3.4.23 3434 3435 345.6 3.4.2-7 3.43.8 34.2.9 3.431 3435 * 3 »* x *» 3 »«? 3,434 3,435 3,43.6 34.3.7 343.8 3,435 34.4.1 3443 34. 43 3.444 344.5 34.4.6 34.4.7 34.48 3.445 3.45.1 345.2 3453 3. 454 3455 3.45.6 345.7 345.8 34.55 3.461 34.6.2 3.463 3.4.64 34. 65 3.46.6 34.6.7 34.6.8 34.65 3.4.71% 3? R * 34.73 34.74 34.75 34.7.6 34.7.7 3.4.7.8 34.75 3.4.8.1 3.48.2 34.83 34.84 3.485 3.4.8.6 3. 4.8.7 3.48.8 3.4.85 3.4.91 3.4J.2 3.4.9.3 * 3 »*» i '. £ r 3.4.9.5 3.4.9.6 34.9.7 3. 45.8 3.4.95 35.1.1 35.13 3513 35.14 35.15 351.6 35.17 35.18 . 19 3.5.21 35.23 353.4 3535 353.6 3.5.2.7 353.8 3.535 353.1 3.53.3 3.53.4 35.35 353.6 353.7 353.8 3535 3541 .42 35.43 354.4 3545 35.4.6 354.7 3 ** J ** tt 40 35.45 3551 3553 3553 35.5.4 3.555 355.6 * tJ **: * i 355.8 3555 35.61 35.6.2 35.63 . 6.4 35.65 35.6.6 35.6.7 35.6.8 35.65 35.71 35.7.2 35.73 35.7.4 . 75 35.7.6 35.7.7 35.7.8 3.5.75 35.81 3.5.83 35.83 35.84 35.85 .8.6 35.8.7 35.8.8 35.85 355.1 35.93 3553 3.55.4 35.95 35.9.6 3. 5.9.7 35.9.8 3.5.95 3.6.11 3.61.2 3.6.13 3.6.1.4 3.6.15 3.6.16 3.6.17 3. 61.8 3.6.19 3.651 3.6.23 3.6.23 3.63.4 3.6.25 3.6.2.6 3.65.7 3.6.2.8 3.6.2.9 3.63.1 3.633 3.633 3.63.4 3.635 3.63.6 3.63.7 3.63.8 3.63.9 3.6.41 3.6.42 3.643 3.644 3.645 3.64.6 3.6.4.7 3.64.8 3.645 3.651 3,65.2 3,65.3 3.65.4 3,655 3,65,6 3.65,7 3,65,8 3,65,9 3,6,6.1 3.6.6,2 3. 6.63 3.6.6.4 3.6.65 3.6.6.6 3.6.6.7 3.6.6.8 3.6.6.9 3.6.71 3.6.73 3.6.73 Table 2 - continued 3.6.74 3.6.75 3.6.7.6 3 , 6.7.7 3.6.7.8 3.6.75 3.6.8.1 3.6.82 3.6.83 3.6.84 3. 6.85 3.6.8.6 3.6.8.7 3.6.8.8 3.6.85 3.651 3.65.2 3.6.93 3.654 3.655 3. 65.6 3.65.7 3.65.8 3.655 3.711 * / * J. «* & 3.713 3.7.14 3.7.15 3.7.16 3.7.17 3.71.8 3.7.19 3.7.21 3.733 3.734 3.7.25 3.72.6 3.72.7 3. 7.2.8 3.75.9 3.7.31 3.7.3.2 3.73.3 3.7.34 3.7.3.5 3.7.3.6 3.73.7 3.73.8 3. 735 3.74.1 3.74.2 3.7.4.3 3.74.4 3.7.45 3.74.6 3.74.7 3.74.8 3.7.45 3. 751 3.75.2 3.753 3.754 3.755 3.75.6 3.75.7 3.7.5.8 3.755 3.7.61 3. 7.6.2 3.7.63 3.7.64 3.7.65 3.7.6.6 3.7.6.7 3.7.6.8 3.7.65 3.7.71 3.7.72 3 * / * / ** j 3.7.7.4 3.7.75 3.7.7.6 3.7.7.7 3.7.7.8 3.7.7.9 3.7.71 3.7 * 82 3.7.83 3. 7.84 3.7.85 3.7.7.6 3.7.8.7 3.7.8.8 3.7.85 3.751 3.7.92 3.7.93 3.75.4 3. 755 3.7.7.6 3.75.7 3.75.8 3.79.95 3.811 3.8.12 3.813 3.81.4 3.815 3,81,6 3,81,7 3,8,18 3,815 3,851 3,85.2 3,823 3,834 3,825 3.82.6 3. 85.7 3.83.8 3.835 3.8.31 3.8.33 3.83.3 3.83.4 3.8.35 3.83.6 3.83.7 3. 83.8 3.83.9 3.841 3.843 3.843 3.8.44 3.845 3.8.46 3.84.7 3.8.48 3,845 3,851 * or-5i2 3,853 3.85.4 3,855 3,85.6 3.8.5,7 3,85,8 3.8.55 3.8.61 3.8.6.2 3.8.63 3.8.64 3.8.65 3.8.6.6 3.8.6.7 3.8.6.8 3.8.65 3.8.71 3. 8,7,2 3,8,73 3.8.74 3.8.75 3.8 . 83 35.83 35.84 35.85 35.8.6 35.8.7 3.9.8.8 35.85 3551 3553 355.3 3.9.94 35J.5 35.9.6 3.9.9.7 3.9.9.8 3.95.9 4111 4112 4.113 4114 411.5 411.6 41.1.7 4.11.8 4.1.19 413.1 4152 4.123 4124 4155 413.6 413.7 413.8 4.125 * t * Jt »-w **? * X rt5 * & 41.33 413.4 4135 413.6 413.7 413.8 4135 4.141 4.142 414.3 41.44 414.5 4.14.6 4147 41.4.8 4,145 4151 41.5.3 415.4 4.155 4.1.5.6 4.15.7 4 »15? 8 415.9 41 * 6.1 prt 1 4.163 41.64 416.5 416.6 416.7 416.8 4165 4171 4,173 417.3 4,174 41.75 41.7.6 4.17.7 41.7.8 4175 4. 181 4,18.2 4183 4184 4,185 418.6 41.8.7 4.18.8 4.185 4151 4. 193 41.93 4154 4195 4.19.6 419.7 415.8 4195 4211 X * £ * 45. 1.3 4215 431.6 *! », & * JL 42.18 43.15 *? -? < * 4522 422.3 4334 45.2.5 4.25.6 455.7 453.8 4235 423.1 4532 4333 4234 43. 35 42.3.6 423.7 433.8 4.235 42.41 4543 4244 4.24.5 43. 46 43.4.7 4.24.8 454.9 4351 4252 4553 43.5.4 435.5 455.6 4,25,7 425.S 4.2,5,9 4.2,61 4.2,6,2 4.2.6.3 42.6.4 4.2.65 4.2.6.6 42.6,7 43. 6.8 45.65 43,71 ¿t »í?« / *. < &- 4.2.73 43.7.4 43.75 45.7.6 43.7.7 45.7.8 43. 7.9 45.81 43.33 43.8.3 43.8.4 45.85 42.8.6 45.8.7 45.8.8 45.8.9 4. 251 45.9.2 4.25.3 4.254 4.255 455.6 * r + - * í '+ 455.8 455.9 * T? 3 «Jk r k 43. 12 ¡s-Ji iiáe 43,14 4,315 4.3.16 43.17 4.3.1S 4.3,19 4331 4,323 4353 43.24 4335 435.6 435.7 435.8 4355 * t «-5 **? * * 4335 4,333 4334 4335 4.33.6 433.7 433.8 4335 43.41 4.342 4.34.3 434.4 4345 4.34.6 43.47 43.48 434.9 4351 4352 4353 4354 4355 4.3.5.6 43.5.7 435.8 4355 4.3.6.1 43.63 43.63 43.6.4 43.65 43.6.6 Table 2 - continued 43. 6.7 43.6.8 4.3.65 4.3.71 43.75 43.7.3 4.3.7.4 43.75 43.7.6 43.7.7 43. 7.8 4.3.75 43.81 43.83 4.3.83 43.84 43.85 43.8.6 43.8.7 4.3.8.S 43. 85 435.1 4353 435.3 435.4 4355 435.6 4.35.7 4.35.S 4.3.9.9 4413 4.413 4.41.4 4415 44.16 4.417 44.18 4.4.15 4.451 4. 4.2.2 * t ** i¿ »44.2.4 4.4.2.5 44.2.6 4.42.7 4.4.2.8 4.42.9 4.4.31 4.4.3.2 4433 44.35 44.3.6 443.7 4.43.S 44.35 4.4.42 4.443 4444 4.4.45 444.6 44.47 4.4.4.8 4.445 4451 4.45.2 4.45.3 4454 4. 45.6 445.7 4.45.8 44.61 44.62 44.63 44.64 4.46.5 4A6.6 4.46.7 44.6.8 44.65 4.471 44.72 44.73 4.4.75 4.4.7.6 44.7.7 4.4.7.8 4.475 4.4, * 81 4.483 44.83 4.4.8.4 44.8.5 4.4.8.6 4.48.7 44. 8.8 4.4.85 4451 4.4.93 4.453 44.9.4 4455 445.6 44.9.7 4.45.8 44.95 451.1 4513 4514 4515 451.6 451.7 451.8 451.9 4. 5.21 4.523 4533 4534 4525 452.6 4.53.7 453.8 4535 4531 4. 53.2 45.33 45.3.4 4.5.3.6 45.3.7 45.3.8 4.5.3.9 4.54.1 45.42 4543 45.44 4.5.45 45.4.6 454.7 45.43 4545 4551 4552 4553 4. 5.5.4 4.555 455.6 45.5.7 455.8 455.9 45.61 4.5.62 45.63 45.64 45. 65 4.5.6.6 45.6.7 45.6.8 45.65 45.71 45.72 45.7-3 45.74 45.75 45.7.6 45.7.7 45.7.8 45.75 45.81 45.8.2 45.83 45.8.4 45.85 45.8.6 45. 8.7 45.8.8 45.85 4551 4.553 4553 45.94 4555 4.55.6 455.7 4. 55.8 4555 4.6.11 4613 4.613 4.614 4.6? 5 4.6.16 4.6.17 46.18 46. 15 4.621 4652 4.6.2.3 4.634 4.625 4.62.6 4.63.7 4.63.8 4635 4631 463.2 4,633 4.63.4 4,635 4.63.6 46.3.7 4.63.8 4635 4.64.41 4642 4643 4.64.4 46.45 4.6.4.6 4.6.4.7 46.48 46.49 4.651 4.653 465.3 4.6.54 4.655 4.65.6 46.5.7 4.65.8 46.55 4.6.61 4.6.63 4.6.6.3 4. 6,6.4 4.6.65 4.6.6.6 4.6.6.7 4.6.6.8 4.6.65 46.71 4.6.72 4.6.73 4.6.7.4 4. 6.7.5 4.6.7.6 4.6.7.7 46.7.8 4.6.75 4.6.81 46.8.2 46.83 46.84 4.6.85 4. 6.8.6 4.6.8.7 4.6.8.8 4.6.8.9 4.6.91 4.652 4.6.9.3 4.654 4.6.95 4.6.9.6 4. 65.7 4.65.8 4.65.9 4.7.11 4.71.2 4.713 471.4 4.7.15 4.71.6 4.71.7 4. 7.18 4715 4751 4,722 4,723 4.72.4 4.725 472.6 4.7.2.7 4.72.8 4. 735 4.731 4.7.35 47.33 4.7.34 4.7.35 47.3.6 4.7.3.7 4.73.8 4.735 4. 741 4,7.42 4,743 4,745 4.74.6 47.47 4.7.48 4.7.45 4.751 4. 4. 835 4.84.1 4843 4.8.43 4.844 48.45 484.6 484.7 4.84.8 4.845 4851 4.852 4.853 4.85.4 485.5 485.6 4.85.7 4.85.8 4.85.9 4.8.61 4. 8.63 4.8.8 4.8.64 48.65 4.8.6.6 4.8.6.7 4.8.6.8 4.8.65 48.71 4.8.75 4. 8.73 4.8.74 48.75 48.7.6 4.8.7.7 4.8.8.8 48.75 48.81 4.8.82 48.83 48. 84 48.85 4.8.8.6 4.8.8.7 48.8.8 4.8.85 485.1 4.852 4.853 4.8.9.4 4,855 4 5.6 4S5.7 4.85.8 4.855 4511 4512 45.13 451.4 45.15 451. 6 451.7 4.9.18 4515 4551 45.22 4523 452.4 4.935 453.6 493.7 452.8 4525 45.31 45.33 4.935 4.93.6 453.7 493. 8 45.35 454.1 45.45 4.944 4.945 45.46 4.9.47 49.4.8 45. 49 45.51 455.2 455.3 4554 45.55 495.6 455.7 455.8 455.9 Table 2 - continued 45.61 45.63 45.63 45.64 45.65 49.6.6 45.6.7 49.6.8 4.9.6.9 45.7.1 45.72 45.7-3 4J.74 49.75 4.9.7.6 49.7.7 45.7.8 49-75 45.81 4.9.85 45. 83 45.84 45.85 49.8.6 45.8.7 49.8.8 45.85 4951 455.2 455.3 4554 4555 455.6 455.7 455.8 4955 51.11 51.13 51.13 51.14 ? .IS 511.6 51.17 511.8 51.15 ** < *-***"* 5? 2 5? 23 512.4 5125 51. 2.6 * 3 ± .l * - »/ 512.8 5,125 5131 5132 5,133 513.4 5135 5.13.6 . 13.7 513.8 5.135 5.14.1 5142 5.143 514.4 5.14.5 51.4.6 5.14.7 51. 4.8 5.145 5151 5.152 $ .153 5.154 5? 55 515.6 515.7 515.8 . 155 51.6.1 51.62 5.16.3 5.16.4 5.1.65 5.16.6 51.6.7 51.6.8 5.165 51. 71 51.72 51.73 51.74 51.75 5.17.6 51.7.7 5.17.8 5.1.75 51.8.1 . 182 51.83 51.84 5.185 51.8.6 51.8.7 51.8.8 5.185 5? 3? 515.2 5153 5154 5155 5.19.6 5.19.7 5.15.8 51.95 52.11 52.12 52.13 5314 52.15 52.16 53.17 5 * 2 * 1 + 0 5215 535.1 5222 5223 522.4 522. 6 522.7 522.8 -3 ** & «Jrf? I? 5.2.31 5532 5233 533.4 5.235 523. 6 523.7 523.S 5235 5241 52.43 52.43 *? - * - fi ** t »* t 5245 524.6 52. 4.7 524.8 52.45 5.251 5252 525? 5255 525.6 525.7 555. 8 5253 52.61 53.62 52.63 52.6.4 52.65 52.6.6 52.6.7 52.6.8 52. 6.9 52.71 D? * * J ¿52.7.3 52.7.4 5.2.7.5 52.7.6 52.7.7 52.7.8 52.7.9 52. 8.1 52.82 52.83 52.8.4 53.85 52.8.6 55.8.7 52.8.8 52.85 5251 52. 92 5,253 5254 5,255 525.6 525.7 525.8 5255 53.1.1 5.3.12 53? 5,314 5,31.5 53.16 53.17 531.8 53.19 53.22 5.32.3 532? 5,325 532.6 53.2,7 533.8 tfsí? £ t 5333 5.33.4 $ 335 533.6 53.3.7 533.8 53.35 *? ? * 5 ** + * 5,344 5.3.45 53. 4.6 5.34.7 5.34.8 5345 5351 5.353 5 353 5.35.6 535.7 5.3.5.8 5353 53.61 53.62 53.63 53.64 5.3.65 53.6.6 5.3.6.7 53. 63 53.65 53.71 53.72 53.73 53.7.4 53.75 53.7.6 53.7.7 5.3.7.8 53. 75 53.81 53.82 5.3.83 53.84 5.3.85 S3? .6 53.8.7 53.8.8 5.3.85 53. 9? 5.352 5.35.3 5.35.4 5355 5.35.6 535.7 5.35.8 533S 5411 5412 5,413 5414 5,415 5,416 5,441.7 5,418 5,415 5,421 5,422 5423 542.4 5,435 542.6 542.7 5.45.8 54.25 54.3.1 54.32 5.43.3 54. 3.4 5.43.5 5.43.6 5.43.7 54.3.8 5.435 54.4.1 54.42 5.4.43 5.4.4.4 . 4? 5 54.46 54.4.7 5.44.8 5.4.45 5451 5.453 5453 5454 5.45.5 . 45.6 545.7 5.45.8 5455 54.61 54.65 54.63 5.46.4 5.465 5.4.6.6 . 4.6.7 54.6.8 54.65 5.4.71 5.4.72 5.4.73 54.74 54.75 54.7.6 5.4.7.7 54. 7.8 5.475 54.8.1 5.482 54.8.3 5.484 54.8.5 54.8.6 '5.4.8.7 5.4.8.8 . 4.85 545.1 545.2 5.45.3 545.4 5.455 5.4.9.6 54.9.7 545.8 5.455 55. 11 551.3 5514 55.15 5.5.16 551.7 551.8 55.15 552? 55. 22 5523 5524 5525 55.2.6 555.7 55.2.8 5523 55.3.1 5.532 55. 3.3 55.34 5535 5.5.3.6 55.3.7 553.8 5535 554.1 554.2 53.43 55. 44 55.4.5 55.4.6 55.4.7 55.48 5.54.9 55.51 55.52 5.5.5.3 5.5.54 . 555 555.6 555.7 555.8 5555 5.5.61 55.62 55.63 55.6.4 55.65 . 5.6.6 55.6.7 5.5.6.8 55.6.9 55.71 55.7.2 55.73 55.7.4 55.75 55.7.6 55. 7.7 55.7.8 55.75 5.5.81 5.5.8.2.88 55.8.4 5.5.o * 5 55.8.6 55.8.7 55.8,8 55 5 ?? ? * °%? FCgf ¿r í3s ¿iw7 * ¿? 555.4 55.9.6 555.7 555.8 . 555 5.6.11 5.612 5.613 5.6.14 5.615 5.6.16 5.6.1.7 5.6.1.8 5.615 . 621 5.622 5.62? 5.625 5.63.6 5.62.7 5.62.8 5.623 5.6.31 . 633 5.634 5.635 5.6.3.6 5.63.7 5.63.8 5.6.35 5.6.41 5.6? 2 . 6.43 5.6.44 5.645 5.64.6 5.64.7 5.64.8 5.645 5.651 5.6.52 5.653 Table 2 - continuation 5.654 5.655 5.65.6 5.65.7 5.65.8 5.655 5.6A1 5.6.62 5.6.63 5.6.6A . 6.6.5 5.6.6.6 5.6.6.7 5.6.6.8 5.6.6.9 5.6.71 5.6.72 5 .6.8.7 5.6.8.8 5.6.85 5.651 5.652 5.65.3 5.63A 5.635 5.6.9.6 5.65.7 ,65.8 5,655 5.7.1.1 D * *! * ^ 5,7,1,3 5,71.4 5.7.1.5 5.71.6 5.7.17 5.7,18 . 715 5,721 5,722 3 »/« - £ - ¥ 5,734 5,755 5.72.6 5.72.7 5.73.8 5.725 . 731 5.7.32 5.7.3.3 5.734 5.73.5 5.73.6 5.73.7 5.73.8 5.735 5.741 . 745 5.7.4.3 5.7.44 5.745 5.74.6 5.74.7 5.74.8 5.7.45 5.751 5.752 . 75.3 5.75.4 5.755 5.7.5.6 5.75.7 5.75.8 5.7.5.9 5.7.6.1 5.7.62 5.7.6.3 . 7,6,4 5.7.65 5.7.6.6 5.7.6.7 5.7.6.8 5.7.6.9 5.7.71 5.7,72 5.7.7.3 5.7.74 .7.75 5.7.7.6 5.7.7.7 5.7.7.8 5.7.75 5.7.81 5.7.82 5.7.83 5.7.84 5.7.8.5 . 7.8.6 5.7.8.7 5.7.8.8 5.7.85 5.751 5.752 5.753 5.75.4 5.755 5.75.6 . 7.9.7 5.75.8 5.555 5.811 5.8.12 5.8.13 5.8.14 5.815 5.81.6 5.81.7 .81.8 5.815 5.831 5.822 5.823 5.824 5.835 5.82.6 5.82.7 5.82.8 . 855 5.831 5.832 5.8.33 5.83.4 5.835 5.8.3.6 5.83.7 5 * a3 * 0 5.835 ,841 5.843 53A3 5.8.44 5.8.45 5.84.6 5.8.4.7 5.8.4.8 5.845 5.85.1 5352 5,853 5,854 5,855 5.8.5.6 5.8.5.7 5.85.8 5353 5.8.61 5.8.62 . 8.6.3 5.8.64 5.8.65 5.8.6.6 5.8.6.7 5.8.6.8 5.8.6.9 5 .71 5.8.72 5.8.73 . 8.7.4 5.8.75 5.8.7.6 5.8.7.7 5.8.7.8 5.8.75 5.8.81 5.8.82 5.8.83 5.8.8.4 . 8.8.5 5.8.8.6 5.8.8.7 5.8.8.8 5.8.85 5.851 5.852 5.853 5.8.94 5.855 . 85.6 5.85.7 5.85.8 5.S55 551.1 5512 55.13 531.4 55.15 55.16 . 91.7 5.9.18 5.913 5521 552.2 ~ Jf * £ * 3 5.92.4 5325 55.2.6 5.92.7 . 9.2.8 55.25 5531 5.932 5.934 5535 553.6 553.7 553.8 . 935 5541 5.9.42 5.943 5.944 53A5 53A.6 5.9.47 55.4.8 5545 555. 1 555.2 555.3 5554 5355 533.6 555.7 555.8 5353 55.61 55. 62 55.6.3 55.64 53.65 53.6.6 55.6.7 55.6.8 53.6.9 55.71 55.7.2 55.73 5.9.74 55.7.5 55.7.6 55.7.7 55.7.8 55.75 55.81 55.83 55.3 55. 84.88 55.5.6 55.8.7 55.8.S 55.85 5551 55.92 5553 55.9.4 5555 555.6 555.7 555.8 5.9.93 6.111 S112 6113 6.114 61.15 6. 116 611.7 6.1.1.8 6 ??. 9 6.121 6? 22 6.123 61.24 6125 612.6 61. 2.7 6.12.8 612.9 6.131 6.1.3.2 6.13.3 6.13.4 6.135 6.13.6 61.3.7 6133 61.35 6.141 61.42 61.43 61.44 6.145 6.1.4.6 6.14.7 6.148 6145 6? 5? 6,152 615.3 6? 5A 6,155 615. 615-7 615.8 6153 6. 161 6.1.62 6.1.63 6.164 6X65 6.16.6 6.16.7 6.1.6.8 6.165 6.171 6.172 61.73 61.7.4 61.75 6.17.6 6.17.7 6.17.8 6.175 6.1-8.1 61.85 61. 83 61.84 61.85 61.8.6 6.1.8.7 6.18.8 6.185 6131 615.2 6133 6. 194 6133 6? 3.6 615.7 6.15.8 6.195 62 ?? 6212 6213 621.4 62. 15 621.6 62.1.7 631.8 6215 622? 6222 622.3 622.4 6225 622. 6 625.7 622.8 62.2.9 623.1 6.235 62.3.3 62.3.4 62.35 623.6 62. 3.7 623.8 62.3.9 62.41 6.2.42 6243 6.24.4 62.4.5 6.246 6.2.4.7 62. 4.8 6245 625.1 625.2 625.3 625.4 625.5 625.6 • 625.7 625.8 6255 62.6.1 62.6.2 62.63 6.2.64 6.2.65 6.2.6.6 62.6.7 62.63 62.6.9 6. 2.71 65.72 62.73 62.74 62.75 62.7.6 6.2.7.7 62.7.8 62.75 62.81 6. 2.8.2 6.2.8.3 6.2.8.4 6.2,85 6.2.8.6 6.2.82 62.8,8 6.28.9 62.91 6232 6. 253 623A 6,25.5 623.6 635.7 623 C?% 93 6.311 6.3.12 6313 6314 63? 5 6.3.16 631.7 6.3.18 63.19 6321 63.22 63.23 6324 6. 3.25 635.6 635.7 632.8 6323 6.3.31 6332 6333 6.33.4 6,335 6. 3.3.6 63.3.7 6.33.8 6333 6341 63.4.2 63.43 63.4.4 6.345 63.46 Table 2 - continuation 63.4.7 6.3.4.8 6.3.45 6.3.5.1 63.52 6.35.3 6.3.34 6.3.55 6.3.5.6 6.3.5.7 635. 8 6.335 6.3.61 63.62 63.63 63.6.4 63.65 63.6.6 63.6.7 6.3.6.8 63. 6.9 6.3.71 63.72 63.7.3 63.74 6.3.75 63.7.6 63.7.7 6.3.7.8 63.75 63. 81 6.3.8.2 63.83 63.84 63.85 63.8.6 63.8.7 6.3.3.8 63.8.9 6.351 6,352 635.3 63.94 63.95 63.9.6 6.35.7 635.8 6.3.9.9 6411 6.412 6. 41.3 64.14 6.415 6.416 64.17 6.4.1.8 6.415 6A31 6.432 6.423 6. 65. 3.4 6535 653.6 6.53.7 6.53.8 6533 654.1 6.542 65.43 6.544 6545 65A.6 65.4.7 654.8 65.45 6551 6552 6.553 6.55A 6555 6.5.5.6 655.7 655.8 6333 65.6.1 65.62 6.5.6.3 65.64 65.65 65.6.6 65. 6.7 6.5.6.8 65.63 65.7.1 65.7.2 65.73 6.5.74 65.75 65.7.6 65.7.7 65. 7.8 65.75 65.81 6.5.82 65.83 65.84 65.85 65.8.6 65.8.7 65.8.8 65. 85 6531 6532 6,533 653.4 6535 633.6 655.7 655.8 655.9 6. 6.1.1 6.612 6.613 6.61A 6.615 6.6.16 6.61.7 6.6.18 6.6.19 6.621 6. 622 6,623 6,624 6,625 6,62.6 6.63,7 6.62,8 6.6.25 6.6.31 6.6.32 6. 633 6.634 6.63.5 6.6.3.6 6.63.7 6.63.8 6.633 6.641 6.6.42 6.643 6. 6.44 6.6.45 6.64.6 6.6.4.7 6.64.8 6.6A3 6,651 6,652 6,653 6,654 6. 655 6.6.5.6 6.65.7 6.6.5.8 6.633 6.6.6.1 6.6.62 6.6.63 6.6.6.4 6.6.65 6. 6.6.6 6.6.6.7 6.6.6.5 6.6.6.9 6.6.71 6.6.72 6.6.73 6.6.7.4 6.6.75 6.6.7.6 6. 6.7.7 6.6.7.8 6.6.75 6.6.81 6.6.82 6.6.83 6.6.84 6.6.85 6.6.8.6 6.6.8.7 6. 6.8.8 6.6,85 6,631 6-632 6-633 6.65-4 6.635 6.65.6 é.6.9.7 6.65.8 6. 655 6.7.1.1 6.712 6.7.13 6.724 6.715 6.7.16 6.7.17 6.7.18 6.71.9 6. 7.21 6.752 6.723 6.724 6.725 6.7.2.6 6.72.7 6.73.8 6.72.9 6.73.1 6. 7.32 6.73.3 6.7.3.4 6.735 6.73.6 6.73.7 6.7.3.8 6.735 6.7.41 6.742 6,743 6.744 6.745 6.7.46 6.7.47 6.74.8 6.745 6.751 6.753 6.75.3 6. 754 6.755 6.75.6 6.75.7 6.75.8 6.755 6.7.61 6.7.62 6.7.63 6.7.64 6. 7.65 6.7.6.6 6.7.6.7 6.7.71 6.7.72 6.7.74 6.7.75 6.7.7.6 6.7.7.7 6.7.7.8 6.7.75 6.7.81 6.7.82 6.7.8.3 6.7.8-4 6.7.8.5 6.7.8.6 6.7.8.7 6.7.8.8 6.7.85 6.751 6.753 6.753 6.754 6.755 6.75.6 6.75.7 6,75,8 6,755 6,811 6.8? 2 6,81.3 6.81A 6315 6.8.16 6.8.17 6.81,8 6. 815 6,821 6,822 6.82.3 6,824 6.8.25 6.82.6 6.82.7 6.83,8 6.825 6,831 6 * 8,33 6333 6 $, 4 6,83,5 6.8.3.6 6,83.7 6.83.8 6.8.35 6,841 6. 84.2 6.843 6.84.4 6.84.5 6: 84.6 6.84.7 6.84.8 6.8.45 6.851 6352 6. 853 6.854 6.855 6.85.6 6.85.7 6.8.5.8 6.855 6.8.61 6.8.63 6.8.6.3 6.8.64 6.8.65 6.8.6.6 6.8.6.7 6.8.6.8 6.8.65 6.8.71 6.8.72 6.8,73 6.8,74 6. 8.75 6.S.7.6 6.8.7.7 6.8.7.8 6.8.75 6.8.8.1 6.8,82 6.8.83 6.8.84 6.8.85 6. 8.8.6 6.8.8.7 6.8.8.8 6.8.85 6.8.91 6 32 6.853 6.8.9.4 6.855 6.85.6 6. 85.7 6.85.8 6.855 6.9.1.1 6312 651.3 6.914 6.915 65.16 651.7 65. 18 6313 6,921 632 6323 632A 6325 652.6 652.7 653.8 65. 25 6331 6332 6333 65.34 6.935 653.6 65.3.7 65.3.8 6333 Table 2 - continuation 654.1 65.42 65.43 6544 63.45 6546 65.47 654.8 65.45 6551 6352 6.95.3 635.4 6355 635.6 655.7 6333 6.933 6.9.61 63.62 63.63 65.64 6.9.65 65.6.6 65.6.7 65.6.8 63.63 6.9.71 63.72 63.72 65.74 65.75 65.7.6 65.7.7 65.7.8 65.75 6331 65.83 65.83 6.9.84 6. 9.85 65.8.6 65.8.7 65.8.8 65.85 63.91 6332 655.3 6554 655.5 65.9.6 655.7 65.9.8 6333 71.11 7112 7113 7114 7115 71.16 711.7 711.8 7.119 7121 7152 i * JL¿5 7.124 7155 712.6 7.12.7 7.12.8 7.125 7131 7132 7.133 7134 7135 713.6 713.7 7.13.8 7.1.3.9 7.14.1 7.142 7.143 71.44 7145 7.14.6 7.147 714.8 7145 7151 7,152 7,153 7,154 7,155 715.6 715.7 71.5.8 7155 7,161 71. 62 7.163 7.164 7.165 71.6.6 7.16.7 71.6.8 7.16.9 7.171 7.175 71. 73 71.7.4 7.175 71.7.6 71.7.7 71.7.8 7.17.9 71.8.1 7.182 71.8.3 7. 184 7.185 7.1.8.6 71.8.7 71.8.8 7,185 i sliír t X 7.152 7153 7154 7. 195 71.9.6 715.7 715.8 7.155 7211 / • ?? 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.9 8.52.1 8522 8.5.2.3 8.52.4 8525 852.6 853.7 S52.8 8525 85.31 8.5.32 8533 8.53.4 85.35 853.6 853.7 S53.S $ 533 85.42 8542 8.54.3 85.44 854.5 854.6 85. 47 85.4.8 854.9 8551 8552 85.53 855.4 8555 855.6 855.7 855. 8 85.55 85.61 85.63 85.63 85.64 85.65 85.6.6 85.6.7 85.6.8 85. 63 85.72 8.5.72 8.5.73 85.7.4 85.75 85.7.6 8.5.7.7 85.7.8 85.75 8. 5.8.1 85.82 85.8.3 85.84 85.85 85.85 85.8.7 8.5.8.8 8.5.85 S552 8552 85.9.3 855.4 855.5 8.55.6 855.7 855.8 8555 8.622 8.62.2 8. 623 8.614 8.615 8.61.6 8.62.7 8.62.8.613 8.621 8.622 8.623 8.62.4 8.62.5 S.62.6 8.62.7 8.6, 8 8.62.9 8.63.1 8.632 8.6.3.3 8.6.3.4 8.635 8.63.6 8.63.7 8.63.8 8.6.35 8.641 8.642 8.643 8.6.44 8.6.4.5 8.64.6 8.6.47 8.6.4.8 8.6.49 8.652 8.652 8.65.3 8.654 8.655 8.65.6 8. 65.7 8.6.5.8 8.655 8.6.61 8.6.62.6.63 8.6.64 8.6.65 8.6.6.6 8.6.6.7 8.6.6.8 8.6.6.9 8.6.72 8.6.72 8.6.7.3 8.6.7.4 8.6.75 8.6.7.6 8.6.7.7 8.6.7.8 8. 6.75 8.6.81 8.6.82 8.6.83 8.6.84 8.6.85 8.6.6.6 8.6.8.7 8.6.6.8 8.6.85 8. 631.632 8.65.3 8.654 8.635 S.6.9.6 8.65.7 8.65.8 8.65.9 8.7.12 8. 712 8.713 8.714 8.715 8.71.6 8.7.17 8.71.8 8.715 8.72, 1 8.72.2 8. 723 8.724 8.72.5 8.72.6 8.72.7 8.72.8 8.72.9 8.7.31 8.732 8.733 8.734 8.7.35 8.73.6 8.73.7 8.7.3.8 8.735 8.741 8.742 8.74.3 8.7.44 S.745 8-746 8.74.7 8.7.4.S 8.7.45 8.751 8.752 8.753 8254 8.755 8. 75.6 8.75.7 8.7.5.8 8.755 8.7.62 8.7.62 8.7.63 8.7.6.4 8.7.65 8.7.6.6 8. 7.6.7 8.7.6.8 8.7.65 8.7.72 8.7.72 8.7.73 8.7.74 8.72.5 8.7.7.6 8.7.7.7 8. 7.7.8 8.7.7.9 8.7.81 8.7.82 8.7.83 8.7.8.4 8.7.85 8.7.8.6 8.7.8.7 8.7.8.8 8. 7.85 8.751 8.7.92 8.753 8.754 8.755 825.6 8.75.7 8.75.8 8.75.9 8. 8.1.1 8.812 8.8.13 8.8.14 8.8.15 8.81.6 8.8.17 8.81.8 8.8.15 8.821 8. # 8554 8,955 855.6 8553 855.8 8555 85.62 85.62 85.63 ^ 3.6.4 85. 65 83.6.6 85.6.7 8.9.6.8 85.65 8.9.72 85.72 3.73 85.74 8.9.75 85. 7.6 85.7.7 85.7.8 85.75 85.81 85.82 85.83 B33A S.9.85 85.8.6 85.8.7 8.9.8.8 85.85 8552 8552 85.93 8554 8.955 85.9.6 855.7 8. 9.9.8 8.9.95 9.1.1.1 9113 9.1.13 9.1.1.4 911.5 9? 1.6 91.17 9.1.1.8 9. 1.1.9 9121 9122 9,123 9.124 91.25 912.6 91.2.7 92.2.8 9125 9132 9133 9134 9.13.6 913.7 91.3.8 9.135 9.141 9. 142 91.43 92.44 9145 914.6 9.14.7 914.8 9.145 915.1 9.152 9. 15.3 9.15.4 9.1.15 9.1.5.6 9.15.7 9.15.8 9.15.9 9.1.61 91.62 9.16.3 9. 164 9.165 9.16.6 91.6.7 91.6.8 9.165 9.1.7.1 92.72 91.73 9.17.4 9. 175 91.7.6 91.7.7 9.17.8 9.175 9.1.8.1 9.182 9.183 91.84 9.185 9,18.6 9.1.8.7 91.8.8 913.9 9? 31 9.192 9133 913A 9.1.95 913.6 915. 7 915.8 9133 9211 9222 9213 921.5 92.16 922.7 921. S 9221 9223 922.4 9325 922.6 922.7 922.8 92. 25 9231 92.33 923A 923.5 933.6 923.7 923.8 9233 924. 1 9242 9.2.43 9244 924.5 92.4.6 92.47 924.8 9.2.4.9 9251 9252 9254 92.55 925.6 925.7 925.8 9353 93.61 9.2.6.2 92. 63 92.6.4 92.65 9.2.6.6 9.2.2.7 9.2.6.S 9.2.49 9.2.71 9.2.7.2 92.7.3 92. 7A 92.75 92.7.6 92.7.7 93.7.8 92.75 9.2.81 92.82 92.83 92.8.4 92. 85 92.8.6 92.8.7 9233 92.85 925.1 92.92 9.253 925.4 92.95 925. 6 925.7 925.8 9233 93.1.1 9312 93.13 931.4 9.3.15 9.3.1.6 931.7 932.8 9313 9321 9.32.2 932.3 9.324 9325 932.6 9.3.2.7 933. 8 9323 9331 9332 933.3 93.34 93.3.5 933.6 933.7 93.3.8 9. 335 9341 9.3.42 934.3 9344 9345 9.3.4.6 934.7 93.43 93.4.9 93. 51 9352 9.3.54 93.5.5 935.6 93.5.7 9.35.8 93.5.9 93.61 9. 3.62 93.63 93.64 9.35 9.3.6.6 93.6.7 93.6.8 93.63 9.3.71 93.72 93.73 93.7.4 93.7.5 93.7.6 9.3.7.7 93.7.8 93.75 9.3.8.1 9.3.82 93.83 93. 84 9335 93.8.6 93.82 93.8.8 93.85 9.3.91 9352 9353 9.35.4 9355 935.6 935.7 935.8 9.3.95 9411 9.412 9413 9414 9.415 9. 4.16 941.7 941.8 941.9 94.21 94.22 9.42.3 9424 9435 9.42.6 9. 42.7 942.8 94.25 9.4.31 9.4.32 94.3.3 9.4.34 94.35 9.43.6 9.4.3.7 943.8 9435 9.441 94.42 94.43 9.444 9445 9.44.6 9.4.47 9.4.43 9. 4.45 94.51 9452 9.453 945.4 9.45.5 9A5.6 9.45.7 9.45.8 9.453 9,461 9,462 9A.63 9A.6A 9.465 9.46.6 94.6.7 94.6.8 9.465 9.471 94.72 94.73 9.4.7.4 9.4.75 94.7.6 9A.7.7 9.47.8 9.475 9.4.82 94.85 9. 483 9,484 94.85 94.8.6 94.8.7 94.8.8 94.85 9.491 945.2 945.3 9454 9455 94.9.6 94.93 94.9.8 9.495 9511 9.512 9513 95.1.4 9515 951.6 95.17 95.18 9515 9551 9,522 9533 952.4 95.2.5 9. 52.6 9.52.7 952.8 9.523 95.31 9532 9533 953.4 9535 953.6 95.3.7 9.5.3.8 9535 9.5.41 9.542 95.4.3 95.4.4 93A3 95.46 954.7 954. S 95.45 955.1 9552 9553 955A 9555 955.6 955.7 95.5.8 9. 555 95.61 95.62 9.5.63 9.5.64 95.65 95.6.6 95.6.7 95.6.8 95.63 95. 71 95.72 95.73 95.74 95.75 953.6 9.53.7 95.7.8 9.5.75 9.5.81 95. 8.2 95.8.3 95.8.4 9.5.85 95.8.6 95.8.2 95.8.8 95.8.9 95.91 9.5.92 955. 3 9554 9555 955.6 9.55.7 955.8 9,555 9.6.1.1 9.61.2 9.6.13 Table 2 - continued 9. 6.14 9.6.15 9.6.16 9.6.17 9.6.18 9.615 9.621 9.622 9.623 9.624 9.6.25 9.62.6 9.62.7 9.62.8 9.65 9.632 9.632 9.63.3 9.6.34 9.6.35 9.63.6 9.63.7 9-63.8 9.635 9.6.41 9.642 9.6.69 9.6.49 9.645 9.6.4.6 9.64.7 9.6.68 9.645 9.651 9.653 9.653 9.654 9.6.55 9.65.6 9.6.53 9.65.8 9.65.9 9.6.61 9.6 , 63 9.6.6.3 9.6.6.4 9.6.65 9.6.6.6 9.6.6.7 9.6.6.8 9.6.65 9.66.1 9.632 9.6.71 9.6.74 9.6.75 9 6.7.6 9.6.7.7 9.6.7.8 9.6.75 9.631 9.6.8.2 9.633 9.6.8A 9.635 9.6.6 9.63.7 9.633 9.633 9.6.91 9.632 S3 9.63.4 9.63.5 9, 63.6 9.63.7 9.633 9.633 9.7.1.1 9.712 9.723 9.715 9.71.6 9.72.7 9.7.18 92.19 9.73.1 9.7.23 9.724 9.725 9.72.6 9.73.7 9.75.8 9225 9.7, 31 9.732 9.733 9.7.34 9.735 933.6 9.7.3.7 9.7.3.8 9.735 9.7.4.1 9.7.42 9.743 9.7.44 9.745 9.74.6 9.7.4.7 9.7.4.8 9.7.45 9.751 9.752 9.75.3 9.754 9.7.5.5 925.6 9.75.7 9.75.8 9.7.55 9.7.62 9.7.62 9.7.63 9.7.64 9.7.65 9.7.6.6 9.7.62 9.7.6.8 9.7.65 9.7.71 9.7.73 9.7.73 9.7.7.4 9.7.75 9.7.7.6 9.7.7.7 93.7.8 93.7.9 9.7-81 9.732 9.7.83 9.7.8.4 9.7.85 9.7 .8.6 92.8.7 9.7.8.8 9.7.85 9.7.91 9.752 9.7.9.3 9.754 9.755 9.75.6 '9.75.7 9.75.8 9.755 9.811 9.81.2 9.8.13 9.824 9315 9.8.16 9.8, 17 9.8.18 9.815 9.821 9.823 9323 9.8.24 9.82.5 932.6 9.82.7 9.82.8 9.825 9.8.31 9.8.32 9.833 9.8.3.4 9.835 9.83.6 9.83.7 9.83.8 9.83.9 9.841 9.842 9.843 9.84.4 9.8.45 9.84.6 9.8.4.7 9.84.S 9.845 9.851 9.852 9.85.3 9.854 9.8.5.5 9.85.6 9.85.7 9.8.5.8 9.855 9.8.6.1 9.8.6.2 9.8. 6.3 9.8.64 93.65 9.8.6.6 9.8.6.7 9.8.6.8 9.8.65 9.821 9.8.72 9.8.73 9.8.7.4 9.8.75 93.7.6 9.8.7.7 9.8.7.8 9.8.7.9 9.8.82 9.832 9.8.8.3 9.8.84 9.8.85 9.8.8.6 9.8.8.7 9.8.8.8 9.8.8.9 9.8.9.1 9.852 9.85.3 9.85.4 9.855 9.85.6 9.85.7 9.85.8 9.85.9 7 ** 'ii A 952.2 9313 9.92.4 931.5 95.16 952.7 951.8 951.9 9321 95.22 9.92.3 952.4, 7, ¿7 * # -3 952.6 952.7 952.8 9525 9331 9,9,32 95.33 9,934 9333 953.6 953.7 95.3.8 9535 9542 93.42 93.43 9544 95.45 95.4.6 95.4.7 95.48 9545 955.1 9352 93.53 935.4 9555 955.6 955.7 955.8 9353 93.61 93.62 93.63 93.6.4 93.65 93.6.6 95.6 .7 95.6.8 93.63 93.71 93.72 93.73 95.74 95.75 9.9.7.6 95.7.7 9.9.7.8 9.9.75 9331 9332 9.933 9.9.84 95.85 95.8.6 95.8.7 9.9.8.8 95.85 9551 93.92 93 33 933.4 95.95 955.6 9553 9.9.9.8 9333 In another aspect the following compounds are included in the invention but the compounds are not limited to those illustrative compounds. The compounds are shown without description of stereochemistry since the compounds are biologically active as the diastereomeric mixture or as a simple stereoisomer. The compounds included are designated by numbers assigned to the variables of formulas XI-XIII using the following convention: VI. V2 V3 V4 V5.V6. Each individual compound from 1.1.1.1.1.1 to 9.9.9.9.9.9 (eg, 2.3.4.5.6.7 or 8.7.3.5.2.1) are included in the present invention as an individual species and can be specifically established as such for inclusion or can be specifically excluded from the present invention. As will be understood, what is included is clear from the description, the Table is not included as to unduly extend the specification.

Formula XI Formula XII Formula XIII Variable V1; 1) -P (0 (OH) 2 2) -P (0 [0-CH2OC (0) C (CH3) 3] 2 3) -P (0 [0-CH2OC (0) CH (CH3) 2] 2 4) -P (0 [0-CH 2 OC (O) OCH 2 CH 3 J 2 5) -P (0 [NH-CH (CH 3) C (O) OCH 2 CH 3] 2 6) -P (0 [NH-C (CH 3) 2 C ( O) OCH2CH2] 2 7) -P (0 (OC6H5) 2 8) -P (0 (O-CH (3-chlorophenyl) CH2CH2-0) 9) -P (0 (O-CH (4-pyridyl) CH2CH2-0) Variable V2: 1) -CH2- 2) -OCH2- 3) -CH2-CH2-4) -NHCH2- 5) -NH (CO) -6) -CH2-CH (NH2) ~ (R-configuration) 7) -CH2-CH (NH2) - (S-configuration) 8) -CH = CH- (trans) 9) -nule Variable V3: 1) -OCH3 2) iodine 3) bromo 4) chloro 5) fluoro 6) methyl 7 ) trifluoromethyl 8) cyano 9) -OCF3 Variable V4: 1) iodine 2) CH (CH 3) 2 3) - (3-trifluoromethylphenoxy) 4) - (3-ethylphenyl) 5) -C (0) NH-CH 2 -CH 2 -phenyl 6) -CH (OH) (4-fluorophenyl) 7) -S02 (4-fluorophenyl) 8) - (4-fluorobenzyl) 9) -1-ethyl-propyl Variable V5 and V6 1) hydrogen 2) iodine 3 ) bromine 4) chloro 5) fluoro 6) methyl 7) trifluoromethyl 8) cyano 9) -OCH3 In another aspect the following compounds are included in the invention but the compounds are not limited to those illustrative compounds. The compounds are shown without description of stereochemistry since the compounds are biologically active as the diastereomeric mixture or as a simple stereoisomer. The compounds included are designated by numbers assigned to the variables of formulas XIV and XV using the following convention: V1.V2. V3.V4.V5.V6.V7 Each individual compound from 1.1.1.1.1.1.1 to 9.9.9.9.9.9.2 (for example, 2.3.4.5.6.7.1 or 8.7.3.5.2.1.1) are included in the present invention as an individual species and can be specifically established as such for inclusion or can be specifically excluded from the present invention. As will be understood, what is included is clear from the description, the Table is not included as to unduly extend the specification.

Formula XIV Formula XV Variable V7: 1) -CH2- 2) -nuil The present invention provides compounds of formula I which include but are not limited to wherein: Phosphonic Acids G is -O-, T is -CH2CH (NH2) -, R1 is -I, R2 is -I, R3 is -I, R4 is -H, R5 is -OH, X is -P03H2; G is -O-, T is -CH2CH (NH2) -, R1 is -I, R2 is -I, R3 is -I, R4 is -I, R5 is -OH, X is -P03H2; G is -O-, T is -CH2-, R1 is -I, R2 is -I, R3 is -I, R4 is -H, R5 is -OH, X is -P03H2; G is -O-, T is - (H) C (O) -, R1 is -CH3, R2 is -CH3, R3 is CH (OH) (4-fluorophenyl), R4 is -H, R5 is -OH, X is -P03H2; G is -CH2-, T is -OCH2-, R1 is -CH3, R2 is -CH3, R3 is i-propyl, R4 is -H, R5 is -OH, X is -P03H2; G is -O-, T is -CH2-, R1 is -Cl, R2 is -Cl, R3 is i-propyl, R4 is -H, R5 is -OH, X is -P03H2; G is -O-, T is -OCH2-, R1 is -I, R2 is -I, R3 is i-propyl, R4 is -H, R5 is -OH, X is P0 H2; BisPOM G is -O-, T is -CH2CH (NH2) -, R1 is -I, R2 is -I, R3 is -I, R4 is -H, R5 is -OH, X is -P (O) [- OCH2OC (O) C (CH3) 3] 2; G is -O-, T is -CH2CH (NH2) -, R1 is -I, R2 is -I, R3 is -I, R4 is -I, R5 is -OH, X is -P (O) [-OCH2OC (O) C (CH3) 3] 2; G is -O-, T is -CH2-, R1 is -I, R2 is -I, R3 is -I, R4 is -H, R5 is -OH, X is -P (O) [-OCH2OC (O) C (CH3) 3] 2; G is -O-, T is -N (H) C (0) -, R1 is -CH3, R2 is -CH3, R3 is CH (OH) (4-fluorophenyl), R4 is -H, R5 is -OH X is -P (0) [-OCH2OC (0) C (CH3) 3] 2; G is -CH2-, T is -OCH2-, R1 is -CH3, R2 is -CH3, R3 is i-propyl, R4 is -H, R5 is -OH, X is -P (O) [-OCH2OC (O ) C (CH3) 3] 2; G is -O-, is -CH2-, R1 is -Cl, R1 is -Cl, R3 is i-propyl, R4 is -H, R5 is -OH, X is -P (O) [-OCH2OC (O ) C (CH3) 3] 2; G is -O-, T is -OCH2-, R1 is -I, R2 is -I, R3 is i-propyl, R4 is -H, R5 is -OH, X is P03H2; Carbonates G is -O-, T is -CH2CH (NH2) -, R1 is -I, R2 is -I, R3 is -I, R4 is -H, R5 is -OH, X is -P (O) [- OCH2OC (O) OCH (CH3) 2] 2; G is -O-, T is -CH2CH (NH2) -, R1 is -I, R2 is -I, R3 is -I, R4 is -I, R5 is -OH, X is -P (O) [-OCH2OC (O) OCH (CH3) 2] 2; G is -O-, T is -CH2-, R1 is -I, R2 is -I, R3 is -I, R4 is -H, R5 is -OH, X is -P (O) [-OCH2OC (O) OCH (CH3) 2] 2; G is -O-, T is -N (H) C (0) -, R1 is -CH3, R2 is -CH3, R3 is CH (OH) (4-fluorophenyl), R4 is -H, R5 is -OH , X is -P (0) [-OCH2OC (0) OCH (CH3) 2] 2; G is -CH2-, T is -OCH2-, R1 is -CH3, R2 is -CH3, R3 is i-propyl, R4 is -H, R5 is -OH, X is -P (O) [-OCH2OC (O OCH (CH3) 2] 2; G is -O-, T is -CH2-, R1 is -Cl, R2 is -Cl, R3 is i-propyl, R4 is -H, R5 is -OH, X is -P (O) [-OCH2OC (O OCH (CH3) 2] 2; G is -O-, T is -OCH2-, R1 is -I, R2 is -I, R3 is i-propyl, R4 is -H, R5 is -OH, X is P03H2; Bisamidates G is -O-, T is -CH2CH (NH2) -, R1 is -I, R2 is -I, R3 is -I, R4 is -H, R5 is -OH, X is -P (O) [ N (H) CH (CH 3) C (O) OCH 2 CH 3] 2; G is -O-, T is -CH2CH (NH2) -, R1 is -I, R2 is -I, R3 is -I, R4 is -I, R5 is -OH, X is -P (O) [N ( H) CH (CH3) C (O) OCH2CH3] 2; G is -O-, T is -CH2-, R1 is -I, R2 is -I, R3 is -I, R4 is -H, R5 is -OH, X is -P (O) [N (H) CH (CH3) C (O) OCH2CH3] 2; G is -O-, T is -N (H) C (0) -, R1 is -CH3, R2 is -CH3, R3 is CH (OH) (4-fluorophenyl), R 4 is -H, R 5 is -OH, X is -P (O) [N (H) CH (CH 3) C (O) OCH 2 CH 3] 2; G is -CH2-, T is -OCH2-, R1 is -CH3, R2 is -CH3, R3 is i-propyl, R4 is -H, R5 is -OH, X is -P (O) [N (H) CH (CH3) C (0) OCH2CH3] 2; G is -O-, T is -CH2-, R1 is -Cl, R2 is -Cl, R3 is i-propyl, R4 is -H, R5 is -OH, X is - P (O) [N (H) CH (CH3) C (O) OCH2CH3] 2; G is -O-, T is -OCH2-, R1 is -I, R2 is -I, R3 is i-propyl, R4 is -H, R5 is -OH, X is P03H2; Bisamidates # 2 G is -O-, T is -CH2CH (NH2) -, R1 is -I, R2 is -I, R3 is -I, R4 is -H, R5 is -OH, X is -P (O) [N (H) C (CH3) 2C (O) OCH2CH3] 2; G is -O-, T is -CH2CH (NH2) -, R1 is -I, R2 is -I, R3 is -I, R4 is -I, R5 is -OH, X is -P (O) [N ( H) C (CH3) 2C (O) OCH2CH3] 2; G is -O-, T is -CH2-, R1 is -I, R2 is -I, R3 is -I, R4 is -H, R5 is -OH, X is -P (O) [N (H) C (CH3) 2C (O) OCH2CH3] 2; G is -O-, T is -N (H) C (0) -, R1 is -CH3, R2 is -CH3, R3 is CH (OH) (4-fluorophenyl), R4 is -H, R5 is -OH , X is - P (O) [N (H) C (CH3) 2C (O) OCH2CH3] 2; G is -CH2-, T is -OCH2-, R1 is -CH3, R2 is -CH3, R3 is i-propyl, R4 is -H, R5 is -OH, X is - P (O) [N (H) C (CH) 2C (O) OCH 2 CH 3] 2; G is -O-, T is -CH2-, R1 is -Cl, R2 is -Cl, R3 is i-propyl, R4 is -H, R5 is -OH, X is - P (O) [N (H) C (CH3) 2C (O) OCH2CH3] 2; G is -O-, T is -OCH2-, R1 is -I, R2 is -I, R3 is i-propyl, R4 is -H, R5 is -OH, X is P03H2; 4-aryl-2-oxo-2-? S-l, 3,2-dioxaphosphonanes G is -O-, T is -CH2CH (NH2) -, R1 is -I, R2 is -I, R3 is -I, R4 is -H, R5 is -OH, X is -P (O) [-OCH (3-chlorofenyl) CH2CH20-]; G is -O-, T is -CH2CH (NH2) -, R1 is -I, R2 is -I, R3 is -I, R4 is -I, R5 is -OH, X is -P (O) [-OCH (3-chloro enyl) CH2CH20-]; G is -O-, T is -CH2-, R1 is -I, R2 is -I, R3 is -I, R4 is -H, R5 is -OH, X is -P (O) [-OCH (3- chlorofenyl) CH2CH20-]; G is -O-, T is -N (H) C (0) -, R1 is -CH3, R2 is -CH3, R3 is CH (OH) (4-fluorophenyl), R4 is -H, R5 is -OH , X is -P (0) [-OCH (3-chlorofenyl) CH2CH20-]; G is -CH2-, T is -OCH2-, R1 is -CH3, R2 is -CH3, R3 is i-propyl, R4 is -H, R5 is -OH, X is -P (O) [-OCH (3 chlorophenyl) CH2CH20-]; G is -O-, T is -CH2-, R1 is -Cl, R2 is -Cl, R3 is i-propyl, R4 is -H, R5 is -OH, X is -P (O) [-OCH (3 - chlorophenyl) CH2CH20-]; G is -O-, T is -OCH2-, R1 is -I, R2 is -I, R3 is i-propyl, R4 is -H, R5 is -OH, X is P03H2; On the other hand, the compounds of the present invention can be administered in combination with other pharmaceutical agents that are used to lower serum cholesterol such as a cholesterol biosynthesis inhibitor or a cholesterol absorption inhibitor, especially a HMG reductase inhibitor. -CoA, or a HMG-CoA synthase inhibitor, or an HMG-CoA synthase or reductase gene expression inhibitor, an inhibitor of cholesterol cholesterol ester transfer protein (CETP) (eg, torcetrapib), a sequestrant of the Bile acid (for example, cholestyramine (Questrant), colesevelam and colestipol (Colestidf)), or an inhibitor of bile acid reabsorption (see, for example, US Pat. No. 6,245,744, US Pat. No. 6,221,897, US Pat. No. 6,277,831, EP 0683 773, EP 0683. 774), a cholesterol absorption inhibitor as described (eg, ezeti iba, tiqueside, pamaqueside or see, for example, in WO 0250027), a PPARalpha agonist, a PPAR alpha / gamma agonist mixture such as, for example, , AZ 242 (Tesaglitazar, (S) -3- (4- [2- (4-ethanesulfonyl-oxyphenyl) ethoxy] phenyl) -2-ethoxypropionic acid), BMS 298585 (N- [(4-methoxyphenoxy) carbonyl] - N- [[4- [2- (5-methyl-2-phenyl-4-oxazolyl) et-hoxy] phenyl] methyl] glycine) or as described in WO 99/62872, WO 99/62871, WO 01 / 40171, WO 01/40169, WO 96/38428, WO 01/81327, WO 01/21602, WO 03/020269, WO 00/64888 or WO 00/64876, an MTP inhibitor such as, for example, implitapide, a fibrate , ACAT inhibitors (eg, avasimibe), an angiotensin II receptor antagonist, a synthetase inhibitor is qualen, a squalene epoxidase inhibitor, a squalene cyclase inhibitor, squalene epoxidase / squalene cyclase inhibitor, a lipoprotein lipase inhibitor, an ATP citrate lyase inhibitor, a lipoprotein (a) antagonist, an antioxidant or niacin (e.g. , slow release niacin). The compounds of the present invention can also be administered in combination with a naturally occurring compound that acts to lower plasma cholesterol levels. Such naturally occurring compounds are commonly called pharmaceuticals for nutrition and include, for example, garlic extract and niacin.

In one aspect, the HMG-CoA reductase inhibitor is from a class of therapeutics commonly called statins. Examples of HMG-CoA reductase inhibitors that can be used include but are not limited to lovastatin (MEVACOR; see US Patent Nos. 4,231,938; 4,294,926; 4,319,039), simvastatin (ZOCOR; see US Patent Nos. 4,444,784; 4,450,171; 4,820,850; 4,916,239), pravastatin (PRAVACHOL; see US Patent Nos. 4,346,227; 4,537,859; 4,410,629; 5,030,447; and 5,180,589), pravastatin lactones (see US Patent No. 4,448,979), fluvastatin (LESCOL; see US Patent Nos. 5,354,772); 4,911,165; 4,739,073; 4,929,437; 5,189,164; 5,118,853; 5,290,946; 5,356,896), fluvastatin lactones, atorvastatin (LIPITOR; see US Patent Nos. 5,273,995; 4,681,893; 5,489,691; 5,342,952), atorvastatin lactones, cerivastatin (also known as rivastatin and BAYCHOL, see U.S. Patent No. 5,177,080, and European Application No. EP-491226A), lactones of cerivastatin, rosuvastatin (Crestor; see U.S. Patent Nos. 5,260,440 and RE37314, and European Patent No. EP521471), lactones of rosuvastatin, itavastatin, nisvastatin, visastatin, atavastatin, bervastatin, compactin, dihydrocompactin, dalvastatin, fluindostatin, pitivastatin, mevastatin (see U.S. Patent No. 3,983,140), and velostatin (also refers to sinvinolin). Other examples of HMG-CoA reductase inhibitors are described in U.S. Patent Nos. 5,217,992; 5,196,440; 5,189,180; 5,166,364; 5,157,134; 5,110,940; 5,106,992; 5,099,035; 5,081,136; 5,049,696; 5,049,577; 5,025,017; 5,011,947; 5,010,105; 4,970,221; 4,940,800; 4,866,058; 4,686,237; 4,647,576; European Application Nos. 0142146A2 and 0221025A1; and PCT Application Nos. WO 86/03488 and WO 86/07054. Also pharmaceutically acceptable forms of the above are included. All of the above references are incorporated herein by reference. Non-limiting examples of suitable bile acid sequestrants include cholestyramine (a styrene-divinylbenzene copolymer containing cationic quaternary ammonium groups capable of binding bile acids, such as QUESTRAN or QUESTRAN LIGHT cholestyramine which are available from Bristol-Myers Squibb), colestipol ( a copolymer of diethylenetriamine and l-chloro-2,3-epoxypropane, such as COLESTID tablets which are available from Pharmacia), colesevelam chlorohydrate (such as WelChol Tablets (poly (allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1- bromodecane and (6-bromohexyl) -trimethylammonium bromide) which are available from Sankyo), water-soluble derivatives such as 3,3-yoene, N- (cycloalkyl) alkylamines and polyglusam, quaternized insoluble polystyrenes, saponins and mixtures thereof.

Other useful bile acid sequestrants are described in PCT Patent Applications Nos. WO 97/11345 and WO 98/57652, and U.S. Patent Nos. 3,692,895 and 5,703,188 which are incorporated herein by reference. Suitable inorganic cholesterol scavengers include montmorillonite clay plus bismuth salicylate, aluminum hydroxide and calcium carbonate antacids.

In the above description, a fibrate base compound is a medicament for inhibiting the synthesis and secretion of triglycerides in the liver and activation of lipoprotein lipase, thereby lowering the level of triglyceride in the blood. Examples include bezafibrate, beclobrate, binifibrate, ciprofibrate, clinofibrate, clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pirifibrate, ronifibrate, simfibrate, and theofibrate. Such ACAT inhibitors include, for example: a compound having the general formula (I) described in WO 92/09561 [preferably FR-129169, of which the chemical name is N- (1,2-diphenylethyl) -2- ( 2-octyloxyphenyl) acetamide]; a compound having the general formula (I) including a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof described in Japanese Patent Publication (Kohyo) Hei 8-510256 (WO 94/26702, U.S. Patent No. 5,491,172). { preferably CI-1011, of which the chemical name is 2,6-diisopropylphenyl-N- [(2,4,6-trisopropylphenyl) acetyl] sulphamate, and in the present invention CI-1011 includes a salt / co-crystal pharmaceutically acceptable, ester or prodrug thereof; a compound having the general formula (I) which includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof described in EP 421441 (U.S. Patent No. 5,120,738). { preferably F-1394, of which the chemical name is (1S, 2S) -2- [3- (2, 2-dimet-ilpropyl) -3-nonylureido] cyclohexan-1-yl 3- [(4R) -N- (2,2,5,5-tetramethyl-l, -3-dioxane-4-carbonyl) amino] propionate, and in the present invention F-1394 includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof}; a compound that includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof described in Japanese Patent Publication (Kohyo) 2000-500771 (WO 97/19918, U.S. Patent No. 5,990, 173) [preferably F- 12511, of which the chemical name is (S) -2 ', 3', 5 '-trimethyl-4' -hydroxy-alpha. -dodeciltio- alpha. phenylaceta-nilide, and in the present invention F-12511 includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof.]; a compound having the general formula (I) includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof described in Japanese Patent Publication (Kokai) Hei 10-195037 (EP 790240, U.S. Patent No. 5,849,732) [preferably T-2591, of which the chemical name is 1- (3-t-butyl-2-hydroxy-5-methoxyphenyl) -3- (2-cyclohexylethyl) -3- (4-dimethylaminophenyl) urea, and in the present invention T-2591 includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof); a compound having the general formula (I) which includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof described in WO 96/26948. { preferably FCE-28654, of which the chemical name is 1- (2,6-diisopropylphenyl) -3- [(4R, 5R) -4,5-di-methyl-2- (4-phosphonophenyl) -1, 3- dioxolan-2-ylmethyl] urea, which includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof; a compound having the general formula (I) or a pharmaceutically acceptable salt thereof described in the specification of WO 98/54153 (EP 987254). { preferably K-10085, of which the chemical name is N- [2, 4-bis (methylthio) -6-methyl-3-pyridyl] -2- [4- [2- (oxazolo [4,5-b] pyridine -2-ilthio) ethyl] piperazin-1-yl] acetamide, which includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof ..}.; a compound having the general formula (I) described in WO 92/09572 (EP 559898, U.S. Patent No. 5,475,130) [preferably HL-004, of which the chemical name is N- (2,6-diisopropylphenyl) -2 -tetradecylthioacetamide. ]; a compound having the general formula (I) which includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof described in Japanese Patent Publication (Kokai) Hei 7-82232 (EP 718281). { preferably NTE-122, of which the chemical name is trans-1,4-bis [l-cyclohexyl-3- (4-dimethylaminophenyl) ureidomethyl] cyclohexane, and in the present invention NTE-122 include pharmaceutically acceptable salts of NTE-122 ..}.; a compound that includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof described in Japanese Patent Publication (Kohyo) Hei 10-510512 (WO 96/10559). { preferably FR-186054, of which the chemical name is 1-benzyl-l- [3- (pyrazol-3-yl) benzyl] -3- [2,4-bis (methylthio) -6-methylpyridin-3-yl] urea, and in the present invention FR-186054 which includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof ..}.; a compound having the general formula (I) which includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof described in WO 96/09287 (EP 0782986, US Patent No. 5,990,150) [preferably N- (1- pentyl-4,6-dimethylindolin-7-yl) -2,2-dimethylpropanamide, and in the present invention including a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof.]; and a compound having the general formula (I) which includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof described in WO 97/12860 (EP 0866059, US Patent No. 6,063,806) [preferably N- (l -octyl-5-carboxymethyl-4,6-dimethylindolin-7-yl) -2,2-dimethylpropanoamide, which includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof.]. The ACAT inhibitor is preferably a compound selected from the group consisting of FR-129169, CI-1011, F-1394, F-12511, T-2591, FCE-28654, K-10085, HL-004, NTE-122, FR. -186054, N- (l-octyl-5-carboxymethyl-4,6-dimet-ylindolin-7-yl) -2, 2-dimethylpropanamide (previously referred to as compound A), and N- (l-pentyl-4, 6-dimethylindolin-7-yl) -2, 2-dimethylpropanamide (previously referred to as compound B), which includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof. The ACAT inhibitor is most preferably a compound selected from the group consisting of CI-1011, F-12511, N- (1-octyl-5-carboxymethyl-4,6-dimethylinindolin-7-yl) -2, 2- dimethylpropanamide (compound A), and N- (l-pentyl-4,6-dimethylindolin-7-yl) -2,2-dimethylpropanamide (compound B), which includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug of the same; more preferred is N- (l-octyl-5-carboxymethyl-4,6-dimethylindolin-7-yl) -2,2-dimethylpropanamide (compound A). An angiotensin II receptor antagonist includes, for example, a tetrazole biphenyl compound or biphenylcarboxylic acid derivative such as: a compound having the general formula (I) which includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof described in Japanese Patent Publication (Kokai) Sho 63-23868 (U.S. Patent No. 5,138,069). { preferably losartan, of which the chemical name is 2-butyl-4-chloro-l- [2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] -lH-imidazole-5-methanol, and in the present invention losartan which includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof}; a compound having the general formula (I) which includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof described in Japanese Patent Publication (Kohyo) Hei 4-506222 (WO 91/14679). { preferably irbesartan, of which the chemical name is 2-N-butyl-4-spirocyclopentan-l- [2 '- (lH-tetrazol-5-yl) bi-phenyl-4-ylmethyl] -2-imidazolin-5-one , and in the present invention irbesartan which includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof.; a compound having the general formula (I), an ester thereof, which includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof described in Japanese Patent Publication (Kokai) Hei 4-235149 (EP 433983) . { preferably valsartan, of which the chemical name is (S) -N-valeryl-N- [2 r - (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] valine, and in the present invention valsartan which includes a salt / pharmaceutically acceptable co-crystal, ester or prodrug thereof ..}.; a carboxylic acid derivative having the general formula (I), which includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof described in Japanese Patent Publication (Kokai) Hei 4-364171 (U.S. Patent No. 5,196,444). { preferably candesartan, of which the chemical name is 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1 - [2 '- (iH-tetrazol-5-yl) biphen-yl-4-ylmethyl] -lH-benzimidazole-7-carboxylate , and in the present invention candesartan which includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof (TCV-116 or the like), which includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof. .; a carboxylic acid derivative having the general formula (I), which includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof described in Japanese Patent Publication (Kokai) Hei 5-78328 (U.S. Patent No. 5,616,599). { preferably olmesartan, of which the chemical name is (5-methyl-2-oxo-l, 3-dioxolen-4-yl) methyl 4- (1-hydroxy-l-methylethyl) -2-propyl-l- \ 2 ' - (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] imidazole-5-carboxylate, and in the present invention olmesartan which includes carboxylic acid derivatives thereof, pharmaceutically acceptable esters of the carboxylic acid derivative (CS-866 or similar), which includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof}; and a compound having the general formula (I), which includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof described in Japanese Patent Publication (Kokai) Hei 4-346978 (U.S. Patent No. 5,591,762, EP 502,314). { preferably telmisartan, of which the chemical name is 4 '- [[2-n-propyl-4-methyl-6- (l-methylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl] biphenyl-2-carboxylate , which includes a pharmaceutically acceptable salt / co-crystal, ester or prodrug thereof} . The angiotensin II receptor antagonist is preferably losartan, irbesartan, valsartan, candesartan, olmesartan, or telmisartan; more preferred is losartan or olmesartan; and more preferred is olmesartan. In addition to being useful in the treatment or prevention of certain diseases and disorders, therapy in combination with compounds of this invention may be useful in reducing the dose of the second drug or agent (e.g., atorvastatin). In addition, the compounds of the present invention can be used in combination with an apolipoprotein B secretion inhibitor and / or protein inhibitor (MTP) microsomal transfer triglycerides. Some inhibitors of apolipoprotein B secretion and / or MTP inhibitors are described in E.U.A. 5,919,795. Any HMG-CoA reductase inhibitor can be employed as an additional compound in the aspect of the combination therapy of the present invention. The term "reductase inhibitor HMG-CoA" refers to a compound that inhibits the biotransformation of hydroxymethylglutaryl-coenzyme A mevalonic acid as catalyzed by the enzyme reductase HMG-CoA. Such inhibition can be easily determined by one skilled in the art in accordance with standard tests (e.g., Methods of Enzymology, 71: 455-509 (1981); and references cited therein). A variety of these compounds are described and are referred to below. E.U.A. 4,231,938 discloses certain compounds isolated after cultivation of a microorganism belonging to the Aspergillus genera, such as lovastatin. Also E.U.A. 4,444,784 describes synthetic derivatives of the aforementioned compounds, such as simvastatin. Additionally, E.U.A. 4,739,073 discloses certain substituted Índles, such as fluvastatin. In addition, E.U.A. 4,346,227 describes ML-236B derivatives, such as pravastatin. In addition, EP 491,226 teaches certain pyridyldihydroxyheptenoic acids, such as rivastatin. Also, E.U.A. No. 4,647,576 describes certain 6- [2- (substituted-pyrrol-1-yl) -alkyl] -pyran-2-ones such as atorvastatin. Other HMG-CoA reductase inhibitors will be known to those skilled in the art. Examples of products currently marketed or previously containing HMG-CoA reductase inhibitors include Na cerivastatin, rosuvastatin Ca, fluvastatin, atorvastatin, lovastatin, pravastatin Na and simvastatin. Any HMG-CoA synthase inhibitor can be used as an additional compound in the aspect of the combination therapy of this invention. The term "HMG-CoA synthase inhibitor" refers to a compound that inhibits the biosynthesis of hydroxymethylglutaryl-coenzyme A from acetyl-coenzyme A and acetoacetyl-coenzyme A, catalyzed by the enzyme synthase HMG-CoA. Such inhibition can be readily determined by one skilled in the art in accordance with standard assays (eg, Methods of Enzymology 35: 155-160 (1975); and Methods of Enzymology, 110: 19-26 (1985); references cited herein). A variety of these compounds are described and are referred to below. The patent of E.U.A. 5,120,729 describes certain beta-lactam derivatives. The patent of E.U.A. No. 5,064,856 discloses certain spiro-lactone derivatives prepared by culturing microorganism MF5253. The patent of E.U.A. No. 4,847,271 discloses certain oxetane compounds such as 11- (3-hydroxymethyl-4-oxo-2-oxetail) -3,5,7-trimethyl-2,4-undecadienoic acid derivatives. Other HMG-CoA synthase inhibitors useful in the methods, compositions and kits of the present invention will be known to those skilled in the art. Any compound that decreases the expression of the HMG-CoA reductase gene can be used as an additional compound in the aspect of the combination therapy of this invention. These agents can be transcription inhibitors of HMG-CoA reductase that blocks transcription of DNA or translation inhibitors that prevents the translation of mRNA encoding for HMG-CoA reductase into protein. Such inhibitors can either affect transcription or translation directly, or they can be biotransformed into compounds having the above-mentioned attributes by one or more enzymes in the cholesterol biosynthetic cascade or can lead to the accumulation of an isoprene metabolite having the above activities mentioned. Such regulation is readily determined by those skilled in the art in accordance with standard assays (Methods of Enzymology, 110: 9-19 (1985)). Various such compounds are described and referred to below; however, other inhibitors of the HMG-CoA reductase gene expression will be known to those skilled in the art, for example, the U.S. patent. 5,041,432 describes certain 15-substituted derivatives of lanosterol which are inhibitors of HMG-CoA reductase gene expression. Other oxygenated sterols that suppress HMG-CoA reductase biosynthesis are discussed by E.I. Mercer (Prog. Lip. Res., 32: 357-416 (1993)). Any compound that has activity as a CETP inhibitor can serve as the second compound in the aspect of the combination therapy of the present invention. The term "CETP inhibitor" refers to compounds that inhibit transport mediated by cholesteryl ester transfer protein (CETP) of various cholesteryl esters and triglycerides from HDL to LDL and VLDL. A variety of these compounds are described and referred to below; however, other CETP inhibitors will be known to those skilled in the art. The patent of E.U.A. 5,512,548 describes certain polypeptide derivatives having activity as CETP inhibitors, while certain rosenonolactone derivatives of the CETP inhibitor and phosphate containing cholesteryl ester analogues are described in J. Antibiot., 49 (8): 815-816 (1996), and Bioorg Med. Chem. Lett., 6: 1951-1954 (1996), respectively. Any ACAT inhibitor can serve as an additional compound in the aspect of the combination therapy of this invention. The term "ACAT inhibitor" refers to a compound that inhibits the intracellular esterification of dietary cholesterol by the enzyme CoA acyl: acyltransferase cholesterol. Such inhibition can be easily determined by one skilled in the art in accordance with standard assays, such as the method of Heider et al. described in Journal of Lipid Research, 24: 1127 (1983). A variety of these compounds are described and referred to below; however, other ACAT inhibitors will be known to those skilled in the art. The patent of E.U.A. 5,510,379 describes certain carboxysulfonates, while WO 96/26948 and WO 96/10559 both describe urea derivatives having ACAT inhibitor activity. Any compound having activity as an inhibitor of squalene synthetase can serve as an additional compound in the aspect of the combination therapy of the present invention. The term "squalene synthetase inhibitor" refers to compounds that inhibit the condensation of two molecules of famesylpyrophosphate to form squalene, a reaction that is catalyzed by the enzyme squalene synthetase. Such inhibition is readily determined by those skilled in the art in accordance with the standard methodology (Methods of Enzymology 15: 393-454 (1969); and Methods of Enzymology 110: 359-373 (1985); and references cited therein) . A summary of squalene synthetase inhibitor has been formed in Curr. Op. Ther Patents, 861-4, (1993). EP 0 567 026 A1 discloses certain 4, 1-benzoxazepine derivatives as an inhibitor of squalene synthetase and its use in the treatment of hypercholesterolemia and as fungicides. EP 0 645 378 Al discloses certain heterocycles of seven or eight members as an inhibitor of squalene synthetase and its use in the treatment and prevention of hypercholesterolemia and fungal infections. EP 0 645 377 A1 discloses certain benzoxazepine derivatives as an inhibitor of squalene synthetase useful for the treatment of hypercholesterolemia or coronary sclerosis. EP 0 611 749 A1 discloses certain substituted ammonium acid derivatives useful for the treatment of arteriosclerosis. EP 0 705 607 A2 discloses certain condensed seven- or eight-membered heterocyclic compounds useful as antihypertriglyceridic agents. WO 96/09827 describes certain combinations of cholesterol absorption inhibitors and cholesterol biosynthesis inhibitors including benzoxazepine and benzothiazepine derivatives. EP 0 701 725 A1 discloses a process for preparing certain optically active compounds, including benzoxazepine derivatives, having plasma triglyceride and cholesterol reducing activities. Other compounds that are currently or previously marketed for hyperlipidemia, including hypercholesterolemia, and which are intended to help prevent or treat atherosclerosis, include bile acid sequestrants, such as colestipol HCl and cholestyramine; and fibric acid derivatives, such as clofibrate, fenofibrate, and gemfibrozil. These compounds can also be used in combination with a compound of the present invention. This also contemplates that the compounds of the present invention are administered with a lipase inhibitor and / or a glucosidase inhibitor, which are typically used in the treatment of the result of the conditions from the presence of excess triglycerides, fatty acids free, cholesterol, cholesterol or glucose esters including, inter alia, obesity, hyperlipidemia, hyperlipoproteinemia, Syndrome X, and the like. In a combination with a compound of the present invention, any lipase inhibitor or glucosidase inhibitor can be employed. In one aspect lipase inhibitors encompasses gastric or pancreatic lipase inhibitors. In a further aspect glucosidase inhibitors encompass amylase inhibitors. Examples of glucosidase inhibitors are those inhibitors selected from the group consisting of acarbose, adiposine, voglibose, miglitol, emiglitate, camiglibose, tendamistate, trestatin, pradimicin-Q and salbostatin. Examples of amylase inhibitors include tendamistate and the various cyclic peptides related thereto described in U.S. Patent No. 4,451,455, AI-3688 and the various cyclic polypeptides related thereto described in the U.S. Patent. A No. 4,623,714, and trestatin, which consists of a mixture of trestatin A, trestatin B and trestatin C and the various amino sugars containing trehalose related thereto described in U.S. Patent No. 4,273,765. A lipase inhibitor is a compound that inhibits the metabolic cleavage of dietary triglycerides into free fatty acids and monoglycerides. Under normal physiological conditions, it presents lipolysis by means of a two-step process involving the acylation of an activated serine portion of the enzyme lipase. This leads to the production of an intermediate fatty acid-hemiacetal lipase, which is then split to release a diglyceride. Following further deacylation, the lipase-fatty acid intermediate is split, resulting in free lipase, a monoglyceride and a fatty acid. The resulting free fatty acids and monoglycerides are incorporated into micelles bile acid phospholipids, which are subsequently absorbed at the level of the hairy border of the small intestine. The micelles eventually incorporate the peripheral circulation as chylomicrons. Accordingly, the compounds include lipase inhibitors that selectively limit or inhibit the absorption of ingested fatty precursors useful in the treatment of conditions including obesity, hyperlipidemia, hyperlipoproteinemia, X Syndrome, and the like. Pancreatic lipase mediates the metabolic cleavage of fatty acids from triglycerides at the positions of carbon 1 and 3. The primary site of the metabolism of ingested fats is in the duodenum and jejunum close to the pancreatic lipase, which is usually secreted in high excess of the amounts necessary for the interruption of fats in the upper small intestine. Because pancreatic lipase is the primary enzyme required for the absorption of dietary triglycerides, the inhibitors have utility in the treatment of obesity and the other related conditions. Gastric lipase is an immunologically distinct lipase that is responsible for approximately 10 to 40% of the digestion of dietary fats. Gastric lipase is secreted in response to mechanical stimulation, food intake, the presence of a fatty meal or by sympathetic agents. Gastric lipolysis of ingested fats is of physiological importance in the provision of fatty acids necessary to trigger pancreatic lipase activity in the intestine and is also of importance for the absorption of fat in a variety of physiological and pathological conditions associated with pancreatic insufficiency. See, for example, C.K Abrams, et al., Gastroenterology 92: 125 (1987). A variety of lipase inhibitors are known to one skilled in the art. However, in the practice of the methods, pharmaceutical compositions, and kits of the present invention, the lipase inhibitors are generally those inhibitors that are selected from the group consisting of lipstatin, tetrahydrolipstatin (orlistat), FL-386, WAY-121898, Bay-N-3176, valilactone, esterastine, ebelactone A, ebelactone B and RHC 80267. The pancreatic lipase inhibitors lipstatin, 2S, 3S, SS, 7Z, 10Z) -5- [(S) -2-formamide-4 -methyl-valeryloxy] -2-hexyl-3-hydroxy-7, 1 (t-hexadecanoic acid lactone, and tetrahydrolipostatin (orlistat), 2S, 3S, 55 lactone) -5- [(S) -2- formamido-4-methyl-valeryloxy] -2-hexyl-3-hydroxy-hexadecanoic, and the various substituted N-formyl leucine derivatives and stereoisomers thereof, are described in the US 4,598,089. The pancreatic lipase inhibitor FL-386, l- [4- (2-methylpropyl) cyclohexyl] -2- [(phenylsulfonyl) oxy] -ethanone, and the various substituted sulfonate derivatives related thereto, are described in the US Pat. USA 4,452,813. The WAY-121898 inhibitor of pancreatic lipase, 4-phenoxyphenyl-4-methylpiperidin-1-yl-carboxylate, and the various carbamate esters and pharmaceutically acceptable salts related thereto, are described in U.S. Pat. ,512,565; 5,391,571 and 5,602,151. The Bay-N-3176 inhibitor of lipase, N-3-trifiuoromethylphenyl-N '-3-chloro-4-trifluoromethylphenylurea, and the various urea derivatives related thereto, are described in US Pat. 4,405,644. The valilactone pancreatic lipase inhibitor, and a process for the preparation thereof by the microbial culture of strain Aetinomycetes MG147-CF2, are described in Kita ara, et al., J. Antibiotics, 40 (11): 1647-50 (1987 ). The lipase-esteracin inhibitor, and certain processes for the preparation thereof by the microbial culture of strain Streptomyces ATCC 31336, are described in E.U.A. 4,189,438 and 4,242,453. The pancreatic lipase inhibitors ebelactone A and ebelactone B, and a process for the preparation thereof by the microbial culture of strain Actinomycetes MG7-G1, are described in Umeza a, et al., J. Antibiotics, 33, 1594-1596 ( 1980). The use of ebelactones A and B in the suppression of monoglyceride formation is disclosed in the Japanese Kokai patent 08-143457, publication date Jun. 4, 1996. The RHC inhibitor 80267 of lipase, cyclo-O, O '- [(1 , 6-hexanediyl) -bis- (iminocarbonyl)] dioxime, and the various bis (iminocarbonyl) dioxides related thereto can be prepared as described in Petersen et al., Liebig's Annalen, 562: 205-29 (1949). The ability of RHC 80267 to inhibit myocardial lipoprotein lipase activity is described in Carroll et al., Lipids, 27 305-7 (1992) and Chuang et al., J. Mol. Cell Cardiol., 22: 1009-16 (1990). In another aspect of the present invention, the compounds of Formula I can be used in combination with an additional anti-obesity agent. The additional anti-obesity agent in one aspect is selected from the group consisting of a β3-adrenergic receptor antagonist, a cholecystokinin-A agonist, a monoamine reuptake inhibitor, a sympathomimetic agent, a serotonergic agent, a dopamine agonist, a melanocyte stimulation hormone receptor agonist or mimetic, a melanocyte stimulation hormone receptor analogue, a cannabinoid receptor antagonist, a hormone antagonist that concentrates melanin, leptin, a leptin analogue, a leptin receptor antagonist, a galanin antagonist , a lipase inhibitor, a bombesin agonist, a neuropeptide-Y antagonist, a thyromimetic agent, dehydroepiandrosterone or an analogue thereof, a glucocorticoid receptor agonist or antagonist, an orexin receptor antagonist, an urocortin binding protein antagonist, a glucagon similar to a peptide-1 receptor agonist, and a ciliary neurotrophic factor. In a further aspect the anti-obesity agents comprise those compounds selected from the group consisting of sibutramine, fenfluramine, dexfenfluramine, bromocriptine, phentermine, ephedrine, leptin, phenylpropanolamine pseudoephedrine, acid. { 4- [2- (2- [6-aminopyridin-3-yl] -2 (R) -hydroxyethylamino) ethoxy] phenyl} acetic, acid. { 4-. { 2- (2- [6-aminopyridin-3-yl] -2 (R) -hydroxyethylamino) ethoxy] phenyl} benzoic,. { 4- [2- (2. {6-aminopyridin-3-yl] -2 (R) -hydroxyethylamino) ethoxy] phenyl} propionic, and acid. { 4- [2- (2- [6-aminopyridin-3-yl] -2 (R) -hydroxyethylamino) ethoxy] phenoxy} acetic. In one aspect, the present invention relates to the prevention or treatment of diabetes, including impaired glucose tolerance, insulin resistance, insulin-dependent diabetes mellitus (Type 1) and non-insulin-dependent diabetes mellitus (NIDDM or Type II). ). Diabetic complications, such as neuropathy, nephropathy, retinopathy or cataracts, are also included in the prevention or treatment of diabetes. In one aspect the type of diabetes to be treated by the compounds of the present invention is diabetes mellitus not dependent on insulin, also known as Type II diabetes or NIDDM. Diabetes can be treated by administering to a patient who has diabetes (Type I or Type II), insulin resistance, impaired glucose tolerance, or any of the diabetic complications such as neuropathy, nephropathy, retinopathy or cataracts, a therapeutically effective amount of a compound of the present invention. This also contemplates that diabetes is treated by administering a compound of the present invention together with other agents that can be used to prevent or treat diabetes. Representative agents that can be used to treat diabetes in combination with a compound of the present invention include insulin and insulin analogs (e.g., LysPro insulin); GLP-1 (7-37) (insulinotropin) and GLP-1 (7-36) NH2. Agents that enhance the secretion of insulin, for example, eblorpropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide, glipizide, glimepiride, repaglinide, nateglinide, meglitinide; biguanides: metformin, phenformin, buformin; A2 antagonists and imidazolines: midaglizol, isaglidol, deriglidol, idazoxan, efaroxan, fluparoxan; other insulin secretagogues, linogliride, A-4166; glitazones: cyglitazone, pioglitazone, englitazone, troglitazone, darglitazone, BRL49653; fatty acid oxidation inhibitors: clomoxir, etomoxir; α-glucosidase inhibitors: acarbose, miglitol, emiglitate, voglibose, MDL 25,637, camiglibose, MDL-73,945; ~ 3-agonists: BRL 35135, BRL 37344, RO 16-8714, ICI D7114, CL 316.243; phosphodiesterase inhibitors: -386, 398; benfluorex lipid reducing agents; anti-obesity agents: fenfiuramine; vanadate and vanadium complexes (eg, bis (cysteinamide N-octyl) oxovanadium) and peroxovanadium complexes; amylin antagonists; glucagon antagonists; gluconeogenesis inhibitors; Somatostatin analogues; antilipolytic agents: nicotinic acid, acipimox, WAG 994. Pramlintide (symlin ™), AC 2993 and nateglinide are also contemplated to be used in combination with a compound of the present invention. Any agent or combination of agents can be administered as described below. In addition, the compounds of the present invention can be used in combination with one or more inhibitors of aldose reductase, DPPIV inhibitor, glycogen phosphorylase inhibitors, sorbitol dehydrogenase inhibitors, NHE-1 inhibitors and / or glucocorticoid receptor antagonists. Any compound having activity as a fructose-1, 6-bisphosphatase inhibitor (FBPase) can serve as the second compound in the aspect of the combination therapy of the present invention (eg, 2-Amino-5-isobutyl-4-) {2- [5- (N, N '-bis ((S) -1- ethoxycarbonyl) ethyl) phosphonamido] furanyl Jiathiazole). FBPase is a key regulatory enzyme in gluconeogenesis, the metabolic path by which the liver synthesizes glucose from the 3 carbon precursors. The term "FBPase inhibitor" refers to compounds that inhibit the activity of the FBPase enzyme and thereby block the conversion of fructose-1,6-bisphosphate, the substrate of the enzyme, to fructose 6-phosphate. The inhibition of FBPase can be determined directly at the enzyme level by those skilled in the art in accordance with standard methodology (eg, Gidh-Jain M, Zhang Y, van Poelje PD et al., J. Biol Chem. 1994 , 269 (44): 27732-8). Alternatively, the inhibition of FBPase can be determined in accordance with standard methodology by measuring the inhibition of glucose production by isolating hepatocytes or in a perfused liver, or by measuring low blood glucose in normal or diabetic animals (e.g. , Vincent MF, Erion MD, Gruber HE, Van den Berghe, Diabetology, 1996, 39 (10): 1148-55, Vincent MF, Marangos PJ, Gruber HE, Van den Berghe G, Diabetes 1991 40 (10): 1259 -66). In some cases, the in vivo metabolic activation of a compound may be required to generate the FBPase inhibitor. This class of compounds can be inactive in the enzyme inhibition screen, they may or may not be active in hepatocytes, but is active in vivo as shown by reduction of glucose in the fasted or normal rat, and / or in animal models of diabetes. A variety of FBPase inhibitors are described and referred to below; however, other FBPase inhibitors will be known to those skilled in the art. Gruber et al. Patent E.U.A. No. 5,658,889 describes the use of AMP site inhibitors of FBPase to treat diabetes; WO 98/39344 and US 6,284,748 disclose purine inhibitors; WO 98/39343 and US 6,110,903 describe benzothiazole inhibitors for treating. diabetes; WO 98/39342 and US 6,054,587 disclose indole inhibitors for treating diabetes; and WO 00/14095 and US Pat. No. 6,489,476 describe heteroaromatic phosphonate inhibitors for treating diabetes. Other FBPase inhibitors are described in Wright SW, Cario AA, Carty MD et al., J Med Chem. 2002 45 (18): 3865-77 and WO 99/47549.

The compounds of the present invention can also be used in combination with sulfonylureas such as amaryl, aliburide, glucotrol, chlorpropamide, diabinese, tolazamide, tolinase, acetohexamide, glipizide, tolbutamide, urinase, glimepiride, DiaBeta, micronase, glibenclamide, and gliclazide. The compounds of the present invention can also be used in combination with antihypertensive agents. Any anti-hypertensive agent can be used as the second agent in such combinations. Examples of currently marketed products containing antihypertensive agents include calcium channel blockers, such as Cardizem, Adalat, Calan, Cardene, Covera, Dilacor, DynaCirc, Procardia XL, Sular, Tiazac, Vascor, Verelan, Isoptin, Ni otop, Norvasc, and Plendil; enzyme inhibitors that convert angiotensin (ACE), such as Accupril, Altace, Captopril, Lotensin, Mavik, Monopril, Prinivil, Univasc, Vasotec and Zestril. Examples of the compounds that can be used in combination with the compounds of the present invention to prevent or treat osteoporosis include: anti-resorptive agents including progestins, polyphosphonates, bisphosphonate (s), estrogen agonists / antagonists, estrogen, estrogen combinations / progestin, Premarin, estrone, estriol or 17. alpha.- or 17. beta, -etinyl estradiol); progestins include algestone acetophenide, altrenogest, amadinone acetate, anagestone acetate, chlormadinone acetate, cingestol, clogestone acetate, clomegestone acetate, delmadinone acetate, desogestrel, di etisterone, dydrogesterone, etinerone, ethinodiol acetate, etonogestrel, flurogestone acetate, gestaclone, gestodena, gestonorone caproate, gestrinone, haloprogesterone, hydroxyprogesterone caproate, levonorgestrel, linestrenol, medrogestone, medroxyprogesterone acetate, melengestrol acetate, methynediol diacetate, norethindrone, norethindrone acetate, norethynodrel, norgestimate, norgesto et , norgestrel, oxogestone fenpropionate, progesterone, quingestanol acetate, quingestrone, and tigestol; and polyphosphonate that inhibit bone resorption including polyphosphonates such as the type described in the U.S. patent. No. 3,683,080, the description of which is incorporated herein by reference. Examples of polyphosphonates include gemone diphosphonates (also referred to as bis-phosphonates), disodium tiludronate, ibandronic acid, alendronate, zoledronic resindronate acid, 6-amino-1-hydroxy-hexylidene-bisphosphonic acid, and 1-hydroxy-3 (methylpentylamino acid. ) -propylidene-bisphosphonic. Salts, co-crystals and esters of similar polyphosphonates are included. Specific examples include ethan-1-hydroxy-1,1-diphosphonic acid, methane diphosphonic acid, pentan-1-hydroxy-1, 1-diphosphonic acid, methane dichlorodiphosphonic acid, methane hydroxy diphosphonic acid, ethan-1-amino-1 acid , 1-diphosphonic acid, ethan-2-amino-1, 1-diphosphonic acid, propan-3-amino-1-hydroxy-1, 1-diphosphonic acid, propan-N, N-dimethyl-3-amino-1-acid hydroxy-l, 1-diphosphonic acid, propan-3, 3-dimethyl-3-amino-1-hydroxy-1, 1-diphosphonic acid, phenyl amino-methano-diphosphonic acid, N, N-dimethylamino-methane-diphosphonic acid, N (2) acid -hydroxyethyl) amino methane diphosphonic, butan-4-amino-l-hydroxy-1, diphosphonic acid, pentan-5-amino-1-hydroxy-1,1-diphosphonic acid, and hexan-6-amino-1 -hydroxy-1, 1-diphosphonic. Estrogen agonists / antagonists include 3- (4- (1,2-diphenyl-but-1-enyl) -phenyl) -acrylic acid, tamoxifen: (ethanamine, 2- (-4- (1, 2-diphenyl- 1-butenyl) phenoxy) -N, N-dimethyl, (Z) -2-, 2-hydroxy-1,2,3-propanetricarboxylate (1: 1)) and related compounds which are described in the US patent No. 4,536,516, the disclosure of which is incorporated herein by reference, 4-hydroxy tamoxifen, which is described in the US patent No. 4,623,660, the description of which is incorporated herein by reference, Raloxifene: (methanone, (6-hydroxy-2- (4-hydroxyphenyl) benzo [b] thien-3-yl) (4- (2- (l-piperidinyl) ethoxy) phenyl hydrochloride) which is described in the US patent No. 4,418,068, the disclosure of which is incorporated herein by reference, toremifene: (ethanamine, 2- (4- (4-chloro-l, 2-diphenyl-1-butenyl) phenoxy) -N, N-dimethyl -, (Z) -, 2-hydroxy-1,2,3-propanetricarboxylate (1: 1) which is described in U.S. Patent No. 4,996,225, the disclosure of which is hereby incorporated by reference, "Cent-chroman" : 1- (2- ((4- (methoxy-2, 2, dimethyl-3-phenyl-chroman-4-yl) -phenoxy) -ethyl) -pyrrolidine, which is described in US Patent No. 3,822,287, the description of which is incorporated herein by reference, levormeloxifen, idoxifen: (E) -1- (2- (4- (1- (4-iodo-phenyl) -2-phenyl-but-l- enyl) -phenoxy) -ethyl) -pyrrolidinone, which is described in U.S. Patent No. 4,839,155, the disclosure of which is incorporated herein by reference, 2- (4-methoxy-phenyl) -3 - [4- (2-piperidin-l-yl-ethoxy) -phenoxy] -benzo [b] thio-phen-6-ol which is described in U.S. Patent No. 5,488,058, the description of which is incorporated herein by reference, 6- (4-hydroxy-phenyl) -5- (4- (2-piperidin-1-yl-ethoxy) -benzyl) -naphthalen-2-ol, which is described in the US patent No. 5,484,795, the disclosure of which is incorporated herein by reference, (4- (2- (2-aza-bicyclo [2.2.1] hept-2-yl) -ethoxy) -phenyl) - (6- hydroxy-2- (4-hydroxy-phenyl) -benzo [b] thiophen-3-yl) - • methanone which is described, together with methods of preparation, in PCT publication no. WO 95/10513 assigned to Pfizer Inc, TSE-424 (Wyeth-Ayerst Laboratories) and arazoxifene, cis-6- (4-fluoro-phenyl) -5- (4- (2-piperidin-1-yl-ethoxy) - phenyl) -5, 6, -1, 8-tetrahydro-naphthalene-2-ol; (-) -cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalene-2-ol (also known as lasofoxifene) ); cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalene-2-ol; cis-1- (6'-pyrrolodinoethoxy-3'-pyridyl) -2-phenyl-6-hydroxy-l, 2,3,4-tetrahydronaphthalene; ~ 1- (4'-pyrrolidinoethoxyphenyl) -2-. { 4 r -fluorophenyl) -6-hydroxy-1,2,3,4-tetrahydroisoquinoline; cis-6- (4-hydroxyphenyl) -5- (4- (2-piperidin-1-yl-ethoxy) -phenyl) -5,6,7,8,8-tetrahydro-naphthalene-2-ol; 1- (4'-pyrrolidinoletoxyphenyl) -2-phenyl-6-hydroxy-l, 2,3,4-tetrahydroisoquinoline, 2-phenyl-3-aroyl-benzothiophene and 2-phenyl-3-aroylbenzothiophene-1-oxide. Other anti-osteoporosis agents, which can be used as the second agent in combination with a compound of the present invention, include, for example, the following: parathyroid hormone (PTH) (an anabolic bone agent), parathyroid hormone secretagogues (PTH) ) (see, for example, US Patent No. 6,132,774), particularly calcium receptor antagonists, calcitonin; and vitamin D and vitamin D analogues. Anti-osteoporosis agents also include a selective androgen receptor modulator (MRSA). Examples of suitable SARMs include compounds such as cyproterone acetate, chlormadinone, flutamide, hydroxyflutamide, bicalutamide, nilutamide, spironolactone, derivatives of 4- (trifluoromethyl) -2 (1H) -pyrrolidino [3, 2-g] quinoline, derivatives of 1 , 2-dihydropyridino [5,6-g] quinoline and piperidino [3,2-g] quinolinone derivatives. Other examples include cipterone, also known as (Ib, 2b) -6-chloro-1,2-dihydro-17-hydroxy-3'-H-cyclopropa [1, 2] pregna-l, 4,6-triene-3 , 20-dione is described in the US patent No. 3,234,093. Chlormadinone, also known as 17- (acetyloxy) -6-chloropregna-4,6-diene-3,20-dione, in the form of acetate, acts as an anti-androgen and is described in the U.S. patent. No. 3,485,852. Nilutamide, also known as 5, 5-dimethyl-3- [4-nito-3- (trifluoromethyl) phenyl] -2,4-imidazolidinedione and by the trade name Nilandron. RTM. it is described in the patent of E.U.A. No. 4,097,578. Flutamide, also known as 2-methyl-N- [4-nitro-3- (trifluoromethyl) phenyl] propanamide and the trade name Eulexin. RTM. it is described in the patent of E.U.A. No. 3,847,988. Bicalutamide, also known as 4'-cyano-a ', a', a '-trifluoro-3- (4-fluorophenylsulfonyl) -2-hydroxy-2-methylpropiono-m-toluidide and the trade name Casodex. RTM. it is described in EP-100172. Enantiomers of biclutamide are described by Tucker and Chesterton, J. Med. Chem. 1988, 31, 885-887. Hydroxyflutamide, an antagonist of the androgen receptor known in most tissues, is suggested to function as a MRSA for effects on the production of IL-6 by osteoblasts as described in Hofbauer et al. J. Bone Miner. Res. 1999,14, 1330-1337. Additional SARMs are described in the US patent. No. 6,017,924; WO 01/16108, WO 01/16133, WO 01/16139, WO 02/00617, WO 02/16310, U.S. Patent Application Publication No. US 2002/0099096, U.S. Patent Application Publication No. US 2003 / 0022868, WO 03/011302 and WO 03/011824. All references above are incorporated herein by reference. Formulations The amounts of unit doses programmed by the pharmaceutical compositions of the present invention can be determined using methods known in the art. In one aspect, the compounds of the invention are administered orally in a total daily dose of about 0.375 μg / kg / day to about 3.75 mg / kg / day. In another aspect, the total daily dose is from about 3.75 μg / kg / day to about 0.375 mg / kg / day. In another aspect the total daily dose is from about 3.75 pg / kg / day to about 37.5 μg / kg / day. In another aspect the total daily dose is from about 3.75 μg / kg / day to about 60 μg / kg / day. In an additional aspect the dose range is from 30 pg / kg / day to 3.0 mg / kg / day. In one aspect, the compounds of the invention are administered orally in a unit dose of about 0.375 ug / kg to about 3.75 mg / kg. In another aspect the unit dose is from about 3.75 ug / kg to about 0.375 mg / kg. In another aspect the unit dose is from about 3.75 μg / kg to about 37.5 μg / kg. In another aspect the unit dose is from about 3.75 μg / kg to about 60 μg / kg. In one aspect, the compounds of the invention are administered orally in a unit dose of about 0.188 μg / kg to about 1.88 mg / kg. In another aspect the unit dose is about 1.88 μg / kg to about 0.188 mg / kg. In another aspect the unit dose is about 1.88 μg / kg to about 18.8 μg / kg. In another aspect the unit dose is from about 1.88 μg / kg to about 30 μg / kg. In one aspect, the compounds of the invention are administered orally in a unit dose of about 0.125 μg / kg to about 1.25 mg / kg. In another aspect the unit dose is about 1.25 μg / kg to about 0.125 mg / kg. In another aspect the unit dose is about 1.25 μg / kg to about 12.5 μg / kg. In another aspect the unit dose is from about 1.25 μg / kg to about 20 μg / kg. In a modality the unit dose is administered once a day. In another modality the unit dose is administered twice a day. In another modality the unit dose is administered three times to the fía. In another modality the unit dose is administered four times a day. The dose refers to the equivalent of the free acid. The use of controlled release preparations for controlling the rate of release of the active ingredient may be preferred. The daily dose can be administered in multiple divided doses during the period of one day. The dose and dose schedule can be adjusted for the form of the drug or the administration form used. For example, different doses and schedule of doses can be used when the drug form is a controlled release form or intravenous release is used with a liquid form. The compounds of this invention when used in combination with other compounds or agents can be administered as a daily dose or an appropriate fraction of the daily dose (eg, given). The administration of the compounds of this invention may occur at or near the time when the other compound or agent is administered at a different time. When the compounds of this invention are used in combination with other compounds or agents, the other compound or agent (e.g., atorvastatin) can be administered at the approved dose or at a lower dose.

For the purposes of this invention, the compounds may be administered by a variety of means including orally, parenterally, by inhalation including but not limited to nasal y, topically, implantable or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants or vehicles. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, and intra-arterial injections with a variety of infusion techniques. Intra-arterial and intravenous injection as used herein includes administration through catheters. Oral administration is generally preferred. The pharmaceutical compositions containing the active ingredient may be in any suitable form by the intended method of administration. When used for oral use for example, tablets, pellets, chips, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, soft or hard capsules, syrups or elixirs may be prepared. The compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents including sweetening agents, flavoring agents, coloring agents and preservatives, in order to provide a preparation of pleasant flavor. Tablets and pellets containing the active ingredient in admixture with the non-toxic pharmaceutically acceptable excipient which are suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating or disintegrating agents, such as corn starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets and pellets can be covered or not covered by known techniques including icroencapsulation for disintegration and delayed absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time-delaying material such as glyceryl monostearate or glyceryl distearate or with a wax may be employed. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oily medium, such as peanut oil, liquid paraffin or olive oil.

The aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum and dispersing agents or humectants such as a naturally occurring phosphatide (e.g., lecithin). ), a condensation product of an alkylene oxide with a fatty acid (for example, polyoxyethylene stearate), a condensation product of ethylene oxide with a long-chain aliphatic alcohol (for example, heptadecaethyleneoxycatanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (for example, polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl p-hydroxy-benzoate or n-propyl, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oral suspensions may contain a 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 an oral preparation with a pleasant taste. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid. The powders, pellets and dispersible granules of the invention suitable for the 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 agents or humectants and suspending agents are exemplified by those described above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. The pharmaceutical compositions can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil, such as olive oil or peanut oil, a mineral oil, such as liquid paraffin or a mixture thereof. Suitable emulsifying agents include naturally occurring gums, such as gamma acacia and tragacanth gum, naturally occurring phosphatides, such as soy lecithin, esters or partial esters derived from fatty acids and hexithiol anhydrides, such as sorbitan monooleate. , and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. The syrups and elixirs can be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain an emollient, preservative, flavoring or coloring agent. In another aspect the pharmaceutical compositions may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleagenous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which are mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, such as a solution in 1,3-butane diol prepared as a lyophilized powder. Among the vehicles and acceptable solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils can conventionally be employed as a solvent or suspension medium. For this purpose any soft fixed oil may be employed including synthetic mono or diglycerides. In addition, fatty acids such as oleic acid can similarly be used in the preparation of injectables.

The amount of active ingredient that can be combined with the carrier material to produce a single dose form varies depending on the host treated and the particular mode of administration. For example, a time release formulation that is intended for oral administration to humans may contain 0.2 to 2000 μmol (approximately 0.1 to 1000 mg) of active material composed of an appropriate and convenient amount of the carrier material which may vary from around from 5 to about 99.9% of the total compositions. It is preferred that the pharmaceutical composition prepared which provides easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion should contain from about 0.05 to about 500 μmol. (approximately 0.025 to 250 mg) of the active ingredient per milliliter of solution in the order of infusion of an appropriate volume at a rate of about 30 mL / h may occur. As indicated above, formulations suitable for oral administration may be presented as distinct units such as capsules, amylaceous capsules, pellets or tablets each containing a predetermined amount of the active ingredient; like a powder or granule; as a solution or suspension in an aqueous or non-aqueous liquid; or as a water-in-oil liquid emulsion or an oil-in-water liquid emulsion. The active ingredient can also be administered as a bolus, electuary or paste. A tablet can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (eg, povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) dispersing agents or surfactants. The molded tablets can be made by molding in a suitable machine a mixture of the wetted powder compound with an inert liquid diluent. The tablets may optionally be provided with an enteric coating, to provide release in parts of the intestines other than the stomach. This is particularly advantageous with the compounds of the present invention when such compounds are susceptible to acid hydrolysis. The pharmaceutical compositions comprising the compounds of the present invention can be administered by delayed or controlled release means. Controlled-release pharmaceutical products have a common goal of improving drug therapy over that obtained by their non-controlled release counterparts. Ideally, the use of a controlled release preparation optimally designated in medical treatment is characterized by a minimum of drug substance used to treat or control the condition in a minimum amount of time. The advantages of controlled release formulations include: 1) extended activity of the drug; 2) reduce the dose frequency; 3) increase patient compliance; 4) use of less total drug; 5) reduction in effects of systemic or local collaterals; 6) minimization of drug accumulation; 7) reduction in blood level fluctuations; 8) improvement in the effectiveness of the treatment; 9) reduction of potentiation or loss of drug activity; 10) improvement in the speed of control of diseases or conditions. (Kim, Chemg-ju, Controlled Relay Dosage Form Design, 2 Technomic Publishing, Lancaster, Pa .: 2000). Conventional dosage forms generally provide rapid or immediate drug release from the formulation. Depending on the pharmacology and pharmacokinetics of the drug, the use of conventional dosage forms can be directed to wide fluctuations in drug concentrations in the blood of patients and other tissues. These fluctuations can be impacted on a number of parameters, such as dose frequency, onset of action, duration of efficacy, maintenance of therapeutic blood levels, toxicity, side effects, and the like. Advantageously, the controlled release formulations can be used to control the onset of drug action, duration of action, plasma levels within the therapeutic window, and peak blood levels. In particular, the controlled or extended release dosage forms or formulations can be used to ensure that the maximum efficacy of a drug is obtained while the potential adverse effects are minimized and the safety concerns, both of which can arise from dose a drug (that is, below the minimum therapeutic levels) as well as exceeding the level of toxicity for the drug. The most controlled release formulations are designed to initially release a quantity of drug (active ingredient) which readily produces the desired therapeutic effect and gradually and continuously releases other amounts of drug to maintain this level of therapeutic or prophylactic effect for an extended period of time. In order to maintain this constant level of the drug in the body, the drug must be released from the dosage form at a rate that replaces the amount of drug metabolized and excreted from the body. The controlled release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, ionic strength, osmotic pressure, temperature, enzymes, water and other physiological or compound conditions. A variety of controlled or extended release forms, formulations and devices can be adapted by use with the compositions of the invention. Examples include, but are not limited to, those described in the US patent. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,733,566; and 6,365,185 Bl; each of which is incorporated herein by reference. These dosage forms may be used to provide controlled or slow release of one or more active ingredients using, for example, hydroxypropylmethyl cellulose, other polymer matrices, permeable membranes, osmotic systems (such as OROS, RTM. (Alza Corporation, Mountain View, Calif. USA)), multilayer coating, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying proportions. Additionally, the ion exchange materials can be used to prepare immobilized forms of the compositions of the invention and thus effect controlled release of the drug. Examples of specific ion changes include, but are not limited to DUOLITE A568 and DUOLITE AP143 (Rohm &Haas, Spring House, Pa. USA). One embodiment of the invention encompasses a unit dosage form which comprises a compound of the present invention or a pharmaceutically acceptable salt or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof, and one or more pharmaceutically acceptable excipients or diluents, wherein the pharmaceutical composition or dosage form is formulated by controlled release. The specific dosage forms utilize an osmotic drug delivery system. A particular and well-known osmotic drug delivery system is referred to as OROS (Alza Corporation, Mountain View, Calif. USA). This technology can readily be adapted for the release of the compounds and compositions of the invention. Various aspects of the technology are described in the U.S. patent. Nos. 6,375,978 Bl; 6,368,626 Bl; 6,342,249 Bl; 6,333,050 B2; 6,287,295 Bl; 6,283,953 Bl; 6,270,787 Bl; 6,245,357 Bl; and 6,132,420; each of which is incorporated herein by reference. OROS-specific adaptations that can be used to administer compounds and compositions of the invention include, but are not limited to, the Push-Pull, Push-Pull, Push-Pull, Push-Pull, and Push-Stick systems, all which are well known. Additional OROS systems that can be used for controlled oral delivery of the compounds and compositions of the invention include OROS-CT and L-OROS. Id .; see also, Delivery Times, vol. II, edition II (Alza Corporation). Conventional OROS oral dosage forms are made by compressing a powder drug (eg, a T3 mimic composition of the present invention) into a hard tablet, coating the tablet with cellulose derivatives to form a semi-permeable membrane, and then drill a hole in the coated one (for example, with a laser). (Kim, Cherng-ju, Controlled Relay Dosage Form Design, 231-238 Technomic Publishing, Lancaster, Pa. 2000). The advantage of such dosage forms is that the rate of administration of the drug is not influenced by physiological or experimental conditions. Even a drug with a pH-dependent solubility can be administered at a constant rate without considering the pH of the administration medium. But because these advantages are provided by an osmotic pressure construct within the dosage form after administration, conventional OROS drug delivery systems can not be used to effectively administer drugs with low water solubility. A specific dosage form of the invention comprises: a wall defining a cavity, the wall having an outlet orifice formed or forming therein and at least a portion of the wall is semipermeable; an expandable layer located within the remote cavity of the outlet orifice and in fluid communication with the semipermeable portion of the wall; a drug layer in the dry or substantially dry state within the cavity adjacent to the exit orifice and in direct or indirect contact with the expandable layer; and a layer that promotes the interposed flow between the inner surface of the wall and at least the outer surface of the drug layer located within the cavity, wherein the drug layer comprises the compound of the present invention, including a form of polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous thereof. See Patent E.U.A. No. 6,368,626, the entirety of which is incorporated herein by reference. Another specific dosage form of the invention comprises: a wall defining a cavity, the wall having an outlet orifice formed or forming therein and at least a portion of the wall is semipermeable; an expandable layer located within the remote cavity of the outlet orifice and in fluid communication with the semipermeable portion of the wall; a drug layer located within the cavity adjacent to the exit orifice and in direct or indirect contact with the expandable layer; the drug layer comprises a liquid active agent formulation that is absorbed into pore particles, the pore particles are adapted to withstand sufficient compaction forces to form a compacted drug layer without significant exudation of the active agent formulation, liquid, the dosage form optionally has a placebo layer between the exit orifice and the drug layer, wherein the active agent formulation comprises the compound of the present invention, including a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous thereof. See 6,342,249, the entirety of which is incorporated herein by reference. Transdermal Administration System: The controlled release formulations of the present invention can be formulated as a transdermal delivery system, such as transdermal patches. In certain embodiments of the present invention, the transdermal patch comprises the compound of the present invention contained in a reservoir or matrix, and an adhesive that allows the transdermal device to adhere to the skin, which allows the passage of the active agent of the transdermal device towards the patient's skin. Once the compound has penetrated the skin layer, the drug is absorbed into the bloodstream where it exerts its desired pharmaceutical effects. The transdermal part releases the compound of the present invention in a controlled release manner, such that the blood levels of the compound of the present invention are maintained at a therapeutically effective level throughout the dosage period, and the blood levels of the The compounds of the present invention are maintained at a concentration which is sufficient to reduce the side effects associated with the immediate release dosage forms but not sufficient to negate the therapeutic effectiveness of the compound. Transdermal refers to the administration of the compound by passing through the skin or mucosal tissue into the bloodstream. There are four main types of transdermal patches listed below: 1. Single-Layer Adhesive Drug: The adhesive layer of this system also contains the drug. In this type of patch the adhesive layer not only serves to adhere the various layers together, together with the entire system to the skin, but is also responsible for the release of the drug. The adhesive layer is surrounded by a temporary coating and a backing. 2. Drug in Multiple-layer Adhesive: The drug patch in multiple-layer adhesive is similar to the single-layer system in which both adhesive layers are also responsible for the release of the drug. The multiple layer system is different however to which another layer of the drug in adhesive is added, usually separated by a membrane (but not in all cases). This patch also has a temporary coating layer and a permanent backing. 3. Deposit: Unlike Drug systems in single layer and multiple layer adhesive, the transdermal deposit system has a separate drug layer. The drug layer is a liquid compartment containing a solution or suspension of the drug separated by the adhesive layer. This patch is also backed by the backup layer. 4. Matrix: The matrix system has a drug layer of a semisolid matrix containing a drug solution or suspension. The adhesive layer in this patch surrounds the drug layer partially covering it. Other modes of transdermal administration are known in the art and are included in the present invention. Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth.; Pills comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwash comprising the active ingredient in an appropriate liquid carrier. Formulations for rectal administration may be presented as a suppository with an appropriate base comprising, for example, cocoa butter or a salicylate. Formulations suitable for vaginal administration may be presented as weighings, buffers, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient, carriers such as those known in the art to be appropriate. Formulations suitable for parenteral administration include non-aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffer solutions, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations can be presented in sealed unit dose or multiple dose containers, eg, ampoules and vials, and can be stored in a freeze-dried condition (lyophilized) that only requires the addition of a sterile liquid carrier, eg water for injections, immediately before use. The injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the type previously described. In one aspect, the unit dose formulations are those containing the daily or unit dose, daily sub-dose, or an appropriate fraction thereof, of a drug.

It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual to be treated; the time and route of administration; the rate of excretion; other drugs that have previously been administered; and the severity of the particular disease experienced by the therapy, as understood by those skilled in the art. Synthesis of the Compounds of Formula I The compounds of this invention can be prepared by the processes described in the following Reaction Schemes, as well as published relevant literature procedures that are used by those skilled in the art.

It will be understood that the following reaction schemes are provided solely for the purpose of illustration and do not limit the invention as defined by the claims. Typically, the synthesis of the compound of Formula I includes the following general steps: (1) Preparation of a phosphonate prodrug; (2) Deprotection of a phosphonate ester; (3) Introduction of a phosphonate group; (4) Construction of the diary ring system; and (5) Preparation of key precursors. The order of introduction of a phosphonate group and the construction of the diaryl column in the synthesis of compounds of Formula I can be freely decided by those skilled in the art based on the structure of the substrate. In all the applicable structures contained in the Schemes described in this invention, PG refers to a protecting group and FG refers to a functional group that can be transformed into T. The protection and deprotection in the Schemes can be carried out in accordance with the procedures generally known in the art (eg, "Protecting Groups in Organic Synthesis", 3rd Edition, Wiley, 1999). All stereoisomers of the compounds of the present invention are contemplated, either in admixture or in pure or substantially pure form. The compounds of the present invention can have stereogenic centers on the phosphorus atom and on any of the carbons including any of the R substituents. Accordingly, the compounds of the Formula I can exist in enantiomeric or diastereomeric forms or in mixtures thereof. . The processes for the preparation can use racemates, enantiomers or diastereomers as starting materials. When enantiomeric or diastereomeric products are prepared, they can be separated by conventional methods for example, chromatographic or fractional crystallization.

Preparation of a Phosphonate Prodrug The prodrugs can be introduced in different stages of the synthesis. Most frequently these prodrugs are made from the phosphonic acids of Formula I due to their instability. The phosphonic acids of Formula I can be alkylated with electrophiles such as alkyl halides and alkyl sulfonates under conditions of nucleophilic substitution to give phosphonate esters. For example, compounds of Formula I wherein YR 11 is an acyloxyalkyl group can be prepared by direct alkylation of the compounds of Formula I with an appropriate acyloxyalkyl halide (eg, Cl, Br, I; Phosphorus Sulfur 1990, 54, 143; Synthesis 1988, 62) in the presence of an appropriate base (e.g., pyridine, TEA, diisopropylethylamine) in appropriate solvents such as DMF (J. Med. Chem. 1994, 37, 1875). The carboxylate component of these acyloxyalkyl halides include but are not limited to acetate, propionate, isobutyrate, pivalate, benzoate, carbonate and other carboxylates. Acetals of dialkyl dimethylformamide can also be used for the alkylation of phosphonic acids (Collect, Czech Chem. Commu. 1994, 59, 1853). Compounds of Formula I wherein YR11 is a cyclic carbonate, a lactone or a phthalidyl group may also be synthesized by direct alkylation of the free phosphonic acids with appropriate halides in the presence of an appropriate base such as NaH or diisopropylethylamine (J. Med. Chem. 1995, 38, 1372; J. Med. Chem. 1994, 37, 1857; J. Pharm. Sci. 1987, 76, 180). Alternatively, these phosphonate prodrugs can be synthesized by the reactions of the corresponding dichlorophosphonates and an alcohol (Collect Czech Chem. Commun. 1994, 59, 1853). For example, a dichlorophosphonate is reacted with substituted phenols and arylalkyl alcohols in the presence of a base such as pyridine or TEA to give the compounds of Formula I wherein YR 11 is an aryl group (J. Med. Chem. 1996, 39 4109; J. Med. Chem. 1995, 38, 1372; J. Med. Chem. 1994, 37, 498) or an arylalkyl group (J Chem. Soc. Perkin Trans. 1 1992, 38, 2345). Prodrugs containing disulfide (Antiviral Res. 1993, 22, 155) can be prepared from a dichlorophosphonate and 2-hydroxyethyldisulfide under standard conditions. The dichlorophosphonates are also useful for the preparation of various phosphonamides as prodrugs. For example, the treatment of a dichlorophosphonate with ammonia gives both a monodosdonamide and a diphosphonamide; the treatment of a dichlorophosphonate with l-amino-3-propanol gives a cyclic 1,3-propylphosphonamide; the treatment of a monophenyl chlorophosphonate ester with an amino acid ester in the presence of an appropriate base gives the substituted monophenyl monophosphonamide. Such reactive dichlorophosphonates can be generated from the corresponding phosphonic acids with a chlorinating agent (for example, thionyl chloride, J. Med. Chem. 1994, 1857; oxalyl chloride, Tetrahedron Lett., 1990, 31, 3261; phosphorus pentachloride; , Synthesis 1974, 490). Alternatively, the dichlorophosphonate can be generated from its corresponding disilyl phosphonate esters (Synth, Commu, 1987, 17, 1071) or dialkyl phosphonate esters (Tetrahedron Lett, 1983, 24, 4405; Bull. Soc. Chim. 1993, 130, 485 ). It is contemplated that the compounds of Formula I may be mixed phosphonate ester (e.g., phenyl and benzyl esters, or phenyl esters and acyloxyalkyl) including chemically combined mixed esters such as combined phenyl and benzyl prodrugs reported in Bioorg Med. Chem. Lett. 1997, 7, 99. Dichlorophosphonates are also useful for the preparation of various phosphonamides as prodrugs. For example, the treatment of a dichlorophosphonate with an amine (for example, an alkyl amino acid ester such as L-alanine ethyl ester) in the presence of an appropriate base (e.g., triethylamine, pyridine, etc.) gives the corresponding bisphosphonamide; the treatment of a dichlorophosphonate with 1-amino-3-propanol gives a cyclic 1,3-propylphosphonamide; the treatment of a monophenyl chlorophosphonate ester with an amino acid ester in the presence of an appropriate base gives the substituted monophenyl monophosphonamide. Direct couplings of a phosphonic acid with an amine (eg, an alkyl amino acid ester such as L-alanine ethyl ester) are also reported to give the corresponding bisamidates under Mukaiyama conditions (J. Am. Chem. Soc, 1972, 94, 8528). The SATE prodrugs (S-acetyl thioethyl) can be synthesized by the coupling reaction of the phosphonic acids of Formula I and S-acyl-2-thioethanol in the presence of DCC, EDCI or PyBOP (J. Med. Chem. 1996, 39 , 1981) . The cyclic phosphonate esters of substituted 1,3-propanediols can be synthesized by any of the reactions of the corresponding dichlorophosphonate with substituted 1,3-propanediol or coupling reactions using appropriate coupling reagents (eg, DCC, EDCI, PyBOP; Synthesis; 1988, 62). The reactive dichlorophosphonate intermediates can be prepared from the corresponding acids and chlorinating agents such as thionyl chloride (J. Med. Chem., 1994, 1857), oxalyl chloride (Tetrahedron Lett., 1990, 31: 3261) and phosphorus pentachloride (Synthesis, 1974, 490). Alternatively, these dichlorophosphonates can also be generated from disilyl esters (Synth Commun., 1987, 17: 1071) and dialkyl esters (Tetrahedron Lett., 1983, 24: 4405; Bull. Soc. Chim. Fr., 1993, 130 : 485).

Alternatively, these cyclic phosphonate esters of substituted 1,3-diols are prepared from phosphonic acids by coupling with diols under Mitsunobu reaction conditions (Synthesis 1 (1981); J. Org Chem. 52: 6331 (1992)), and other acid coupling reagents including, but not limited to, carbodiimides (Collect, Czech, Chem. Commun. 59: 1853 (1994); Bioorg Med. Chem. Lett., 2: 145 (1992), Tetrahedron Lett 29: 1189 (1988)), and benzotriazolyloxytris- (dimethylamino) phosphonium salts (Tetrahedron Lett, 34, 6743 (1993)). Phosphonic acids can also undergo cyclic prodrug formation with cyclic acetals or ortho-cyclic esters of substituted propan-1,3-diol to provide prodrugs as in the case of carboxylic acid esters (Helv. Chim. Acta. 48: 1746 ( 1965)). Alternatively, the more reactive cyclic sulphites or sulfates are also suitable coupling precursors for reacting with phosphonic acid salts. These precursors can be made from the corresponding diols as described in the literature. Alternatively, the cyclic phosphonate esters of substituted 1,3-propane diols can be synthesized by trans esterification reaction with substituted 1,3-propane diol under appropriate conditions. The mixed anhydrides of mixed precursor phosphonic acids generated in situ under appropriate conditions react with diols to give the prodrugs as in the case of carboxylic acid esters (Bull, Chem. Soc. Jpn. 52: 1989 (1979)). The aryl esters of the phosphonates are also known to undergo transesterification with alkoxy intermediates (Tetrahedron Lett, 38: 2597 (1997); Synthesis 968 (1993)). One aspect of the present invention provides methods for synthesizing and isolating the simple isomers of prodrugs of phosphonic acids of Formula I. Because phosphorus is a stereogenic atom, the formation of a prodrug with a substituted 1,3-propane diol racemic will produce a mixture of isomers. For example, the formation of a prodrug with a racemic 1- (V) -substituted-1, 3-propane diol gives a racemic mixture of cis prodrugs and a racemic mixture of trans prodrugs. In another aspect, the use of enantiomerically-enriched substituted 1,3-propane diol with the R configuration gives enantiomerically enriched R-cis and R-trans prodrugs. These compounds can be separated by a combination of column chromatography and / or fractional crystallization. A. Deprotection of a Phosphonate Ester The compounds of Formula I wherein X is -P03H2 can be prepared from phosphonate esters using the known cleavage methods. Silyl halides are generally used to split several phosphonate esters and give the desired phosphonic acid during the mild hydrolysis of the resulting silyl phosphonate esters. When necessary, acid scavengers (eg, HMDS) can be used for acid-sensitive compounds. Such silyl halides include TMSC1 (J. Org Chem. 1963, 28, 2975), TMSBr (Tetrahedron Lett., 1977, 155) and TMSI (J. Chem. Soc, Chem. Commu., 1978, 870). Alternatively, the phosphonate esters can be cleaved under strong acid conditions (Tetrahedron Lett, 1992, 33, 4137; Synthesis-Stuttgart 1993, 10, 955). Those phosphonate esters can also be split by dichlorophosphonates prepared by treating the phosphonate esters with halogenating agents such as PC15, S0C12 and BF3 (J. Chem. Soc. 1961, 238) followed by aqueous hydrolysis to give the phosphonic acids. The aryl and benzyl phosphonate esters can be split under hydrogenolysis conditions (Synthesis 1982, 412; J. Med. Chem. 1985, 28, 1208) or metal reduction conditions (J. Chem. Soc. 1977, 99, 5118). . The electrochemical conditions (J. Org. Chem. 1979, 44, 4508) and pyrolysis conditions (Synth, Commu, 1980, 10, 299) are used to split several phosphonate esters. Introduction of a Phosphonate Group The introduction of a phosphonate group can generally be carried out in accordance with known methods. The compounds of Formula I wherein T is -0 (CRb2) (CRa2) n-, -S (CRb2) (CRa2) n- or -N (RC) (CRb2) (CRa2) n- can be prepared by coupling a phenol, thiophenol, or aniline with a phosphonate ester component such as I (CRb2) (CRa2) nP (0) (OEt) 2, TsO (CRb2) (CRa2) nP (0) (OEt) 2, or TfO ( CRb2) (CRa2) nP (0) (0Et) 2 in the presence of a base such as NaH, K2C03, KO-t-Bu or TEA (Tetrahedron Lett, 1986, 27, 1477; J. Chem. Soc. Perkin Tran 1 1994, 1987) as described in Reaction Scheme 1. Following the procedures described above, deprotection of the phosphonate ester 2 gives the desired phosphonic acid 3. The compounds of Formula I wherein T is -N (Rb) C (0) (CRa2) n- can be prepared by coupling an aniline 1 (M = NH) with a carboxylic acid containing a phosphonate (EtO) 2P (0) (CRa2) moiety? -2C02H in the presence of DCC or EDC according to the known methods (for example, J. Org. Chem. 1977, 42, 2019) or converting the aniline 1 (M = NH) to an isocyanate with diphosgene followed by the reaction with P (0Et) 3 (J. Org. Chem. 1956, 1661, Tetrahedron Lett., 1996, 37, 5861).

Deprotection of the phosphonate ester 2 as described above leads to phosphoric acid 3. For the compounds of Formula I wherein T is - (CRa2) k _ / - the phosphonate group can be introduced by a number of known methods. For example, the coupling reaction of a phenyl bromide (J. Org Chem. 1999, 64, 120), iodide (Phosphorus Sulfur 1997, 130, 59) or triflate (J. Org. Chem. 2001, 66, 348) with diethyl phosphonate in the presence of a Pd catalyst, is widely used within the art (when k is 0 ). Other methods such as the Michaelis-Arbuzov reaction (Chem. Rev. 1981, 81, 415) can also be an efficient way to introduce the phosphonate group by coupling a -benzyl or arylalkyl halide with triethyl phosphonate (when m is 1- 3) . For compounds of the formula I wherein T is - (CRa2) n-CRb = CR-, the phosphonate group can be introduced by coupling a tetraethyl aldehyde or methylene diphosphonate in the presence of an abse such as NaH, NaOH or KO-t-Bu (Tetrahedron Lett., 1988, 29, 3007). For compounds of Formula I wherein T is -CRb = CRb- (CRa2) n- or - (CRa2) -CRb = CRb- (CRa2) -, the phosphonate group can be introduced by Michaelis-Arbuzov reaction of the corresponding olefinic halide with Triethyl phosphite. For the compounds of Formula I wherein T is - (CRa2) m (CO) -, the phosphonate group can be introduced by reacting the diethyl phosphite with an acid chloride (J.

Org, Chem. 1964, 29, 3862; Tetrahedron 1998, 54, 12233) or an aldehyde followed by oxidation (Tetrahedron 1996, 52, 9963). Also, this type of compounds can be transformed into the compounds of Formula I wherein T is - (CRa2) nCH (NRbRc) - in accordance with known procedures (Tetrahedron Lett, 1996, 37, 407). For compounds of Formula I wherein T is (CO) (CRa2) m-, the phosphonate group can be introduced by a number of known methods such as reacting a substituted benzoyl chloride with diethylphosphonoacetic acid (Synthetic Commu. 2000, 30, 609) or a copper phosphonate reagent (Tetrahedron, Lett, 1990, 31, 1833). Alternatively, the coupling of triethyl phosphonate with a silyl enol ether (Synthetic Commu., 1994, 24, 629) or an a-bromobenzophenone (Phosphorus Sulfur 1994, 90, 47) can also introduce the phosphonate group. For compounds of Formula I wherein T is C (0) NH (CRb2) (CRa2) p-, the phosphonate group can be introduced by coupling reaction of a substituted benzoic acid and an aminophosphonate in accordance with the methods of bond formation standard amide (Tetrahedron Lett, 1990, 31, 7119; Tetrahedron Lett, 1989, 30, 6917; J Org. Chem. 1993, 58, 618). For compounds of Formula I wherein T is (CRa2) C (0) (CRa2) n- or (CRa2) nC (0) (CRa2), the phosphonate group can be introduced by reacting a benzyl bromide with a functionalized phosphonate (Tetrahedron Lett, 1989, 30, 4787). Alternatively, the coupling reaction of the substituted phenylacetate and methylphosphonate also provides the desired product (J. Am. Chem. Soc. 1999, 121, 1990).

Reaction scheme 1 to. l (CRa2) nP. { 0) (OEt) 2, or TsO (CRa2) nP (0) (OEt) 2 Deprotection b. P (0) (OEt) 2 (CRa2) nC02H, DCC c. Diphosgene, P (OEt) 3 M = 0, S, NH T = 0 (CRa2) n, S (CRa2) n, NR (CRa2) n, NRb (CO) (CRa2) n Construction of the aryl ring The compounds of the formula I wherein G is -0- can be prepared according to the known methods. As described in reaction scheme 2, 2a is reacted with 2b at room temperature in the presence of Cu powder and a suitable base such as TEA, diisopropylamine or pyridine to provide coupling product 4 (J. Med. Chem. 1995, 3N, 695). Deprotection of the methoxy group with suitable agents such as boron tribromide, boron trichloride or boron trifluoride in CH2C12 gives the intermediate 5. The introduction of the phosphonate group followed by the deprotection of the phosphonate ester as described in Reaction Scheme 1 leads to the desired phosphonic acid 6. Those skilled in the art can use known methods such as coupling an arylboronic acid and a phenol in the presence of Cu (OAc) 2 (Tetrahedron Lett, 1998, 39, 2937), nucleophilic a fluorobenzene (Synthesis-Stuttgart 1991, 1, 63) or iodobenzene (J. Am. Chem. Soc. 1997, 119, 10539) with a phenol and coupling of a bromobenzene with a phenol in the presence of Pd2 (dba) 3 (Tetrahedron Lett., 1997, 35, 8005) to form the diaryl ether system.

Reaction scheme 2 Deprotection FG = functional group that can be transformed into T For the compounds of the formula I wherein G is -CH2-, the installation of the diaryl ring can be completed by a number of known methods. For example, as described in reaction scheme 3, benzyl alcohol 7 was formed by treating 3a with n-BuLi at -78 ° C in THF followed by reacting with 3b (Bioorg, Med. Chem. Lett. 2000, 10, 2607). Hydrogenolysis with Pd-C or dehydroxylation of benzyl alcohol 7 by NaBH4 (Synthetic Commu. 1987, 17, 1001) and (i-Bu) 3A1 (Synthesis 1987,736) followed by removal of the protecting group gives the diaryl intermediary 8. Phosphonic acid 9 was formed from 8 in accordance with the same procedures as described in reaction scheme 1. Alternatively, the coupling of benzyl bromide with a Grignard aryl reagent (Tetrahedron Lett, 1981,22, 2715), an arylboronic acid (Tetrahedron, Lett. 1999, 40, 7599) or a zinc reagent (Chem. Lett, 1999, 11, 1241) and the reduction of a diaryl ketone (J. Org Chem. 1986, 51, 3038) are all methods widely used for the construction of the diaryl ring.

Reaction scheme 3 PG = protecting group FG = functional groups that can be transformed into T For the compounds of the formula I wherein G is -S-, -S (= 0) - u -S (= 02) -, the formation of the diaryl ring it can be carried out according to known methods. As illustrated in reaction scheme 4, 3a can be reacted with 4a in the presence of a catalyst such as Pd2 (dba) 3 or CuBr to provide diaryl sulfide 10 (Tetrahedron 2001, 57, 3069; Tetrahedron Lett. , 41, 1283). The phosphonic acid 12 was formed from the 10 after removal of the protecting groups followed by the same procedures as described in Reaction Scheme 1. The diaryl sulfide 10 can also be converted to the sulfoxide 13 according to the known methods ( Synthetic Commu 1986, 16, 1207, J. Org Chemin, 1997, 62, 4253, Tetrahedron Lett, 1990, 31, 4533), which lead to phosphonic acid 15 following the same procedures as described in the Reaction Scheme. 1. Also, biaryl sulfide 10 can be converted to sulfone (Tetrahedron Lett, 1991, 32, 7353, J. Prakt.Chenu, 1942, 160) which leads to phosphonic acid (G is -S (= 02) - ) following the same procedures as described above. In addition, nucleophilic substitution of chlorobenzene and bromobenzene with a thiol is also an efficient way to install the diaryl ring sulfide ring (J. Med. Chem. 1988, 31, 254; J. Org. Chem. 1998, 63, 6338 ).

Reaction scheme 4 Pd2 (dba) 3 PG = protective group FG = functional group that can be transformed into T For compounds of the formula I wherein G is -NH- or -N (C3-C4 alkyl) -, the The diarylamine column can be formed by a number of known methods. Among these conditions, one widely used by those skilled in the art is the coupling reaction of an aniline with an aryl bromide (J Org., Client, 1999, 64, 5575; J. Org Chent, 1997, 62, 6066; Tetrahedron; Lett, 1996, 37, 6993; Org Lett, 1999, 1, 2057) or an aryl tosylate (J. Org Chez, 1997, 62, 1268) in the presence of a catalyst such as PdCl 2 or Pd 2 (dba) 3 . As illustrated in reaction scheme 5, the adiarylamine 16 intermediate can be prepared by the coupling of bromide 3a and aniline 5a in the presence of Pd2 (dba) 3. After removal of the protecting group, diarylamine 17 was converted to phosphonic acid 18 by following the same procedures as described in Reaction Scheme 1. Alternatively, the coupling of an aniline and aryl halide using another catalyst such as copper-beonce ( Org Synth 1943, 2, 446, J. Org. Crew, 1955, 20) and Cu (OAc) 2 (J. Med Cheni, 1986, 4, 470, Synthetic Comn., 1996, 26, 3877) to construct the Diarylamine column is also a possible approach.

Reaction scheme 5 3a 5a Deprotection 17 18 PG = Protective group FG = Functional group that can be transformed into T For the compounds of formula I where G is -CHF- or -CF2 ~, the diaryl column can be established from benzyl alcohol 7. Accordingly , as described in reaction scheme 6, benzyl alcohol 7 can be converted to benzyl fluoride 19 by being reacted with DAST in CH2C12 according to known procedures (J. Chem. Soc., Chem. Commu. 1981, 11 , 511; Tetrahedron Lett, 1995, 36, 6271; Tetrahedron 1988, 14, 2875). Also, benzyl alcohol 7 can easily be oxidized to benzophenone 22 according to known methods such as Mn02 oxidation, PCC oxidation, S ern oxidation and Dess-Martin oxidation, which subsequently was converted to benzyl difluoride 23 by treatment with DAST (J. Fluorine 1993, 61, 117) or other known reagents (J Org Chein, 1986, 51, 3508, Tetrahedron 1999, 55, 1881).

After removal of the protecting groups, the benzyl fluoride 20 and difluoride 24 were converted to the desired phosphonic acids following the same procedures as described in Reaction Scheme 1.

Reaction scheme 6 The compounds of the formula I wherein G is CH (OH) - or -C (0) - can be prepared from the intermediates 7 and 22. The removal of the protective groups of 7 and 22 followed by the intrusion of phosphate and deprotection as described in Reaction Scheme 1 provides the desired phosphonic acids of formula I.

Synthesis of the compounds of the Formula II The synthesis of the compounds of the Formula II wherein A is -NH- and B is -CH- or ~ C-alkyl- can be completed from the corresponding diaryl amino precursor 1 using the synthesis of Indole Fisher, well known, by those of skill in the art, (Reaction Scheme 6a) (Phosphorus and Sulfur, 1988, Vol. 37, pp 41-63). Alternatively, the aryl indole scaffold was constructed using the previously described procedures and the phosphonic acid portion is introduced by making the following anion to the nitrogen of the indole derivative, protecting the nitrogen, with a base such as BuLi and the anion was turned off diethyl chlorophosphate. The additional protecting group and the functional group manipulations of intermediates 2 provide the compounds of formula II.

Reaction scheme 6a The compounds of the formula II wherein A is -O- and B is -CH- are synthesized from the corresponding diaryl phenol precursor 3 and the cyclization of the ring with the bromoacetaldehyde dimethylacetal to give benzofuran 4 (Reaction scheme 6b) ( J. Cem. Soc., Perkin Trans. 1, 1984, 4, 729). The phosphonic acid portion can then be introduced by making the following anion to the benzofuran oxygen with a base such as BuLi and the anion quenched with diethyl chlorophosphate to provide phosphonate 5. The additional protecting group and the functional group manipulations of the intermediate provide the compounds of formula II.

Reaction scheme 6b - ** Formula II The compounds of the formula II wherein A is NH-, -0- or -S- and B is -N- can be made from the condensation of the corresponding diaryl precursor 6 with an orthoformate such as triethyl orthoformate in the presence of acid to give heterocycle 7 (Org. Prep. Int.Proc., 1990, 22 (5), 613-618). The phosphonic acid portion can then be introduced by making the anion in the 2-position of the heterocycle 7 with a base such as BuLi and the anion was quenched with diethyl chlorophosphate to give the phosphonate 8. The additional protecting group and the functional group manipulations of intermediates 8 provide the compound of formula II.

Reaction scheme 6c K = 0, NH, S Formula II Synthesis of the compounds of Formula III Reaction scheme 6d Formula The general synthesis of the compounds of Formula III wherein G is -O-, -S- or -NH- utilizes the displacement of an appropriately substituted phenol, thiophenol or aniline 1 with a pentasubstituted pyridine such as 3,5-dichloro- 2,4,6-trifluoro-pyridine 2 to provide intermediate 3 (Reaction scheme 6d) (Org Prep Int.Procedure, 2000.32 (5), 502-504). The subsequent displacement of the 2-fluoro and 6-fluoro substituents on the pyridine ring with the nucleophiles 4 and HR7 sequentially provide intermediates 5 and 6. Examples of suitable nucleophiles, include but are not limited to, hydroxymethyl phosphonate. diethyl and diethyl aminomethyl phosphonate. The example of the HR7 reagents, include but are not limited to, alkyl thiol, sodium alkoxide, alkylamine or benzylamine. The compounds of the formula III where G is -S (= 0) - and -S (= 0) 2-can be derived from the intermediates 5 and 6 when G is -S- by means of oxidation with an oxidation agent such as mCPBA. The additional protecting group and manipulations of the functional group of intermediates 5 and 6 will provide the compounds of formula III.

Reaction scheme 6e eleven The compounds of the formula III wherein G is -CH 2 - or -C (0) - were synthesized according to reaction scheme 6e. The condensation of benzyl cyanide 7 with pentasubstituted pyridine 2 provides intermediate 8. The displacement of 2-fluoro with reagent 4 gives intermediate 9. Oxidation of benzyl cyanide 9 provides keto derivative 10 which after deprotection and manipulation of the functional group gives a compound of formula III. Alternatively, the reductive deoxygenation of the intermediate keto followed by deprotection and manipulation of the functional group gives a compound of the formula III. Preparation of Key Precursors A. Preparation of compounds with substituents in the ring The starting material and key intermediates required for the synthesis of the compounds in this invention are either commercially available or are prepared using an existing literature methods or a modification of a known method. The synthesis of some of these compounds are described herein. The precursor 2a was prepared by reacting an anisole with trifluoroacetate iodide according to the aforementioned procedures (J. Med. Chez. 1995, 38, 695). Anisols with different R3 and R4 groups are either commercially available or can be prepared according to literature procedures (eg, J. Med. Chem. 1989, 32, 320). The starting material 2b is either commercially available or can be prepared according to known procedures. For example, the compounds of 2b wherein FG is a derivative group NH2 can be prepared by reacting 3a with benzophenone imine in the presence of a Pd catalyst such as Pd2 (dba) 3 or Pd (OAc) 2 (Tetrahedron Lett. 38, 6367; J Am. Chem. Soc. 1998, 120, 827). The compounds of 2b wherein FG is a derivative group S that can be prepared by reacting a possible 4-aminoanisole with NaN02 and ethyl potassium xanthate (J. Am. Chez. Soc. 1946, 68; Heterocycles 1987, 26, 973) . The useful precursor 3a can either be a commercially available reagent or be prepared according to the existing methods. As described in Reaction Scheme 7, a protection sample of commercially available 4-bromophenol 7b with different R and R groups according to methods known in the art leads to 3a. Compound 3a can also be prepared by bromination of the protected phenol 7d (J. Org. Chem. 1988, 53, 5545; J. Org. Chem. 1994, 59, 4473; Synthesis-Stuttgart 1986, 10, 868). The introduction of several groups R3 and R4 for 4-bromophenol 7a can be carried out to give 7b which leads to 7a after protection (Tetrahedron Lett, 1995, 36, 8453, J. Heterocyclic Claem, 1991, 28, 1395; J. Fluorine Chem. 1988, 40, 23; Synthesis-Stuttgart 1999, 11, 1878; Synthetic Commu. 1986, 16, 681). 7b can also be prepared by the bromination of phenol 7c (J. Cob.Chem., 2000, 2, 434; Chem. Soc. JPN, 1988, 61, 2681; Synthesis-Stuttgart 1992, 5, 467; Org. Synth., 1993 , 72, 95). Reaction scheme 7 7c 7d A number of methods are available for the preparation of benzaldehyde 3b. As illustrated in Reaction Scheme 8, bromobenzene 8a can be converted to benzaldehyde 3b by reacting with DMF (Aust. J. Chem. 1998, 51, 177; Bioorg, Med.Chem. Lett., 2000, 10, 2607) or carbon monoxide in the presence of a palladium catalyst (Bull, Chem. Soc. Jpn 1994, 67, 2329). 3b can be formed by oxidation of the benzylic alcohol 8c using common methods such as Mn02 oxidation, PCC oxidation, Swern oxidation and Dess-Martin oxidation. The reduction of benzonitrile 8b and benzoyl chloride 8d also produces benzaldehyde 3b (Org Synth 1995, 3, 551, J. Org Chem 1981, 46, 602).

Reaction scheme 8 Reduction For some of the compounds of Formula I, the R3 and R4 groups may be introduced after the biaryl ring column is installed. As illustrated in reaction scheme 9, intermediate 4 (R3, R4 = H) was converted to benzylaldehyde 26 during the treatment with SnCl and methoxymethyl dichloride. The various (C? -C12) alkyl groups were introduced by reacting the benzylaldehyde 26 with a Wittig reagent followed by reduction of the resulting alkene with Et3SiH to provide intermediate 27 (J. Med. Chefn. 1988, 31, 37). Also, benzylaldehyde 31 can be oxidized by NaOCl 2 to give benzoic acid 29 (Bioorg, Med.Chem. Lett, 2003, 13, 379) which can be reacted with an alcohol or amine under standard conditions to give the ester or amide. Intermediates 27 and 30 can be converted to the corresponding phosphonic acids 28 and 33 by following the procedures as described in Reaction Scheme 2. In addition, deprotection of intermediate 4 provided phenol 32 which can be converted to a variety of sulfonamides. during treatment with CIS03H and an amine. The phosphonic acids (R3 = S (= 0) 2NRfR9) can be formed following the same procedures as described in Reaction Scheme 1.

Reaction scheme 9 33 Reaction scheme 1 3. 4 action 2 R = NRfR9, 0Rd B. Preparation of 1,3-diols Various methods can be used to prepare the 1,3-propanediols such as 1,3-propanediols 1-substituted, 2- substituted, 1,2- or 1,3- canceled. 1. I-Substituted 1,3-propanediols The 1,3-propanediols useful in the synthesis of the compounds in the present invention can be prepared using various synthetic methods. As described in Reaction Scheme 10, the additions of a Grignard aryl to a 1-aryl-substituted l-hydroxy-propan-3-al 1,3-propanediol (path a). This method is suitable for the conversion of various aryl halides to 1-arylsubstituted 1, 3-propanediols (J. Org. Chem. 1988, 53, 911). Conversions of the aryl halides to 1-substituted 1,3-propanediols can also be carried out using Heck reactions (eg coupling with 1, 3-diox-4-ene) followed by reductions and subsequent hydrolysis reactions ( Tetrahedron Lett, 1992, 33, 6845). Various aromatic aldehydes can also be converted to 1-substituted-1,3-propanediols using Grignard alkenyl addition reactions followed by hydroboration oxidation reactions (path b).

Reaction scheme 10 Aldol reactions between an enolate (e.g., lithium, boron, tin enolates) of a carboxylic acid derivative (e.g., tert-butyl acetate) and an aldehyde (e.g., aldol Evans reactions) are especially useful by the asymmetric synthesis of 1, 3-propanediols enantiomerically enriched. For example, the reaction of a metal enolate of t-butyl acetate with an aromatic aldehyde followed by reduction of the ester (path e) yields a 1,3-propanediol (J. Org. Chem. 1990, 55 4744). Alternatively, the epoxidation of cinnamyl alcohols using known methods (e.g., Sharpless epoxidations and other asymmetric epoxidation reactions) followed by reduction reactions (e.g., using Red-Al) gives various 1,3-propanediols (path c). The enantiomerically enriched 1, 3-propanediols are obtained by means of asymmetric reduction reactions (for example, enantioselective borane reductions) of 3-hydroxyketones (Tetrahedron Lett, 1997, 38 761). Alternatively, the resolution of racemic 1, 3-propanediols using various methods (eg, enzymatic or chemical methods) can also yield enantiomerically enriched 1,3-propanediol. Propan-3-ols with a 1-heteroaryl substituent (eg, a pyridyl, a quinolinyl or an isoquinolinyl) can be oxygenated to give 1-substituted 1,3-propanediols using N-oxide forming reactions followed by a reaction of configuration under acetic anhydride conditions (trajectory d) (Tetrahedron 1981, 37, 1871). 2. 1, 3-Substituted 1-3-propanediols A variety of 2-substituted 1, 3-propanediols useful for the synthesis of the compounds of the Formula I can be prepared from various other 1,3-propanediols (e.g., 2- (hydroxymethyl) -1,3-propanediols) using conventional chemistry (Comprehensive Organic Transormations, VCH, New York, 1989). For example, as described in Reaction Scheme 11, reductions of a trialcoxycarbonylmethane under known conditions to give a triol by means of complete reduction (path a) or a bis (hydroxymethyl) acetic acid by means of selective hydrolysis of one of the ester groups followed by reduction of the other two ester groups resulting. The nitrotrioles also known to give triols by means of reductive elimination (trajectory b) (Synthesis 1987, 8, 742). In addition, a 2- (hydroxymethyl) -1,3-propanediol can be converted to a mono acylated derivative (eg, acetyl, methoxycarbonyl) using an acyl chloride or an alkyl chloroformate (eg, acetyl chloride or chloroformate). methyl) (trajectory d) using known chemistry (Protective Groups In Organic Synthesis; Wiley, New York, 1990). Other manipulations of functional groups can also be used to prepare 1,3-propanediols such as oxidation of one of the hydroxymethyl groups in a 2- (hydroxymethyl) -1,3-propanediol to an aldehyde followed by addition reactions with a Grignard aryl ( trajectory c). Aldehydes can also be converted to alkyl amines by means of reductive amination reactions (trajectory e).

Reaction scheme 11 3. Disrupted 1,3-propane diols Compounds of the formula I wherein V and Z or V and W are connected by four carbons to form a ring can be prepared from a 1,3-cyclohexanediol. For example, cis, cis-1, 3, 5-cyclohexanotriol can be modified to give various other 1,3-cyclohexanetriols which are useful for the preparations of the compounds of Formula I wherein R 11 and R 12 together are wherein V and W together are connected by means of 3 atoms to form a cyclic group containing 6 carbon atoms substituted with a hydroxy group. It is projected that these modifications can be carried out either before or after the formation of a cyclic 1,3-propanediol phosphonate ester. Various 1,3-cyclohexanediols can also be prepared using Diels-Alder reactions (for example, using a pyrone such as the diene: Tetrahedron Lett, 1991, 32, 5295). The 2-hydroxymethylcyclohexanols and 2-hydroxymethylcyclopentanols are useful for the preparations of the compounds of the Formula I wherein R11 and R11 together are wherein V and Z together are connected by means of 2 or 3 atoms to form a cyclic group containing 5 or 6 carbon atoms. The derivatives of 1,3-Cyclohexanediol are also prepared by means of other cycloaddition reaction methodologies. For example, cycloadducts from the cycloaddition reactions of nitrile oxide and an olefin can be converted to a 2-ketoethanol derivative which can further be converted to 1,3-propanediol (including, 3-cyclohexanediol, 2-hydroxymethylcyclohexanol and 2-hydroxymethylcyclopentanol) using known chemistry (J. Am. Chem. Soc. 1985, 107, 6023). Alternatively, 1,3-cyclohexanediol precursors can be made from chemical acid (Tetrahedron Lett, 1991, 32, 547.).

EXPERIMENTAL Example 1: Compound 1: N- [3,5-dimethyl-4- (3'-iso-propyl-4-hydroxyphenoxy)] carbamoylphosphonic acid Step a: A mixture of 3,5-dimethyl-4- (3 ') -iso-propyl-4 '-methoxyphenoxy) aniline (J. Med. Chem. 1995, 38, 695, 0.1 g, 0.35 mmol) and. diphosgene (0.04 g, 0.19 mmol) in dioxane (3.0 mL) was heated at 60 ° C for 3 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. To the residue was added a solution of diethyl phosphite (0.06 g, 0.42 mmol) in hexanes (1.0 mL with 3 drops of triethylamine) and the reaction mixture was heated under reflux for 3 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1: 3) to give the diethyl phosphonate as an oil (0.1 g, 64%): 1 H NMR (300 MHz, CDC13 ): d 8.44 (s, 1H), 7.17 (s, 2H), 6.10-6.60 (m, ^ 3H), 4.10 (m, 4H), 3.58 (s, 3H), 3.07 (m, 1H), 1.92 ( s, 3H), 1.93 (s, 3H), 1.22 (m, 6 H), 0.99 (m, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (3: 1); Rf = 0.3.

Step b: To a solution of N- [3,5-dimethyl-4 ~ (3'-iso-propyl-4'-methoxy-phenoxy)] carbamoylphosphonate diethyl (0.1 g, 0.22 mmol) in CH2C12 (1.5 mL ) at -78 ° C was added bromotrimethylsilane (0.30 mL, 2.2 mmol). The reaction mixture was stirred at room temperature for 16 h and the solvent was removed under reduced pressure. The residue was dissolved in CH2C12 (2.0 L) and the solution was cooled to -78 ° C. The boron tribromide (1.3 mL, 1.3 mmol, 1.0 M in CH2C12) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was emptied on ice and extracted with ethyl acetate (20 mL). The organic layer was dried over MgSO, filtered and concentrated under reduced pressure. The crude product was purified by preparative LC-MS to give the title compound as a yellow solid (0.035 g, 42%): mp 67-70 ° C; Anal. Calculated for (C18H22N06P + 0.2 H20 + 0.3 CH3OH): C, 55.99; H, 6.06; N, 3.57. Found: C, 55.79; H, 6.21; N, 3.39. Example 2 Compound 2: l-amino-2- [3, 5-diiodo-4-acid. { 4'-Hydroxy-3'-Iodophenoxy) phenyl] ethylphosphonic Step a: To a solution of 4-benzyloxyphenylacetyl chloride (4.0 g, 16.2 mmol) in THF (10.0 mL) at room temperature was slowly added triethyl phosphite (3.33 mL , 19.5 mmol).

The reaction mixture was stirred at room temperature for 16 h and the solvent was removed under reduced pressure. The residue was treated with hexanes (20 mL) and the mixture was filtered. The white solid was collected and air dried. The solid was dissolved in pyridine (25.0 mL) and hydroxylamine hydrochloride (1.96 g, 28 mmol) was added. The reaction mixture was stirred at room temperature for 72 h and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (7: 3) to give diethyl 2- (4-benzyloxyphenyl) -1- (hydroxyimino) ethylphosphonate as a colorless oil (5.2 g, 85%): XH NMR (300 MHz, CDC13): d 7.18-7.38 (m, 7 H), 6.80 (d, J = 6.2 Hz, 2H), 4.94 (s, 2H), 3.80-4.10 (m , 4H), 3.80 (s, 1H), 3.76 (s, 1H), 1.16 (t, J = 6.0 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (2: 3); Rf = 0.55. Step b: To a mixture of diethyl 2- (4-benzyloxyphenyl) -1-hydroxyiminoethylphosphonate (2.0 g, 5.3 mmol) and NiCl2 (2.53 g, 10.6 mmol) in CH3OH (40.0 mL) at room temperature was slowly added NaBH4 ( 1.0 g, 26.4 mmol). The reaction mixture was stirred at room temperature for 16 h and the solvent was removed under reduced pressure. The residue was treated with 10% aqueous KOH (100 mL) and the mixture was extracted with ethyl ether (2 x 100 mL). The organic layers were dried over MgSO, filtered and concentrated under reduced pressure. The residue was dissolved in THF (14.0 mL) and (BOC). (0.74 g, 3.4 mmol) was added. The reaction mixture was heated under reflux for 4 h and cooled to room temperature. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with 4% CH3OH in CH2C12 to give diethyl 2- (4-benzyloxyphenyl) -1- (tert-butoxycarbonylamino) ethylphosphonate as a oil (1.12 g, 46%): 1 H NMR (300 MHz, CD3OD): d 7.38 (m, 5H), 7.13 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8. 4 Hz, 2H), 4.88 (s, 2H), 4.12 (m, 5H), 3.08 (m, 1H), 2.70 (m, 1H), 1.34 (m, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = CH3OH-CH2Cl2 (5:95); Rf = 0.45. Step c: A mixture of diethyl 2- (4-benzyloxyphenyl) -1- (tert-butoxycarbonylamino) ethylphosphonate (1.1 g, 2.4 mmol) and Pd-C (0.23 g, 10%) in CH3OH (10 mL) was stirred under an H2 atmosphere for 16 h and filtered through a plug of celite. The solvent was removed under reduced pressure and the residue was dissolved in CHC13 (15.0 mL). To the solution was added bis (pyridine) iodonium tetrafluoroborate (1.90 g, 5.1 mmol). The reaction mixture was stirred at room temperature for 1 h and the solvent was removed under reduced pressure.

The crude product was purified by column chromatography on silica gel, eluting with acetone-hexanes (1: 1) to give 1- (tert-butoxycarbonylamino) -2- (3, 5-diiodo-4-hydroxyphenyl) ethylf osf onate diethyl as a yellow solid (1.30 g, 88%): X NMR (300 MHz, CD3OD): d 7. 67 (s, 2H), 7.13 (d, J = 8.4 Hz, 1H), 4.00-4.25 (m , 5H), 3.00 (, 1H), 2.64 (m, 1H), 1.38 (m, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = CH3OH-CH2Cl2 (5: 95); Rf = 0.70. Step d: To a mixture of diethyl 1- (tert-butoxycarbonylamino) -2- (3,5-diiodo-4-hydroxyphenyl) ethylphosphonate (0.6 g, 0.96 mmol), 4 ~ (tert-butyldimethylsilyloxy) phenylboronic acid (0.73) g, 2.89 mmol), copper acetate (0.21 g, 1.16 mmol) and 4A molecular sieves (1.20 g) in CH2C12 (8.0 mL) were added a solution of pyridine (0.4 mL, 4.8 mmol) and TEA (0.7 mL, 4.8 mmol). The reaction mixture was stirred at room temperature for 48 h, filtered through a plug of celite and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with acetone-hexanes (1: 3) to give 1- (tert-butoxycarbonylamino) -2- [4- (4 '- (tert-butyldimethylsilyloxy) phenoxy) - 3, 5-diiodophenyl] ethylphosphonate from diethyl as a white solid (0.48 g, 60%): -? NMR (300 MHz, CD3OD): d 7.64 (s, 2 H), 7.18 (d, J = 8.4 Hz, 1 H), 6.64 (d, J = 8.4 Hz, 1 H), 6.53 (d, J = 8.4 Hz, 1 H), 6.38 (d, J = 8.4 Hz, 1 H), 4.00 (m, 5 H), 2.90 (m, 1 H), 2.58 (m, 1 H), 1.20 (m, 6 H) , 0.90 (m, 9 H), 0.03 (s, 3 H), 0.02 (s, 3 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (3: 7); Rf = 0.60. Step e: To a mixture of diethyl 1- (tert-butoxycarbonylamino) -2- [4- (4- (tert-butyldimethylsilanyloxy) phenoxy) -3,5-diiodophenyl] ethylphosphonate (0.45 g, 0.54 mmol) in THF ( 6.0 mL) at 0 ° C TBAF (0.81 mL, 0.81 mmol, 1.0 M in THF) was added. The reaction mixture was stirred at room temperature for 20 min and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with acetone-hexanes (1: 1) to give 1- (tert-butoxycarbonylamino) -2- [3, 5-diiodo-4- (4'-hydroxyphenoxy) diethyl phenyl] ethylphosphonate as a white solid (0.24 g, 62%): aH NMR (300 MHz, CD3OD): d 7.74 (s, 2 H), 6.58 (d, J = 8.4 Hz, 2 H), 6.45 (d, J = 8.4 Hz, 2 H), 4.12 (m, 5 H), 3.08 (m, 1 H), 2.64 (m, 1 H), 1.32 (m, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (1: 1); Rf = 0.40. Step f: A mixture of diethyl 1- (tert-butoxycarbonylamino) -2- [3,5-diiodo-4- (4'-hydroxyphenoxy) phenyl] ethylphosphonate (0.14g, 0.20 mmol) in 70% aqueous TFA (5.0 mL) was stirred at room temperature for 1 h and the solvent was removed under reduced pressure. The residue was dissolved in C2H5OH (4.0 L) and cooled to 0 ° C. To the solution was added 40% aqueous methylamine (0.80 mL) followed by a solution of potassium iodide (0.16 g, 0.96 mmol) and iodine (0.06 g, 0.23 mmol) in H20 (0.6 mL). The reaction mixture was stirred at 0 ° C for 1 h, quenched with water and extracted with ethyl acetate (2x10 mL). The organic layers were dried over MgSO, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with 4% CH3OH in CH2C12 to give l-amino-2- [3,5-diiodo-4- (4'-hydroxy-3'-iodo) diethyl (phenoxy) phenyl] ethylphosphonate as a yellow solid (0.10 g, 69%): XH NMR (300 MHz, CD3OD): d 7.85 (s, 2 H), 7.00 (d, J = 5.2 Hz, 1 H), 6.74 (d, J = 8.4 Hz, 1 H), 6.64 (dd, J = 3.2, 8.4 Hz, 1 H), 4.18 (m, 5 H), 3.08 (, 1 H), 2.78 (m, 1 H), 1.36 (m, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile Phase = CH30H-CH2C12 (5:95): Rf = 0.55. Step g: To a mixture of diethyl 1-amino-2- [3,5-diiodo-4- (4'-hydroxy-3'-iodo-phenoxy) phenyl] ethylphosphonate (0.05 g, 0.07 mmol) in CHC12 ( 2.0 mL) at -78 ° C was added bromotrimethylsilane (0.18 mL, 1.34 mmol). The reaction mixture was stirred at room temperature for 24 h and the solvent was removed under reduced pressure. The crude product was treated with CH3CN-H20 (5.0 mL, 9: 1) and the solvent was removed under reduced pressure to provide l-amino-2- [3,5-diiodo-4- (4'-hydroxy-3-acid. '-iodophenoxy) phenyl] ethylphosphonic acid as a yellow solid (0.044 g, 95%): mp 140 ° C, dec; LC-MS m / z = 688 [C 14 H 13 I 3 N0 5 P + H] +; Anal. Calculated for (C14H? 3I3N05P + 1.0 H20 + 0.3 HBr): C, 23.06; H, 2.11; N, 1.92. Found: C, 22.74; H, 2.16; N, 1.67. Example 3 Compound 3j 2- [3,5-Diiodo-4-acid. { 4 '-hydroxy-3-iodo-enoxy) phenyl] -ethyl-ions-onic Step a: To a solution of tetraethyl methyl methylene glyph (1.6 g, 5.6 mmol) in THF (16.0 mL) at 0 ° C was slowly added sodium hydride. (0.14 g, 5.6 mmol). The reaction mixture was stirred at 0 ° C for 30 min and a solution of 4-benzyloxybenzaldehyde (1.0 g, 4.7 mmol) in THF (4.0 mL) was added. The reaction mixture was stirred at 0 ° C for 30 min, quenched with H20, (30 mL) and extracted with ethyl acetate (30 mL). The organic layer was dried over MgSO 4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1: 1) to give the phosphonate as a white solid (1.5 g). The solid was dissolved in CH3OH (15.0 mL) and Pd-C (0.40 g) was added. The reaction mixture was stirred under an H 2 atmosphere for 16 h, filtered through a plug of celite and concentrated under reduced pressure to provide diethyl 2- (4-hydroxyphenyl) ethylphosphonate as an oil (1.10 g). , 91%):? Ñ NMR (300 MHz, CD3OD): d 7.03 (d, J = 8.4 Hz, 2 H), 6.69 (d, J = 8.4 Hz, 2 H), 4.05 (m, 4 H), 2.77 (m, 2 H), 2.05 (m, 2 H), 1.30 (t, J = 6.9 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (1: 1); Rf = 0.5 Step b: To a solution of diethyl 2- (4-hydroxyphenyl) ethylphosphonate (0.5 g, 1.9 mmol) in CH2C12 (12.0 mL) at room temperature was added bis (pyridine) iodonium tetrafluoroborate (1.6 g, 4.3 mmol). The reaction mixture was stirred at room temperature for 1 h and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with acetone-hexanes (1: 1) to give diethyl 2- (3,5-diiodo-4-hydroxyphenyl) ethylphosphonate as a white solid (0.92 g, 90%): X NMR (300 MHz, CD3OD): d 7.62 (s, 2 H), 4.05 (, 4 H), 2.77 (m, 2 H), 2.05 (m, 2 H), 1.29 (t, J = 6.9 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (1: 1); Rf = 0.57. Step c: 2- [3,5-Diiodo-4- (4'-hydroxyphenoxy) phenyl] ethyl diethylphosphonate was synthesized from diethyl 2- (3,5-diiodo-4-hydroxyphenyl) ethylphosphonate (0.5 g, 0.98 mmol) by following the procedure described in example 2, step d followed by example 2, step e: white solid (0.15 g, 25%) XH NMR (300 MHz, CD30D): d 7.81 (s, 2 H), 6.68 (d, J = 8.4 Hz, 2 H), 6.53 (d, J = 8.4 Hz, 2 H), 4.07 (m, 4 H), 2.84 (, 2 H), 2.16 (m, 2 H), 1.32 (t, J = 6.9 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (1: 1); phenol: Rf = 0.35. Step d: To a solution of diethyl 2- [3,5-diiodo-4- (4'-hydroxyphenoxy) phenyl] ethylphosphonate (0.15 g, 0.25 mmol) in ethanol (5.0 L) at 0 ° C was added slowly a solution of potassium iodide (0.19 g, 0.75 mmol) and iodine (0.07 g, 0.3 mmol) in H20 (0.5 mL). The reaction mixture was stirred at 0 ° C for 1 h, quenched with H20 (10.0 mL) and extracted with ethyl acetate (15.0 mL). The organic layer was dried over MgSO 4, filtered and concentrated under reduced pressure.

The crude product was purified by column chromatography on silica gel, eluting with 2% CH3OH in CH2C12 to provide 2- [3,5-diiodo-4- (4'-hydroxy-3'-iodophenoxy) phenyl] ethylphosphonate diethyl as a white solid (0.10 g, 56%): aH NMR (300 MHz, CD3OD): d 7.83 (s, 2 H), 6.96 (d, J = 5.4 Hz, 1 H), 6.73 (d, J = 8.4 Hz, 2 H), 6.62 (dd, J = 4.2, 8.4 Hz, 1 H), 4.08 (m, 4 H), 2.88 (m, 2 H), 2.18 (m, 2 H), 1.32 (t, J = 6.9 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile Phase = CH30H-CH2C12 (5:95); Rf = 0.50. Step e: To a solution of 2- [3,5-diiodo-4-. { 4'-Hydroxy-3'-iodophenoxy) phenyl] ethylphosphonate diethyl (0.06 g, 0.08 mmol) in CH2C12 (1.5 mL) at 0 ° C was slowly added bromotrimethylsilane (0.11 mL, 0.80 mmol) .- The reaction mix it was stirred at room tempera for 16 h and the solvent was removed under reduced pressure. The residue was treated with CH3CN-H20 (1: 1, 5.0 mL) and the solvent was removed under reduced pressure to give 2- [3,5-diiodo-4- (4'-hydroxy-3'-iodophene) phenyl acid. ] ethyl phosphonic as an off white solid (0.05 g, 96%): mp 188 ° C, dec; LC-MS m / z = 673 [C 14 H 2 I305P + H] +; Anal. Calculated for (C14H? 2I305P + 1.0 CH3OH + 0.3 HBr): C, 24.45; H, 2.02; I, 53.45. Found: C, 24.79; H, 1.87; I, 53.36. Example 4 Compound 4: 2- [3,5-diiodo-4- (4'-hydroxy-3'-iso-propyl enoxi) enyl] ethylphosphonic acid Step a: To a mix of bis (4-methoxy-3-tetrafluoroborate -iso-propylphenyl) iodonium (0.30 g, 0.59 mmol, N. Yokoyama et al., J. Med. Chem. 1995, 38, 695) and copper (0.05 g, 0.78 mmol) in CH2C12 (1.5 mL) at 0 ° C. A solution of diethyl 2- (3,5-diiodo-4-hydroxyphenyl) ethylphosphonate (0.2 g, 0.39 mmol) and TEA (0.10 L, 0.66 mmol) in CH2C12 (0.6 mL) was added slowly. The reaction mix was stirred at room tempera for 96 h, filtered through a plug of celite and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with acetone-hexanes (2: 3) to provide 2- [3,5-diiodo-4- (4-r-methoxy-3'-iso-propylphenoxy) diethyl phenyl] ethylphosphonate as a white off solid (0.25 g, 97%): 2 H NMR (300 MHz, CD3OD): d 7.82 (s, 2 H), 6.78 (d, J = 9.0 Hz, 1 H), 6.68 (d, J = 3.0 Hz, 1 H), 4.07 (m, 4 H), 3.30 (m, 1 H), 2.85 (m, 2 H), 2.18 (m, 2 H), 1.30 (t, J = 6.9 Hz, 6 H), 1.15 (d, J = 7.2 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (3: 7); Rf = 0.64. Step b: To a solution of diethyl 2- [3,5-diiodo-4- [4 r -methoxy-3'-iso-propylphenoxy) phenyl] ethylphosphonate (0.25 g, 0.38 mmol) in CH2C12 (3.0 mL) a 0 ° C was slowly added bromotrimethylsilane (0.60 mL, 3.8 mmol). The reaction mix was stirred at room tempera for 16 h and the solvent was removed under reduced pressure. The residue was dissolved in CH2C12 (3.0 mL) and cooled to -78 ° C. The boron tribromide (1.80 mL, 1.80 mmol, 1.0 M CH2C12) was added slowly and the reaction mix was stirred at room tempera for 16 h. The reaction mix was emptied on ice (50 g) and extracted with ethyl acetate (20 mL). The organic layer was dried over MgSO4, filtered and concentrated to give 2- [3,5-diiodo-4- (4'-hydroxy-3'-iso-propylphenoxy) phenyl] ethylphosphonic acid as an off white solid (0.20 g. 91%): mp 184-186 ° C; LC-MS m / z = 589 [C? 7H? 9I205P + H] +; Anal. Calculated for C? 7H19I205P: C, 34.72; H, 3.26.

Found: C, 34.75; H, 3.12. Example 5 Compound 5 3,5-Diiodo-4-acid. { 4 '-hydroxy-3' -iso-propylphenoxy) benzylphosphonic Step a: A mix of 4-benzyloxybenzyl bromide (Chow et al., J. Org. Chem. 1997, 62, 5116-27) (1.0 g, 4.4 mmol ) and triethyl phosphite (1.0 mL, 5.8 mmol) in DMF (2.8 mL) was heated at 155 ° C for 4 h. The reaction mix was cooled to room tempera, quenched with H20 (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with acetone-hexanes (2: 3) to give the phosphonate as an oil (1.3 g). The phosphonate was dissolved in CH30H (12.0 mL) and Pd-C (10%, 0.33 g) was added. The reaction mix was stirred under an H2 atmosphere for 16 h, filtered through a plug of celite and concentrated under reduced pressure to provide diethyl 4-hydroxybenzylphosphonate as an oil (0.9 g, 84%): XH NMR ( 300 MHz, CD30D): d 7.12 (d, J = 8.4 Hz, 2 H), 6.73 (d, J = 8.4 Hz, 2 H), 4.05 (, 4 H), 3.16 (s, 1 H), 3.09 ( s, 1 H), 1.26 (t, J = 6.9 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (1: 1); Rf = 0.5 Step b: 3,5-Di-odo-4-hydroxybenzylphosphonate diethyl ester (0.85 g, 85%) was synthesized from diethyl 4-hydroxybenzylphosphonate (0.5 g, 2.1 mmol) by following the procedure described in Example 3, step b aH NMR (300 MHz, CD3OD): d 7.67 (d, J = 2.7 Hz, 2 H), 4.08 (m, 4 H), 3.15 (s, 1 H), 3.08 (s, 1 H), 1.28 ( t, J = 6.9 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (2: 3); Rf = 0.6. Step c: 3, 5-Diiodo-4- (4'-methoxy-3'-iso-propylphenoxy) benzylphosphonate diethyl (0.22 g, 88%) was synthesized from diethyl 3,5-diiodo-4-hydroxybenzylphosphonate (0.2 g, 0.4 mmol) by following the procedure described in example 4, step a: XH NMR (300 MHz, CD3OD): d 7.87 (d, J = 2.7 Hz, 2 H), 6.80 (d, J = 8.7 Hz, 1 H), 6.62 (d, J = 2.0 Hz, 1 H) 6.42 (dd, J = 3.3, 8.7 Hz, 1 H), 4.08 (m, 4 H), 3.78 (s, 3 H), 3.25 (m, 3 H), 1.32 (t, J = 6.9 Hz, 6 H), 1.14 (d, J = 6.9 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (2: 3); Rf = 0.6. Step d: 3,5-Diiodo-4- (4'-hydroxy-3'-iso-propylphenoxy) benzylphosphonic acid (0.18 g, 92%) was synthesized from 3, 5-diiodo-4- (3 '- diethyl iso-propyl-4 '-methoxyphenoxy) benzylphosphonate (0.22 g, 0.34 mmol) by following the procedure described in Example 4, step b: pf > 220 ° C; LC-MS m / z = 575 [C 16 H 17 I 204 P + H] +; Anal. Calculated for (C 16 H 7 I 205 P + 0.3 H 20 + 0.5 CH 3 OH): C, 33.28; H, 3.32; I, 42.62. Found: C, 33.49; H, 3.23; I, 42.51. Example 6 Compound 6: 3,5-diiodo-4-acid. { 4'-Hydroxy-3-Iodophenoxy) benzylphosphonic Step a: 3,5-Diiodo-4- (4'-hydroxyphenoxy) encylphosphonate diethyl ester (0.11 g, 17%) was obtained from 3, 5-diiodo-4- diethyl hydroxybenzylphosphonate (0.55 g, 1.1 mmol) by following the procedure described in Example 3, step c: 1 H NMR (300 MHz, CD 3 OD): d 7.87 (d, J = 2.7 Hz, 2 H), 6.70 (d, J = 8.7 Hz, 2 H), 6.54 (d, J = 2.0 Hz, 2 H) 4.10 (, 4 H), 3.30 (s, 1 H), 3.22 (s, 1 H), 1.31 (m, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (1: 1); Rf = 0.4. Step b: 3, 5-diiodo-4- (4'-hydroxy-3'-iodophenoxy) benzylphosphonate diethyl ester (0.08 g, 63%) was obtained from 3,5-diiodo-4- (4'-hydroxyphenoxy) ) diethyl benzylphosphonate (0.1 g, 0.1 mmol) by following the procedure described in Example 3, step d: a H NMR (300 MHz, CD3OD): d 7.87 (d, J = 2.4 Hz, 2 H), 6.92 (d , J = 6.4 Hz, 1 H), 6.74 (d, J = 8.7 Hz, 1 H), 6.62 (d, J = 2.4, 8.7 Hz, 1 H), 4.10 (m, 4 H), 3.30 (s, 1 H), 3.22 (s, 1 H), 1.31 (t, J = 6.9 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile Phase = CH30H-CH2C12 (2:98); Rf = 0.6. Step c: 3,5-Diiodo-4- (4'-hydroxy-3'-dodeophenoxy) benzylphosphonic acid (0.06 g, 90%) was obtained from 4- (4 '-hydroxy-3' -iodophenoxy) - 3,5-diethyloxybenzylphosphonate (0.08 g, 0.1 mmol) by following the procedure described in example 3, step e: mp 168 ° C, dec; LC-MS m / z = 659 [C13H? 0I3O5P + H] +; Anal. Calculated for (C13H10I305P + 1.6 H20 + 0.5 CH3OH): C, 23.07; H, 2.18; I, 54.17. Found: C, 22.71; H, 1.80; I, 53.82. Example 7 Compound 7 [3,5-dimethyl-4-acid. { 4'-Hydroxy-3'-iso-propylbenzyl) phenoxymethylphosphonic Step a: To a stirred solution of NaH (0.855 g, 21.4 mmol) in DMF (40.0 mL) at 0 ° C was added a solution of 3,5-dimethyl -4- (4'-methoxymethoxy-3"-isopropylbenzyl) phenol (5.60 g, 17.8 mmol), (G. Chiellini et al., Bioorg, Med.Chem. Lett. 2000, 10, 2607) in DMF ( 7.0 mL). The reaction mixture was stirred at room temperature for 1 h and cooled to 0 ° C. A solution of diethyl tosyloxymethylphosphonate (6.89 g, 21.4 mmol) in DMF (7.0 mL) was added. The reaction mixture was stirred at room temperature for 16 h, quenched with CH3OH followed by dilution with water (100 mL) and extracted with ether (100 mL x 2). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with acetone-hexanes (1: 3) to provide [3,5-dimethyl-4-. { 4-diethyl r -methoxymethoxy-3'-iso-propylbenzyl) phenoxy] methylphosphonate as a colorless oil (5.32 g, 64%): XR NMR (300 MHz, DMSO-d6): d 6.94 (d, J = 3.0 Hz, 1 H), 6.87 (d, J = 9.0 Hz, 1 H), 6.73 (s, 2 H), 6. 58 (m, 1 H), 5.14 (s, 2 H), 4.36 (d, J = 9.0 Hz, 2 H), 4.10 (m, 4 H), 3.85 (s, 2 H), 3.36 (s, 3 H), 3.21 (, 1 H), 2.17 (d, J = 6.0 Hz, 6 H), 1.25 (m, 6 H), 1.12-1.10 (d, J = 6.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-acetone (1: 1); Rf = 0.62. Step b: To a solution of diethyl 3,5-dimethyl-4- (4'-methoxymethoxy-3"-isopropylbenzyl) phenoxymethylphosphonate (5.32 g, 11.45 mmol) in dichloromethane (60.0 mL) at 0 °. C was added bromotrimethylsilane (22.67 mL, 171.7 mmol). The reaction mixture was stirred at room temperature for 16 h and the solvent was removed under reduced pressure. The residue was treated with acetonitrile-water (1: 1, 50 mL) and the solvent was removed under reduced pressure. The residue was treated with toluene and sonicated for 10 min. The mixture was filtered and washed with hexanes to provide [3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy] methylphosphonic acid as a pink solid (4.00 g, 95%): mp 55-58 ° C; LCMS m / z = 365 [C19H25? 5P + H] +; Anal. Calculated for (Ci9H2505P + 0.5 H20 + 0.2 CH3OH): C, 60.72; H, 7.11. Found: C, 60.72, H, 7.18. Using the appropriate starting material, compounds 7-1 through 7-21 were prepared in an analogous manner as described by the synthesis of compound 7. Compound 7-1: Acid [3,5-dimethyl-4- (4 ' -hydroxy-3'-phenylbenzyl) phenoxymethylphosphonic The intermediate 3, 5-dimethyl-4 ~ (4 '-methoxymethoxy-3'-phenylbenzyl) phenol was prepared from 2-phenylphenol according to the procedure described in G. Chiellini et al. to the. Biorg. Med. Chem. Lett. 2000, 10, 2607 and was transformed into the title compound by the procedure used for the synthesis of compound 7.? E NMR (300 MHz, DMSO-d6): d 9.29 (s, 1 H), 6.60-7.60 (m , 8 H), 4.02 (d, J = 15 Hz, 2 H), 2.18 (s, 2 H); LCMS m / z = 399 [C29H4? O? P + H] +; Anal. Calculated for (C29H4? 011P + 1.7 H20 + 0.4 CH30H): C, 60.89; H, 6.39. Found: C, 60.53; H, 6.19. Compound 7-2: Acid [3,5-dimethoxy-4-. { 4 '-hydroxy-3' -iso-propylbenzyl) phenoxymethylphosphonic The intermediate 3,5-dimethoxy-4- (3'-iso-propyl-4'-methoxy ethoxybenzyl) phenol was prepared from 2,6-dimethoxy-4 -hydroxybenzaldehyde according to the procedure described in G. Chiellini et al. Biorg. Med. Chem. Lett. 2000, 10, 2607 and was transformed into the title compound by the procedure used for the synthesis of compound 7. X H NMR (300 MHz, DMSO-d 6): d 8.86 (s, 1 H), 6.96 (d, J = 1.8 Hz, 1 H), 6.64 (dd, J = 1.8 Hz, J = 8.4 Hz, 1 H), 6.54 (d, J = 8.4 Hz, 1 H), 6.27 (s, 2 H), 4.07 (d, J = 10.2 Hz, 2 H), 3.74 (s, 6 H), 3.64 (s, 2 H), 3.08 (m, 1 H), 1.08 (d, J = 6.9 Hz, 6 H); LC-MS m / z = 397 [C? 9H2507P + H] +; Anal Calculated for (C19H2507P + 0.4 CH3C02C2H5 + 0.9 H20): C, 55.25; H, 6.75. Found: C, 55.22; H, 7.13. Compound 7-3: [3,5-Dimethyl-4- (3 '-sec-butyl-4'-hydroxybenzyl) phenoxy] methylphosphonic acid The intermediate 3,5-dimethyl-4- (3'-sec-butyl-4) '-methoxymethoxybenzyl) phenol was prepared from commercially available 2-sec-butylphenol according to the procedure described in G. Chiellini et al. Biorg Med. Chem. Lett. 2000, 10, 2607 and was transformed into the title compound by the procedure used for the synthesis of compound 7. X H NMR (200 MHz, DMSO-d 6): d 8.92 (s, 1 H), 6.77 (s, 1 H) , 6.68 (s, 2 H), 6.61 (d, J = 8.6 Hz, 1 H), 6.47 (d, J = 8.6 Hz, 1 H), 4.02 (d, J = 10.2 Hz, 2 H), 3.78 ( s, 2 H), 2.90 (m, 1 H), 1.45 (q, J = 6.6 Hz, 2 H), 1.05 (d, J = 7.0 Hz, 3 H), 0.74 (t, J = 7.0 Hz, 3 H); LC-MS m / z = 379 [C 20 H 27 O 5 P + H] +; Anal Calculated for (C20H27O5P + 0.7 H20): C, 61.43; H, 7.32. Found: C, 61.22; H, 7.55. Compound 7-4: [3,5-Dimethyl-4- (3'-iso-propyl-4'-methoxybenzyl) phenoxymethylphosphonic acid The intermediate 3,5-dimethyl-4- (3'-iso-pro? Il-4 '-methoxybenzyl) phenol was prepared from 2-iso-propylanisole according to the procedure described in G. Chiellini et al. Biorg. Med. Chem. Lett. 2000, 10, 2607 and was transformed into the title compound by the procedure used for the synthesis of compound 7. X H NMR (300 MHz, DMSO-d 6): d 6.99 (d, J = 2.1 Hz, 1 H), 6.88 (d, J = 8.4 Hz, 1 H), 6.76 (s, 2 H), 6.66 (, 1 H), 4.09 (d, J = 10.2 Hz, 2 H), 3.91 (s, 2 H), 3.78 ( s, 3 H), 3.23 (m, 1 H), 2.29 (s, 6 H), 1.16 (d, J = 7.2 Hz, 6 H); LC-MS m / z = 378 [C 20 H 27 O 5 P + H] ~; Anal. Calculated for (C20H27O5P + 0.3 H20): C, 62.59; H, 7.25. Found: C, 62.37; H, 7.40. Compound 7-5: Acid [3,5-dichloro-4-. { 4 '-hydroxy-3' -iso-propylbenzyl) phenoxymethylphosphonic The intermediate 3,5-dichloro-4- (3'-sec-butyl-4'-methoxymethoxybenzyl) phenol was prepared from 2,6-dichloro-4- benzyloxybenzaldehyde (Organic Letters 2002, 4, 2833) according to the procedure described in G. Chiellini et al. Biorg. Med. Chem. Lett. 2000, 10, 2607 and was transformed into the title compound by the procedure used for the synthesis of compound 7. mp: 118-120 ° C; 1 H NMR (300 MHz, CD 3 OD): d 7.01 (s, 2 H), 6.87 (d, J = 1.8 Hz, 1 H), 6.60 (dd, J = 3.0, 8.4 Hz, 1 H), 6.47 (d, J = 8.4 Hz, 1 H), 4.12 (d, J = 9.9 Hz, 2 H), 4.02 (s, 2 H), 3.20-3.10 (m, 1 H), 1.03 (d, J = 6.9 Hz, 6 H); LC-MS m / z = 405 [C? 7H? 9Cl205P] +; Analysis calculated for: (C? 7H19Cl205P): C, 50.39, H, 4.73 Cl: 17.60. Found: C, 50.33, H, 5.03; Cl, 16.09. Compound 7-6: Difluoro- [3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxymethylphosphonic acid The intermediate 3,5-dimethyl-4- (3'-iso-propyl-4) '-methoxymethoxybenzyl) phenol was prepared from 2-iso-propylphenol according to the procedure described in G. Chiellini et al. Biorg. Med. Chem. Lett. 2000, 10, 2607 and was transformed into the title compound by the procedure used for the synthesis of compound 7 using diethyl bromodifluoromethylphosphonate. X H NMR (300 MHz, DMSO-d 6): d 9.02 (s, 1 H), 6.88 (m, 3 H), 6.65 (ra, 1 H), 4.46 (, 1 H), 3.84 (s, 3 H) , 3.12 (s, 2 H), 3.12 (m, 1 H), 2.19 (s, 6 H), 1.12 (d, J = 6.0 Hz, 6 H); CLAR conditions: Column = 3 Chromolith SpeedRODs RP-18e, 100 x 4.6 mm; Mobile Phase = Solvent A (Acetonitrile) = Acetonitrile grade CLAR; Solvent B (buffer) = 20 mM ammonium phosphate buffer solution (pH 6.1, 0.018 M NH4H2PO4 / 0.002 M (NH4) 2HP04) with 5% acetonitrile. Flow ratio = 4 mL / min; UV @ 255 nm. Retention time in minutes (tr = 5.68, 95% purity). Compound 7-7: [3,5-Dimethyl-4- [4'-hydroxy-3'-methylbenzyl] phenoxy] methylphosphonic acid The intermediate 3,5-dimethyl-4- [3'-methyl-4'-methoxymethoxybenzyl] phenol was prepared from 4-bromo-2-methyl-phenol according to the procedure described in G. Chiellini et al. Biorg. Med. Chem. Lett. 2000, 10, 2607 and was transformed into the title compound by the procedure used for the synthesis of compound 7 pf > 230 ° C; X H NMR (300 MHz, DMS0-d 6): d 8.99 (s, 1H), 6.68-6.525 (m, 5H), 6.71 (s, 2H), 4.03 (d, 2H, J = 7.5 Hz), 3.77 (s) , 2H), 2.15 (s, 6H), 2.02 (s, 3H); LCMS m / z = 335 [C17H2? 05 P-H]; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = isopropyl alcohol / water / ammonium hydroxide [7: 2: 1]; Rf = 0.23; Anal. Calculated for (C17H2105P + 0.6 H20): C, 58.82; H, 6.45; Found: C, 58.73, H, 6.73. Compound 7-8: [3,5-Dimethyl-4- [3'-ethyl-4'-hydroxybenzyl] phenoxy] methylphosphonic acid The intermediate 3, 5-dimethyl-4- [3'-ethyl-4 '-methoxymethoxybenzyl] phenol was prepared from 4-bromo-2-ethyl-phenol according to the procedure described in G. Chiellini et al. Biorg. Med. Chem. Lett. 2000, 10, 2607 and was transformed into the title compound by the procedure used for the synthesis of compound 7. XH NMR (300 MHz, DMSO-d6): d 8.96 (s, 1H), 6.72-6.49 (m, 5H ), 4. 03 (d, 2H, J = 10.2 Hz), 3.78 (s, 2H), 2.48 (q, 2H, J = 8.1 Hz), 2.16 (s, 6H), 1.06 (t, 3H, J = 7.5 Hz); LC-MS m / z = 349 [Ci8H2305P-H]; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = isopropyl alcohol / ammonium hydroxide / water [7: 2: 1]; Rf = 0.20; Anal. Calculated for (C? 7H2? 05P + 1.3 H20 + 0.3 CH2C12): C, 55.30; H, 6.59; Found: C, 55.36, H, 6.66. Compound 7-9: [3,5-Dimethyl-4- [3 '- (1-ethylpropyl) -4'-hydroxybenzyl] phenoxy] methylphosphonic acid The intermediate 3, 5-dimethyl-4- [3' - (1- ethylpropyl) -4'-methoxymethoxybenzyl] phenol was prepared from 2- (1-ethylpropyl) phenol (J. Chem. Soc. Perkins Trans. 2, 1985, 165) in accordance with the procedure described in G. Chiellini et al. . Biorg. Med. Chem. Lett. 2000, 10, 2607 and was transformed into the title compound by the procedure used for the synthesis of compound 7 mp: 60-64 ° C; X H NMR (300 MHz, DMSO-d 6): d 8.84 (s, 1 H), 6.72 (s, 1 H), 6.67 (s, 2 H), 6.60 (m, 1 H), 6.46 (m, 1 H ), 4. 04 (d, J = 9.0 Hz, 2 H), 3.78 (s, 2 H), 2.74 (m, 1 H), 2.15 (s, 6 H), 1.49 (m, 4 H), 0.68 (m, 6) H); LC-MS m / z = 393 [C2? H2905P + H] +; Anal. Calculated for (C2? H2905P + 0.5 H20 + 0.2 CH3C02CH2CH3): C, 62.48; H, 7.60. Found: C, 62.22; H, 7.83. Compound 7-10: [3,5-Dimethyl-4- (4'-hydroxy-3'-iso-propyl-5'-methylbenzyl) phenoxymethylphosphonic acid The intermediate 3,5-dimethyl-4- (3'-iso) propyl-5'-methyl-4'-methoxymethoxybenzyl) phenol was prepared from 2-iso-propyl-6-methylphenol (J. Med. Chem. 1980, 12, 1350) in accordance with the procedure described in G. Chiellini et al. Biorg. Med. Chem. Lett. 2000, 10, 2607 and was transformed into the title compound by the procedure used for the synthesis of compound 7 mp: 65-68 ° C; X H NMR (300 MHz, CD 3 OD): d 6.75 (s, 2 H), 6.69 (d, J = 2.1 Hz, 1 H), 6.49 (d, J = 2.1 Hz, 1 H), 4.22 (d, J = 10.2 Hz, 2 H), 3.89 (s, 2 H), 3.27 (m, 1 H), 2.23 (s, 6 H), 2.14 (s, 3 H), 1.15 (d, J = 7.2 Hz, 6 H ); LC-MS m / z = 377 [C 20 H 27 O 5 P-H] +; Anal. Calculated for (C20H27O5P + 1.0 H20): C, 60.60; H, 6.37. Found: C, 60.70; H, 7.75. Compound 7-11: [3,5-Dimethyl-4- [5'-fluoro-4 '-hydroxy-3'-iso-propylbenzyl] phenoxy] methylphosphonic acid Step a: To a mixture of 4-bromo-2-fluoroanisole (2.0 g, 9.70 mmol) and 2-propanol (1.2 g, 19.4 mmol) at room temperature was added 80% H2SO4 (10.0 mL). The reaction mixture was heated at 80 ° C for 12 h, cooled to room temperature, quenched with ice (50 g) and extracted with ether (20 mL x 2). The combined organic extracts were dried over MgSO, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with 5% ethyl acetate in hexanes to provide 4-bromo-6-fluoro-2-iso-propylanol (0.92 g, 38%):? E NMR (300 MHz, CD3OD): d 7.36 (d, J = 10.5 Hz, 1 H), 7.22 (d, J = 10.5 Hz, 1 H), 3.91 (s, 3 H), 3.24 (m, 1 H), 1.26 (d, J = 6.6 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (5:95); Rf = 0.50. Step b: To a solution of 4-bromo-6-fluoro-2-iso-propylanol (0.92 g, 3.70 mmol) in CH2C12 (10.0 mL) at -78 ° C was added BBr3 (5.5 mL, 5.5 mmol, 1.0 M in CH2C12). After 5 min, the reaction mixture was stirred at room temperature for 16 h, emptied on ice (50 g) and extracted with ethyl acetate (20.0 mL). The organic layer was separated, dried over MgSO4 and filtered. The solvent was removed under reduced pressure to provide 4-bromo-6-fluoro-2-iso-propylphenol (0.90 g, 100%) as a dark oil, which was used during the next step without further purification: ""? NMR (300 MHz, CD3OD): d 7.26 (d, J = 10.5 Hz, 1 H), 6.92 (d, J = 10.5 Hz, 1 H), 3.30 (, 1H), 1.23 (d, J = 6.6 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 9); Rf = 0.40. The intermediate 3,5-dimethyl-4- (5'-fluoro-3'-iso-propyl-4'-methoxymethoxybenzyl) phenol was prepared from 4-bromo-6-fluoro-2-iso-propylphenol in accordance with the procedure described in G. Chiellini et al. Biorg. Med. Chem. Lett. 2000, 10, 2607 and was transformed into the title compound by the procedure used for the synthesis of compound 7. MP: 166-168 ° C; X H NMR (300 MHz, CD 3 OD): d 6.89 (d, J = 9.0 Hz, 1 H), 6.80 (s, 2 H), 6.03 (d, J = 9.0 Hz, 1 H), 4.25 (d, J = 8.4 Hz, 2 H), 3.91 (s, 2 H), 3.34 (, 1 H), 2.18 (s, 6 H), 1.30 (d, J = 6.9 Hz, 6 H); LC-MS m / z = 383 [C19H24F05P + H] +; Anal Calculated for (C? 9H24F05P + 0.6 H20): C, 58.04; H, 6.46. Found: C, 57.88; H, 6.46. Compound 7-12: [4- (4'-acetylamino-3 '-iso-propylbenzyl) -3, 5-dimethylphenoxy] methylphosphonic acid Step a: To a cold solution of aniline 2-isopropyl (714 mg, 5.28 mmol) in dichloromethane (20 mL) at -50 ° C in a dry ice / acetone bath was added a solution of bromine (269 μL, 5.28 mmol) in dichloromethane (5 mL) for 20 min. After the addition was complete, the reaction mixture was stirred for an additional hour. Purification by column chromatography (silica gel, hexane / ethyl acetate) gave 4-bromo-2-iso-propyl-phenylamine as a brown oil (1.53 g, 57%); 1E NMR (300 MHz, DMSO-d6): d 7.01 (m, 2H), 6.55 (d, 1H, J = 13 Hz), 5.05 (bs, 2H), 2.92 (m, 1H), 1.11 (d, 6H , J = 7 Hz); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = Hexane / ethyl acetate [10: 1]; Rf = 0.11 Step b: A solution of 4-bromo-2-iso-propyl-phenylamine (780 mg, 3.64 mmol) in acetic anhydride (4 mL) was stirred at room temperature overnight. The reaction was poured into water and the resulting white precipitate was filtered off completely and dried under vacuum to give N- (4-bromo-2-iso-propyl-phenyl) -acetamide as a light pink solid (0.770 g, 83%); ^? NMR (300 MHz, DMSO-de): d 9.39 (s, 1H), 7.43 (d, 1H, J = 2.4 Hz), 3.16 (m, 1H), 2.04 (s, 3H), 1.13 (d, 6H, J = 7 Hz); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = dichloromethane; Rf = 0.21 The intermediate 3, 5-dimethyl-4- (5'-fluoro-3'-iso-propyl-4'-methoxymethoxybenzyl) phenol was prepared from N- (4-bromo-2-iso-propyl) phenyl) -acetamide according to the procedure described in G. Chiellini et al. Biorg Med. Chem. Lett. 2000, 10, 2607 and was transformed into the title compound by the procedure used for the synthesis of compound 7: pf > 230 ° C; LC-MS m / z = 404 [C21H28N05P-H]; 1 H NMR (300 MHz, DMS0-d 6): d 9.23 (s, 1 H), 7.03 (m, 2 H), 6.71 (s, 2 H), 6.60 (d, 1 H, J = 9.3 Hz), 4.04 (d, 2H, J = 9.3 Hz), 3.91 (s, 2H), 2.17 (s, 6H), 2.00 (s, 3H), 1.06 (d, 6H, J = 6.9 Hz); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = isopropyl alcohol / water / ammonium hydroxide [7: 2: 1]; Rf = 0.26; Anal. Calculated for (C21H28N05P + 0.4 H20): C, 61.13; H, 7.03; N, 3.39 Found: C, 61.36, H, 7.22, N, 3.03. Compound 7-13: [4- (3 '-isopropyl-4'-methanesulfonylaminobenzyl) -3,5-dimethylphenoxy] methylphosphonic acid Step a: The intermediate N- [4- (4'-hydroxy-2', 6 '-dimethyl-benzyl) -2-iso-propyl-phenyl] -acetamide from the synthesis of compound 7-12 (320 mg, 0.68 mmol) was combined with HCl (10 mL) and water (2 mL) in a flask with a round bottom and heated to reflux overnight. The solvent was removed under reduced pressure and the resulting solid was dissolved in a mixture of ethyl acetate (50 mL) and water (2 mL). The organic layer was stirred and dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4- (4'-amino-3'-iso-propylbenzyl) -3,5-dimethylphenol as a white powder (0.179 g. , 98%): a H NMR (300 MHz, DMSO-d 6): d 8.934 (s, 1H), 6.73 (d, 1H, J = 1.8 Hz), 6.43 (m, 5H), 4.58 (bs, 2H), 3.69 (s, 2H), 2.92 (m, 1H), 2.10 (s, 6H), 1.07 (d, 6H, J = 6.6 Hz); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate; Rf = 0.69. Step b: To a solution of 4- (4'-amino-3'-iso-propylbenzyl) -3,5-dimethylphenol (80 mg, 0.30 mmol) in DMF (3 mL) was added sodium hydride (8.5 mg, 0.36 mmol) and the reaction was stirred for 10 min. at room temperature. The trifluoromethanesulfonic acid diethoxyphosphorylmethyl ester was added and the reaction was stirred overnight. A saturated aqueous solution of ammonium chloride (3 mL) was added and the resulting mixture was added to ethyl acetate (50 mL) and water (10 mL). The aqueous layer was stirred and the ethyl acetate layer was washed 5 x with 10 mL water and 1 x with 10 mL brine. The ethyl acetate was dried over sodium sulfate, filtered and concentrated. The residue was purified by CCD preparative plate using a 2000 μm silica gel plate eluting with ethyl acetate / dichloromethane [3: 1] to give [4- (4'-amino-3 '-isopropylbenzyl) - 3, 5-dimethylphenoxy] methylphosphonate diethyl (0.061 g, 49%): "" "H NMR (300 MHz, DMSO-d6): d 6.74 (d, 1H, J = 1.8 Hz), 6.72 (s, 2H) , 6.45 (d, 1H, J = 14.4 Hz), 6.36 (dd, 1H, J = 2 Hz, J = 7.5 Hz), 4.60 (s, 2H), 4.35 (d, 2H, J = 9.6 Hz), 4.11 (m, 4H), 3.75 (s, 2H), 2.90 (, 1H), 2.17 (s, 6H), 1.25 (t, 6H, J = 7 Hz), 1.07 (d, 6H, J = 7.2 Hz); CCD conditions: Silica gel uniplaca, 250 microns, Mobile phase = ethyl acetate / dichloromethane [1: 1], Rf = 0.54, Step c: To a solution consisting of [4- (4'-amino-3 ' -iso-propylbenzyl) -3,5-dimethylphenoxy] methylphosphonate (43.6 mg, 0.104 mmol), in dichloromethane (2 mL) was added sulfonyl methane chloride (1 eq, 8 μL), and pyridine (1 eq, 8.4 μL). The reaction was stirred overnight at room temperature under an atmospheric to N2 (balloon). The solvent was removed under reduced pressure and the resulting residue was dissolved in ethyl acetate (25 mL) and washed 2 x with water (10 mL), Ix with IN HCl (10 mL), and 1 x with brine (10 mL). ). The ethyl acetate was dried over sodium sulfate, filtered and concentrated under reduced pressure to yield [pure diethyl 4- (3'-iso-propyl-4'-methansulfonylaminobenzyl) -3,5-dimethylphenoxy] methylphosphonate (0.047 g, 97%): E NMR (300 MHz, DMSO-d6): d 8.94 (s, 1H), 7.08 (m, 2H), 6.76 (s, 2H), 6.68 (dd, 1H, J = 2.1 Hz, J = 8.7 Hz), 4.36 (d, 2H, J = 10.2 Hz), 4.11 (, 4H), 3.39 (, 1H), 2.94 (s, 3H), 2.23 (s, 6H), 1.25 (m, 6H), 1.08 (d, 6H, J = 7 Hz); Terms CCD: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate / dichloromethane [1: 1]; Rf = 0.36. Step d: To a solution consisting of diethyl 4- (3 '-iso-propyl-4'-methansulfonylaminobenzyl) -3,5-dimethylphenoxy] ethylphosphonate (43.8 mg, 0.09 mmol) and dichloromethane (2 mL) was added HMDS (191 μl, 0.9 mmol) and TMSBr (191 μl, 0.9 mmol). The reaction was stirred overnight at room temperature. The solvent was removed under reduced pressure and the resulting residue was co-evaporated 3 x with 2 mL dichloromethane. The resulting residue was taken in IN NaOH (2 mL) and washed 2 x with dichloromethane. The residual dichloromethane was removed under reduced pressure and the resulting aqueous layer was acidified with concentrated HCl. The resulting precipitate was filtered off completely and dried under vacuum to give the title compound as a light brown powder (0.022 g, 55%): 1 H NMR (300 MHz, DMSO-d 6): d 8.93 (s, 1 H), 7.10 (m, 2 H), 6.67 (m, 3 H), 4.02 (d, 2 H, J = 10 Hz), 3.91 (s, 2H), 2.93 (s, 3H), 2.16 (s, 6H), 1.08 (d, 6H, J = 7 Hz); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = isopropyl alcohol / water / ammonium hydroxide [7: 2: 1]; Rf = 0.36; Anal. Calculated for (C2oH2806PS + 0.9 H20): C, 52.48; H, 3.56; N, 3.06. Found: C, 52.49, H, 6.56, N, 3.23. Compound 7-14: [3,5-dichloro-4- (5'-bromo-4 '-hydroxy-3'-iso-propylbenzyl) phenoxy] methylphosphonic acid Step a: To a mixture of [3,5-dichloro- 4- (3'-Isopropyl-4'-methoxymethoxybenzyl) phenoxymethylphosphonate diethyl ester (0.25 g, 0.49 mmol, intermediate for the synthesis of compound 7-5) in methanol (3.0 mL) at 0 ° C was added 2N HCl (1.0 mL). The reaction mixture was stirred at room temperature for 24 h, quenched with water (10.0 mL) and extracted with ethyl acetate (10.0 mL). The organic layer was dried over MgSO, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with 30% acetone in hexanes to provide [3,5-dichloro-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxymethylphosphonate diethyl ester (0.17. g, 74%) as a colorless oil: 1 H NMR (300 MHz, CD 3 OD): d 7.18 (s, 2 H), 7.00 (d, J = 2.4 Hz, 1 H), 6.75 (dd, J = 8.1, 2.4 Hz, 1 H), 6.62 (d, J = 8.1 Hz, 1 H), 4.48 (d, J = 10.5 Hz, 2 H), 4.25 (m, 4 H), 4.17 (s, 2 H), 3.25 ( m, 1 H), 1.38 (t, J = 7.2 Hz, 6 H), 1.18 (d, J = 6.6 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (2: 3); Rf = 0.70. Step b: A mixture of diethyl [3, 5-dichloro-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxymethylphosphonate (0.16 g, 0.35 mmol) in CH2C12 (3.0 mL) at 0 ° C was added. added tetrabutylammonium tribromide (0.18 g, 0.38 mmol). The reaction mixture was stirred at room temperature for 4 h and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with 30% acetone in hexanes to provide [3,5-dichloro-4- (5'-bromo-4 '-hydroxy-3'-iso-propylbenzyl) diethyl phenoxymethylphosphonate (0.12 g, 64%) as a yellow oil: 1 H NMR (300 MHz, CD3OD): d 7.18 (s, 2 H), 7.02 (s, 2 H), 4.50 (d, J = 10.5 Hz, 2 H), 4.25 (m, 4 H), 4.18 (s, 2 H) 3.25 (m, 1 H), 1.38 (t, J = 7.2 Hz, 6 H), 1.18 (d, J = 6.6 Hz, 6 H); Terms CCD: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (2: 3); Rf = 0.80. The title compound was prepared by the procedure described for the synthesis of compound 7, step b: mp: 188-190 ° C; X H NMR (300 MHz, CD 3 OD): d 7.18 (s, 2 H), 7.03 (s, 2 H), 4.32 (d, J = 10.2 Hz, 1 H), 4.18 (s, 2 H), 3.20-3.40 (m, 1 H), 1.19 (d, J = 7.2 Hz, 6 H); LC-MS m / z = 483 [C 20 H 27 O 5 P-H] +; Anal. Calculated for (C17H? 8BrCl205P + 0.4 H20): C, 41.56; H, 3.86. Found: C, 41.44; H, 4.15. Compound 7-15: [3,5-Dimethyl-4- [3'-ethoxy-4'-hydroxybenzyl] phenoxy] methylphosphonic acid The intermediate 3, 5-dimethyl-4- [3'-ethoxy-4'-methoxymethoxybenzyl] phenol was prepared from 4-bromo-2-ethoxy-phenol according to the procedure described in G. Chiellini et al. Biorg Med. Chem. Lett. 2000, 10, 2607 and was transformed into the title compound by the procedure used for the synthesis of compound 7: aH NMR (300 MHz, DMSO-d6): d 8.62 (s, 1 H), 6.71 (s, 2 H ), 6.65 (d, J = 8.1 Hz, 1 H), 6.59 (d, J = 1.5 Hz, 1 H), 6.27 (dd, J = 1.5, 8.1 Hz, 1 H), 4.04 (d, J = 10.2 Hz, 2 H), 3.93 (q, J = 6.9 Hz, 2 H), 3.82 (s, 2 H), 2.16 (s, 6 H), 1.29 (t, J = 6.9 Hz, 3 H); pf: it contracts at 145 ° C; LC-MS m / z = 367 [C18H2306P + H] +; Anal Calculated for (C18H2306P + 0.2MeOH + 0.4H20): C, 57.53; H, 6.53. Found: C, 57.39; H, 6.23. Compound 7-16: [3,5-Dimethyl-4- (4'-hydroxy-3'-iso-propyl-2'-methylbenzyl) phenoxy] methylphosphonic acid Step a: To a solution of 2-methoxy-6-methylbenzoate of ethyl (1.0 g, 5.1 mmol) in THF (15.0 mL) at -78 ° C was added methylmagnesium bromide (3.78 mL, 11.32 mmol). After 5 min, the reaction mixture was allowed to warm to room temperature and stirred for 4 h. The mixture was cooled to 0 ° C, quenched with 1.0 M HCl and extracted with ether. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with 10% ethyl acetate in hexanes to give 2- (2-methoxy-6-methylphenyl) -2-propanol (0.60 g, 65%) as oil colorless: aH NMR (300 MHz, DMSO-d6): d 6.80 (dd, J = 12.0 Hz, 11. 7 Hz, 1 H), 6.60 (d, J = 12.0 Hz, 1 H), 6.45 (d, J = 11.7 Hz, 1 H), 4.47 (s, 1 H), 3.52 (s, 3 H), 2.33 (s, 3 H), 1.33 (s, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 5); Rf = 0.54. Step b: A solution of 2- (2-methoxy-6-methylphenyl) -2-propanol (0.50 g, 2.77 mmol) in ethyl acetate-acetic acid (9: 1, 10.0 mL) at room temperature was stirred under a H2 atmosphere for 16 h. The mixture was filtered through a plug of celite and the solvent was removed under reduced pressure. The residue was dissolved in hexanes and washed with water. The organic layer was dried MgSO 4, filtered and concentrated under reduced pressure to provide 2-iso-propyl-3-methylanisole (0.45 g, 100%) as a colorless oil, which was used during the next step without further purification: XE NMR (300 MHz, DMSO-d6): d 7.01 (dd, J = 12.0 Hz, 11.7 Hz, 1 H), 6.78 (d, J = 12.0 Hz, 1 H), 6.70 (d, J = 11.7 Hz, 1 H ), 3.74 (s, 3 H), 3.28 (m, 1 H), 2.26 (s, 3 H), 1.24 (d, J = 10.8 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 9); Rf = 0.80. Step c: To a solution of 2-iso-propyl-3-methylanisole (0.44 g, 2.7 mmol) in CH2C12 at room temperature was added a solution of tetrabutylammonium tribromide (1.42 g, 2.94 mmol) in CH2C12. The reaction mixture was stirred for 2 h and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with 5% ethyl acetate in hexanes to provide 4-bromo-2-iso-propyl-3-methylanisole as a yellowish oil (O.dOg, 92%): X H NMR (300 MHz, DMSO-d 6): d 7.37 (d, J = 13.2 Hz, 1 H), 6.78 (d, J = 13.2 Hz, 1 H), 3.74 (s, 3 H), 3.38 (m, 1 H), 2.38 (s, 3 H), 1.25 (d, J = 10.8 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (5:95); Rf = 0.80. The title compound was prepared from 4-bromo-2-iso-propyl-3-methylanisole according to the procedure described for the synthesis of compound 7-11: mp: 180-183 ° C; 1 H NMR (300 MHz, CD 3 OD): d 6.76 (s, 2 H), 6.34 (d, J = 8.4 Hz, 1 H), 6.03 (d, J = 8.4 Hz, 1 H), 4.22 (d, J = 10.5 Hz, 1 H), 3.81 (s, 2 H), 3.50 (m, 1 H), 2.37 (s, 3 H), 2.16 (s, 3 H), 1.39 (d, J = 6.9 Hz, 6 H ); LC-MS m / z = 379 [C 20 H 27 O 5 P + H] +; Anal. Calculated for (C20H27O5P + 0.5 H20): C, 62.01; H, 7.28. Found: C, 61.98; H, 7.26. Compound 7-17: [2, 5-Dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxymethylphosphonic acid Step a: To a stirred suspension of 2,5-dimethyl phenol (5.0 g, 40.9 mmol) in H0 (150 mL), at room temperature, tetrabutylammonium tribromide (19.9 g, 41.39 mmol) in CHC13 (150 mL) was added. The reaction mixture was stirred for 2 h at room temperature, the organic layer was separated and dried over Na 2 SO, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane-ethyl acetate (1: 5) to give 2,5-dimethyl-4-bromophenol as a brown solid (6.2 g, 76%); 1 H NMR (300 MHz, DMSO-d 6): d 9.47 (s, 1 H), 7.24 (s, 1 H), 6.74 (s, 1 H), 2.21 (s, 3 H), 2.07 (s, 3 H) ); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (9: 1); Rf = 0.52. Step b: The intermediate 2, 5-dimethyl-4- (3 '-iso-propyl-4' -methoxymethoxybenzyl) phenol was prepared from 2,5-dimethyl-4-bromo-t-butyldimethylsilyloxyphenol, and 3-iso -propyl-4-methoxymethoxybenzaldehyde according to the procedure described in (G. Chiellini et al., Biorg, Med. Chem. Lett., 2000, 10, 2607) and was transformed into the title compound by the procedure used for the synthesis of the compound 7-13, step b followed by example 7, step b, (0.14 g, 90%); 2 H NMR (300 MHz, CD3OD): d 6.88 (d, J = 8.7 Hz, 2 H), 6.79 (s, 1 H), 6.64-6.72 (m, 2 H), 4.20 (d, J = 10.2 Hz, 2 H), 3.80 (s, 2 H), 3.10-3.15 (m, 1 H), 2.22 (s, 3 H), 2.20 (s, 3 H), 1.17 (d, J = 6.9 Hz, 6 H); LC-MS m / z = 365 [C 20 H 25 O 6 P + H] +; CLAR conditions: ODSAQ column AQ-303-5; Mobile phase = CH3OH: 0.05% TFA (7: 3) flow ratio = 1.0 mL / min; detection = UV @ 254 nm retention time in min: 10.96; Anal Calculated for (C20H25O6P + 0.3 H20): C, 61.84; H, 6.92. Found: C, 61.60; H, 6.72. Compound 7-18: [2,5-Dimethyl-6-iodo-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy] methylphosphonic acid Step a: To a stirred solution of 2,5-dimethyl-4 - (4'-methoxymethoxy-3'-iso-propylbenzyl) phenol (intermediate for the synthesis of compound 7-17, 0.35 g, 1.11 mmol) in EtOH (5.0 mL) and CH3NH2 40% in water (2.5 mL) was added iodine (0.34 g, 1.33 mmol) and Kl (0.27 g 1.66 mmol) in H20 (3 mL) at 0 ° C. The reaction mixture was stirred at 0 ° C for 2 h, quenched with brine (50 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1: 3) to provide 2,5-dimethyl-6-iodo-4- (4'-methoxymethoxy-3'-iso -propylbenzyl) phenol as a colorless oil (0.32 g, 64%): XH NMR (300 MHz, CDC13): d 7.02 (d, J = 2.4 Hz, 1 H), 6.95 (d, J = 8.7 Hz, 1 H ), 6.88 (s, 1 H), 6.75 (dd, J = 2.4, 8.4 Hz, 1 H), 5.20 (s, 2 H), 3.95 (s, 2 H), 3.51 (s, 3 H), 3.35 -3.30 (m, 1 H), 2.39 (s, 3 H), 2.30 (s, 3 H), 1.22 (d, J = 6.9 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (9: 1); Rf = 0.6. Step b: The title compound was prepared from 6-iodo-3,5-dimethyl-4- (4'-methoxymethoxy-3'-iso-propylbenzyl) phenol according to the procedure described for the synthesis of Example 7 -17, stage b as the white solid (0.15 g, 75%) mp 190 ° C; a H NMR (300 MHz, CD3OD): d 6.99 (s, 1 H), 6.92 (s, 1 H), 6.65 (s, 2 H), 4.16 (d, J = 10.5 Hz, 2 H), 3.94 (s) , 2 H), 3.30-3.18 (m, 1 H), 2.38 (s, 6 H), 1.18 (d, J = 6.9 Hz, 6 H); LC-MS m / z = 490 [C? 9H23I205P + H] +; Anal Calculated for (C2oH25? 6P + 1.2 H2O + 1.0 CHC13): C, 38.05; H, 4.37. Found: C, 38.04; H, 4.33. Compound 7-19: [2,6-Dimethyl-4- [4'-hydroxy-3'-iso-propylbenzyl] phenoxymethylphosphonic acid The intermediate 2,6-dimethyl-4- (4'-methoxymethoxy-3'-iso- propylbenzyl) phenol was prepared from 3,5-dimethyl-4-hydroxybenzaldehyde and bromo-4-methoxymethoxy-3-isopropylbenzene according to the procedure described in G. Chiellini et al. Biorg. Med. Chem. Lett. 2000, 10, 2607 and was transformed into the title compound according to the procedure described for the synthesis of compound 7-17, step b; (0.12 g, 85%); a H NMR (300 MHz, CD3OD): d 6.97 (s, 1 H), 6.83 (s, 2 H), 6.77 (d, J = 7.5 Hz, 1 H), 6.65 (d, J = 7.5 Hz, 1 H ), 4.0 (d, J = 9.9 Hz, 2 H), 3.75 (s, 2 H), 3.20-3.29 (m, 1 H), 2.28 (s, 6 H), 1.19 (d, J = 6.6 Hz, 6 H); LC-MS m / z = 363 [C 20 H 25 O 6 P-H] +; (94%) CLAR conditions: ODSAQ column AQ-303-5; Mobile phase = CH3OH: 0.05% TFA / H20 (7: 3) flow ratio = 1.0 mL / min; detection = UV @ 254 nm retention time in min: 10.92; Anal Calculated for (C20H25O6P + 1.2 H20): C, 59.12; H, 7.15. Found: C, 58.96; H, 6.77. Compound 7-20: [4- (4'-Hydroxy-3'-iso-propylbenzyl) -3-methyl-phenoxy] methylphosphonic The intermediate 4- (4'-methoxymethoxy-3'-iso-propylbenzyl) -3-methyl -phenol was prepared from 4-bromo-3-methyl-phenol (J. Med. Chem. 1980, 12, 1350) and 4-methoxymethoxy-3-iso-propylbenzaldehyde in accordance with the procedure described in G. Chiellini et al. to the. Biorg. Med. Chem. Lett. 2000, 10, 2607 and was transformed into the title compound by the procedure used for the synthesis of compound 7. XH NMR (300 MHz, DMS0-d6): d 9.04 (s, 1 H), 7.02-6.99 (d, J = 8.7 Hz, 1 H), 6.92 (s, 1 H), 6.81-6.76 (, 2 H), 6.67 (s, 2 H), 4.03 (d, J = 10.5 Hz, 2H), 3.76 (s, 2 H), 3.16-3.14 (m, 1 H), 2.19 (s, 3 H), 1.14-1.12 (d, J = 6.9 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate; Rf = 0.11; Compound 7-21: [2,5-Dimethyl-4- (4'-methoxy-2'-methyl-3'-iso-propylbenzyl) phenoxymethylphosphonic acid Step a: First step: To a stirred solution of 2,5-dimethyl -4-methoxybenzaldehyde (0.82 g, 5.0 mmol) at -20 ° C in CH2C12 (10 mL) was added BBr3 (10 mL, 1M in CH2C12). The reaction mixture was stirred at room temperature for 16 hrs. To this ice was added and diluted with CH2C12. The organic layer was dried over Na 2 SO, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate / hexanes (1: 1) to give 2,5-dimethyl-4-hydroxy-benzaldehyde as a yellow solid (0.43 g, 57%) : X H NMR (300 MHz, DMS0-d 6): d 10.41 (s, 1 H), 9.99 (s, 1 H), 7.56 (s, 1 H), 6.69 (s, 1 H), 2.51 (s, 3 H), 2.14 (s, 3 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 20% ethyl acetate in hexanes; Rf = 0.48. Step b: To a stirred solution of 2,5-dimethyl-4-hydroxy-benzaldehyde (0.43 g, 2.86 mmol) in DMF (8 mL) at room temperature was added imidazole (0.43 g, 6.29 mmol) and chloro-triisopropyl- silane (0.74 mL, 3.43 mmol). The mixture was stirred at room temperature for 16 hrs. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (15:75) to provide 2,5-dimethyl-4-triisopropylsilanyloxy-benzaldehyde as a colorless oil (0.7 g, 80%). : X H NMR (300 MHz, DMSO-de): d 10.07 (s, 1 H), 7.65 (s, 1 H), 6.69 (s, 1 H), 2.55 (s, 3 H), 2.21 (s, 3 H), 1.35 (m, 3 H), 1.10 (d, J = 6.9 Hz, 18 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile Phase = 5% ethyl acetate in hexanes; Rf = 0.68. The intermediate 2,5-dimethyl-4- (4'-methoxy-2'-methyl-3'-iso-propylbenzyl) phenol was prepared from 2,5-dimethyl-4-triisopropylsilanyloxy-benzaldehyde and l-bromo- 4-methoxy-2-methyl-3-iso-propylbenzene according to the procedure described in G. Chiellini et al. Biorg Med. Chem. Lett. 2000, 10, 2607 and was transformed into the title compound by the procedure described for the synthesis of compound 7: 1 H NMR (300 MHz, DMSO-d 6): d 6.93 (s, 1 H), 6.75 (d, J = 8.4 Hz, 1 H), 6.65 (d, J = 8.4 Hz, 1 H), 6.64 (s, 1 H), 4.09 (d, J = 9.9 Hz, 2 H), 3.79 (s, 2 H), 3.77 (s, 3 H), 3.34 (m, 1 H), 2.22 (s, 3 H), 2.20 (s, 3 H), 2.10 (s, 3 H), 1.31 (d, J = 7.2 Hz, 6 H); LC-MS m / z = 391 [C21H2905P-H] ~. Alternative method for the preparation of compound 7: Step a: A 2-neck 3-necked flask equipped with mechanical stirring, nitrogen burburger, sodium hydroxide trap, and a cold water bath was charged with 2-iso-propyl phenol ( 157.8 g, 1.1 mol) and dichloromethane (1000 ml). While maintaining the internal temperature at 15 ° C to 20 ° C, bromine (179.4 g, 1.1 mol) was added dropwise during 45 min. (The addition ratio is controlled so that the color of the bromine dissipates almost immediately). The reaction was completed by CCD (silica gel plates, 20% EtOAC / hexanes, Rf S.M. = 0.7, product Rf = 0.8). The flask was purged with nitrogen to remove the majority of the hydrogen bromide. The reaction mixture was then concentrated to an oil (252.0 g, 100%) which is sufficiently pure to be used in the next step. NMR: See Berthelot et al. Can J. Chem. 1989. 67, 2061. Step b: A 3-liter 3-neck round bottom flask equipped with mechanical stirring, temperature probe, cooling bath, and addition funnel with nitrogen inlet was charged with 4- bromo-2-iso-propylphenol (160 g, 0.75 mol) and methylene chloride (750 ml). While maintaining the temperature between 15 ° C and 20 ° C, a solution of diisopropylethylamine (146 g, 1.13 mol) and chloromethyl methyl ether (66.4 g, 0.83 mol) in methylene chloride (100 ml) was added for 15 minutes. The solution was heated to reflux for 16 hours. The reaction was completed by CCD (silica gel plate, 10% EtOAC / hexanes, Rf S.M. = 0.5, product Rf = 0.9). After cooling to room temperature, the reaction was quenched by the addition of water (800 ml). After separation of the layers, the aqueous phase was extracted with methylene chloride (500 ml). The combined organic layers were dried over MgSO4, and then concentrated to an oil (204 g). The oil was purified by column chromatography (1.8 kg silica gel, 2.5% EtOAc / hexanes) to yield a clear oil (154 g, 79%). NMR See G. Chiellini et al. Biorg Med. Chem. Lett. 2000, 10, 2607. Step b Alternative A 5 liter round bottom flask 4 toothed necks equipped with a multiple vane mechanical stirrer, and an addition funnel with nitrogen inlet was charged with 4-bromo-2-iso-propylphenol ( 100 g, 0.47 mol) and methylene chloride (2000 ml). Under high agitation, half of P205 (75 g, 1.1 mol) was added. The reaction was stirred for one hour during which pulp balls were formed. P205 (75 g, 1.1 mol) was added and stirred for one hour. The reaction was completed by CCD (silica gel plate, 10% EtOAC / hexanes, Rf S.M. = 0.5, product Rf = 0.9). The reaction was carefully quenched by the addition of 10% K2CO3 (2000 mL). After separation of the layers, the aqueous phase was extracted with methylene chloride (1000 ml). The combined organic layers were dried over MgSO, and then concentrated to an oil (116 g). The oil was purified by column chromatography (1.5 kg silica gel, 2.5% EtOAc / hexanes) to yield a clear oil (99.9 g, 83%). Step c: A 2-neck 3-neck round bottom flask equipped with mechanical stirring, cooling bath, temperature probe, and addition funnel with nitrogen inlet was charged with 4-bromo-3,5-dimethylphenol (90.0 g, 448 mmol), imidazole (90 g, 1.32 mol), and methylene chloride (900 ml). The solution was cooled to 10 ° C. The triisopropylsilyl chloride (95.0 g, 493 mmol) was added for 10 minutes. The temperature was raised to 20 ° C. The solution became cloudy, and a white precipitate formed. The reaction mixture was stirred at room temperature for 2.5 hours. The reaction was completed by CCD (silica gel plates, 10% EtOAc / hexane, Rf S.M. = 0.3, product Rf = 0.9). Water (600 ml) was added and stirred for 20 minutes. After separation of the layers, the organic phase was dried over MgSO4 and concentrated to an oil (178 g) which is acceptable for use in the next step. The oil was purified by column chromatography (1.8 kg silica gel, 5% EtOAc / hexane) to yield an oil (153 g, 96%). NMR See G. Chiellini et al. Biorg Med. Chem. Lett. 2000, 10, 2607. Step d: A 3-liter 3-neck round bottom flask equipped with mechanical stirring, thermometer, cooling bath and 250 ml addition funnel was charged with 4-bromo-3,5-dimethylphenoxy-phenoisopropylsilane (150 g, 420 mmol) and THF (1125 ml). The solution was cooled to -73 ° C. While maintaining the temperature less than or equal to -70 ° C, n-butyllithium 2.5 M (252 ml, 630 mmol) was added for 1.5 hours. The solution was stirred at -73 ° C for an additional 2.5 hours. While maintaining the temperature less than or equal to -70 ° C, a solution of dimethylformamide (61.3 g, 840 mmol) in THF (60 mL) was added over 35 minutes. After stirring for 30 minutes at -73 ° C, CCD indicates that the reaction was complete (silica gel plates, 10% EtOAc / hexane, Rf S.M. = 0.9, product Rf = 0.7). The reaction was warmed to room temperature, and then quenched by the addition of saturated ammonium chloride in water (1000 ml). After separation of the layers, the aqueous phase was extracted with MTBE (250 ml). The combined organic layers were dried over MgSO4, and concentrated to an oil (125 g). The oil was purified by column chromatography (1.5 kg silica gel, 5% EtOAc / hexanes) to yield an oil (113 g, 87%). NMR See G. Chiellini et al. Biorg. Med. Chem. Lett. 2000, 10, 2607. Step e: A 3-neck, 3-neck round bottom flask equipped with a cooling bath, mechanical stirring, temperature probe, and addition funnel with nitrogen inlet, was charged with bromo-4-methoxymethoxy- 3-iso-propyl (136 g, 525 mmol) and THF (1300 mL). The solution was cooled to -75 ° C. While maintaining the temperature less than or equal to -70 ° C, n-butyllithium solution (310 ml, 775 mmol) was added for 45 minutes. The solution was stirred at -75 ° C for 1 hour. While keeping the temperature less than or equal to -70 ° C, a solution of 2,6-dimethyl-4-triisopropylsilyloxybenzaldehyde (134 g, 438 mmol) in THF (200 ml) was added for 2 hours. The solution was stirred at -75 ° C for 1 hour. CCD indicates that the reaction was complete (silica gel plates, 10% EtOAc / hexane, Bromide Rf = 0.9, Aldehyde Rf = 0.7, product Rf = 0.2). After warming to room temperature, the reaction was quenched with saturated ammonium chloride in water (200 ml). After separation of the layers, the aqueous phase was extracted with ethyl acetate (800 ml). The combined organic layers were washed with brine (700 ml), dried over MgSO 4, and concentrated to an oil (262 g). The oil was split in halves, and each half was purified by column chromatography (1.8 kg silica gel, 5 to 10% EtOAc / hexane) to yield the product as a clear oil containing some EtOAc (148 g of the product, 69%). The fractions containing the product and an impurity were combined to give a clear oil (19.3 g). This was purified by column chromatography (400 g silica gel, 5 to 10% EtOAc / hexanes) to give additional product as a clear oil (16.9 g, 7%). RMN View G. Chiellini et al. Biorg. Med. Chem. Lett. 2000, 10, 2607. Step f: A 2-liter round bottom flask equipped with magnetic stirring and a 3-way adapter was charged with (4-methoxymethoxy-3-iso-propylphenyl) - (2,6-dimethyl-4- triisopropylsilyloxy) -methanol (72.1 g, 139 mmol), ethyl acetate (665 mL), acetic acid (35 mL), and Pd 10% Carbon (5.22 g). The flask was purged 3 times with nitrogen, and then a hydrogen balloon was attached to the adapter. After purging 3 times with hydrogen, the mixture was stirred at room temperature for 3 hours. The reaction was completed by CCD (silica gel plates, 10% EtOAc / hexane, Rf S. M. = 0.2, product Rf = 0.9). After purging with nitrogen, the mixture was filtered through a small pad of Celite; rinsed with EtOAc (70 ml). The filtrate was washed with water (2 x 100 mL), then NaHC03 saturated in water until the wash became basic (4 x 100 mL). The organic layer was dried over MgSO4 and then concentrated to an oil (62.5 g, 96%). NMR See G. Chiellini et al. Biorg. Med. Chem. Lett. 2000, 10, 2607. Step g: A 1-liter 1-neck round bottom flask equipped with magnetic stirring was charged with 2,6-dimethyl- (4'-methoxymethoxy-3'-iso-propylbenzyl) -4-triisopropylsilyloxybenzene. (62.5 g, 133 mmol) and THF (600 ml). The tetraethylammonium hydrate fluoride (25.9 g, 174 mmol) was ground lightly in a cuvette and then charged to the flask. The thick mixture was stirred at room temperature for 1 hour until CCD indicated that the reaction was complete (silica gel plates)., 20% EtOAc / hexane, Rf S.M. = 0.9, product Rf = 0.4). The water (300 ml) was added and stirred for 15 minutes. The mixture was diluted with MTBE (600 mL), and the layers separated. The aqueous phase was extracted with MTBE (600 ml). The combined organic layers were washed with water (100 ml) followed by brine (200 ml). After drying over MgSO4, the organic layer was concentrated to an oil (65 g). This was purified by column chromatography (1300 g silica gel, 10 to 20% EtOAc / hexanes) to give the product as a clear oil (57.0 g, 95%). NMR See G. Chiellini et al. Biorg. Med. Chem. Lett. 2000, 10, 2607.

Step h: A 3-neck, 3-neck round bottom flask equipped with a cooling bath, mechanical stirring, temperature probe, and addition funnel with nitrogen inlet, was charged with 60% sodium hydride in mineral oil (10.62 g, 266 mmol). The sodium hydride was washed with hexanes (150 ml). Dimethylformamide (250 ml) was added, and the mixture was cooled to 5 ° C. While maintaining the temperature < At 10 ° C a solution of 3,5-dimethyl-4- (4 '-methoxymethoxy-3'-iso-propylbenzyl) -phenol (55.53 g, 117 mmol) in DMF (150 mL) was added over 30 minutes. The solution was stirred at room temperature for 1 hour, and then cooled again to 5 ° C. While keeping the temperature less than or equal to 10 ° C, a solution of the diethyl p-toluenesulfonyloxymethyl phosphonate (86.93 g, 269 mmol) in DMF (150 ml) was added for 15 minutes. The solution was stirred at room temperature for 16 hours. The reaction was concentrated to a paste. The paste was treated with water (330 ml) and extracted with ethyl acetate (330 ml, 2 x 250 ml). The combined organic layers were washed with brine (150 ml), dried over MgSO 4, and concentrated to an oil (116 g). The oil was purified by column chromatography (1.5 kg silica gel, 10 to 50% EtOAc / hexane) to yield the product as a clear oil containing some EtOAc (54.76 g of the product, 66%). The fractions containing the product and diethyl p-toluenesulfonyloxymethyl were combined to give a clear oil (6. 03 g). This was purified by column chromatography (silica gel 120 g, 30 to 40% EtOAc / hexanes) to give the product as a clear oil (3.74 g, 4%). NMR See compound 7, stage a. Step i: A 500 ml 3-necked round bottom flask equipped with magnetic stirring, temperature probe, addition funnel with a nitrogen inlet, and a cooling bath was charged with [3, 5-dimethyl-4- ( Diethyl 4'-methoxymethoxy-3'-iso-propylbenzyl) phenoxy] methylphosphonate (19.61 g, 42.2 mmol) and dichloromethane (200 mL). The solution was cooled to -30 ° C. Trimethyl silyl bromide (64.96 g, 424 mmol) was added for 15 min. The bath was removed, and the solution was stirred at room temperature for 16 hours. The reaction was concentrated on the rotary evaporator at 50 ° C. The oil was then placed in the vacuum pump for 30 minutes. The oil was dissolved in acetonitrile / water (110 ml / 110 ml) and stirred at 50 ° C for 30 min. The solution was concentrated to an oil. Acetonitrile (110 mL) was added, and the solution was concentrated to an oil. Methanol / toluene (30/190 ml) was added and the solution was concentrated to an oil. Methanol / toluene (30/190 ml) was added and the solution was concentrated to a foam. Toluene (220 ml) was added and the solution was concentrated to a solid. Toluene / hexane (190 ml / 30 ml) was added, and the mixture was sonicated for 5 minutes. The solids were scraped under the sides of the flask, and the mixture was stirred at room temperature for 2 hours. The solids were collected by vacuum filtration and washed with hexane / toluene (2 ml / 8 ml). The solids were dried overnight in the vacuum oven at 45 to 50 ° C to yield MB7344 as an off white solid (14.36 g). NMR See compound 7, stage b. Preparation of diethyl p-toluenesulfonyloxymethylphosphonate A 3-neck, 3-neck round bottom flask was equipped with a mechanical stirrer, condenser, thermometer and heating layer. The flask was wetted with nitrogen and charged with diethyl phosphite (554 g, 3.77 mol), paraformaldehyde (142 g, 4.72 mol), toluene (2 L) and triethylamine (53 mL, 5.76 mol). The mixture was stirred at 85-90 ° for 2 h, then refluxed for 1 h. The resulting yellow solution was cooled to 4 ° C (ice bath) and p-toluenesulfonyl chloride (718 g, 3.77 mol) was added. The condenser was replaced with an addition funnel and triethylamine (750 mL) was added slowly with stirring, maintaining the temperature < 10 ° C. After the addition was completed (45 min.), the resulting mixture was stirred at room temperature for 14 h. The mixture was filtered and the filter cake was washed with toluene (2 X 250 mL). The combined filtrate and washings were washed with water (2 X 1 L, dried (MgSO 4, 200 g), filtered through Celite 521, and concentrated under reduced pressure to provide 1004 g of a cloudy yellow oil (77.6%). ). "." "H NMR (CDCl 3): NMR (DMSO): 7.82 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 4.36 (d, J = 9.6 Hz, 2H ), 4.00 (m, 4H), 2.41 (s, 3H), 1.16 (m, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 40% EtOAc / hexanes, Rf = 0.24. Example 8 Compound 8_: [3,5-Diiodo-4- (4'-hydroxy-3'-iso-propylphenoxy) phenoxymethylphosphonic acid Step a: To a solution of 4-benzoyloxyphenol (0.2 g, 0.93 mmol) in dichloromethane (9.3 mL) at 0 ° C bis (pyridine) iodonium tetrafluoroborate (0.76 g, 2.06 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with acetone-hexanes (1: 9) to provide 4-benzoyloxy-3,5-diiodophenol as an off white solid (0.22 g). , 50%):? E NMR (300 MHz, DMS0-d6): d 9.60 (s, 1 H), 8.06 (m, 2 H), 7.72 (s, 2 H), 7.59 (m, 3 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-acetone (4: 1); Rf = 0.45. Step b: To a mixture of bis (4-methoxy-3-iso-propylphenyl) iodonium tetrafluoroborate (0.77 g, 1.51 mmol) and copper powder (0.13 g, 2.01 mmol) in CH2C12 (4.4 mL) at 0 ° C A solution of TEA (0.15 L, 1.10 mmol) and 4-benzoyloxy-3,5-diiodophenol (0.47 g, 1.00 mmol) in dichloromethane (4.0 mL) was added. The reaction mixture was stirred at room temperature for 24 h and filtered through a plug of celite. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with acetone-hexanes (1: 9) to give 3,5-diiodo-4- (4 '-methoxy-3-benzoate. '-iso-propylphenoxy) phenyl as an off white solid (0.61 g, 98%): 1 H NMR (300 MHz, DMSO-d 6): d 8.10 (m, 2 H), 7.96 (s, 2 H), 7.73 ( m, 1 H), 7.60 (m, 2 H), 6.85 (d, J = 9.0 Hz, 1H), 6.73 (d, J = 3.0 Hz, 1H), 6.35 (m, 1 H), 3.74 (s, 3 H), 3.21 (m, 1 H), 1.13 (d, J = 6.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-acetone (1: 9); Rf = 0.42. Step c: A mixture of 3,5-diiodo-4- (4'-methoxy-3'-iso-propylphenoxy) phenyl benzoate (0.10 g, 0.16 mmol) and 1 N NaOH (0.81 mL, 0.81 mmol) in methanol (1.63 L) was at room temperature for 24 h. The reaction mixture was neutralized with 2N HCl, diluted with H20 and extracted with CH2C12 (10 mL x 2). The organic layers were concentrated under reduced pressure and the crude product was purified by preparative CCD with acetone-hexanes (1: 4) as Mobile Phase to provide 3,5-diiodo-4- (4'-methoxy-3'-iso-). propylphenoxy) phenol as an off white solid (0.079 g, 95%): X H NMR (300 MHz, DMSO-d 6): d 9.99 (s, 1 H), 7.28 (s, 2 H), 6.81 (d, J = 12.0 Hz, 1 H), 6.67 (d, J = 3.0 Hz, 1 H), 6.30 (, 1 H), 3.72 (s, 3 H), 3.18 (, 1 H), 1.11 (d, J = 6.9 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-acetone (7: 3); Rf = 0.42. Step d: To a stirred solution of 3,5-diiodo-4- (4 '-methoxy-3'-iso-propylphenoxy) phenol (0.28 g, 0.55 mmol) in dichloromethane (17.0 L) at -78 ° C was added BBr3 (13.1 L, 13.1 mmol, 1.0 M solution in CH2C12). The reaction mixture was stirred at -78 ° C for 10 min, allowed to warm to room temperature and stirred for 16 h. The reaction mixture was emptied on ice and extracted with CH2C12 (20 mL x 2). The organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with acetone-hexanes (3: 7) to provide 3,5-diiodo-4- (4'-hydroxy-3'-iso-propylphenoxy) phenol as a Off white solid (0.18 g, 66%): X H NMR (300 MHz, DMSO-d 6): d 9.95 (s, 1 H), 8.91 (s, 1 H), 7.27 (s, 2 H), 6.62 (d , J = 9.0 Hz, 1H), 6. 56 (d, J = 3.0 Hz, 1 H), 6.18 (m, 1 H), 3.72 (s, 3 H), 3.14 (m, 1 H), 1.10 (d, J = 6.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-acetone (7: 3); Rf = 0.28.

Step e: To a mixture of 3,5-diiodo-4- (4'-hydroxy-3'-iso-propylphenoxy) phenol (0.067 g, 0.14 mmol) and Cs2CO3 (0.220 g, 0.675 mmol) in DMF (1.35 mL) ) at 0 ° C the trifluoromethanesulfonic acid diethoxyphosphoryl methyl ester (0.040 g, 0.14 mmol) was added. The reaction mixture was stirred at room temperature for 5 h, quenched with 1N HCl and extracted with EtOAc (10 mL x 2). The organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by preparative CCD with acetone-hexane (2: 3) as Mobile Phase to provide diethyl 3,5-diiodo-4- (4'-hydroxy-3'-iso-propylphenoxy) phenoxy] methylphosphonate as a off white solid (0.048 g, 55%): X H NMR (300 MHz, DMSO-d 6): d 8.95 (s, 1 H), 7.57 (s, 2 H), 6.63 (d, J = 9.0 Hz, 1 H ), 6.56 (d, J = 3.0 Hz, 1 H), 6.19 (m, 1 H), 4.51 (d, J = 9.0 Hz, 2 H), 4.08 (m, 4 H), 3.14 (m, 1 H), 1.25 (m, 6 H), 1.10 (d, J = 6. 0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-acetone (3: 2); Rf = 0.29. Step f: To a solution of diethyl [3, 5-diiodo-4- (4'-hydroxy-3'-iso-propylphenoxy) phenoxy] methylphosphonate (0.14 g, 0.22 mmol) in CH2C12 (2.5 mL) at 0 ° C was added bromotrimethylsilane (0.28 mL, 2.20 mmol). The reaction mixture was stirred at room temperature for 16 h and the solvent was removed under reduced pressure. The residue was treated with acetonitrile-water (1: 1, 5.0 mL) and the solvent was removed under reduced pressure. The crude product was treated with methanol (10 mL) and the solvent was removed under reduced pressure to give [3,5-diiodo-4- (4'-hydroxy-3'-iso-propylphenoxy) phenoxymethylphosphonic acid as an off white solid ( 0.080 g, 63%): mp 180 ° C, dec; LC-MS m / z = 589 [Ci6H? 7I206P-H] ~; CLAR conditions: Column = 3 Chromolith SpeedRODs RP-18e, 100 x 4.6 mm; Mobile Phase = Solvent A (Acetonitrile) = Acetonitrile grade CLAR; Solvent B (buffer solution) = 20 mM ammonium phosphate buffer solution (pH 6.1, 0.018 M NH4H2PO4 / 0.002 M (NH4) 2HP04) with 5% acetonitrile. Flow ratio = 4 mL / min; UV @ 255 nm. Retention time in minutes, (tr = 6.46, 97% purity). Using the appropriate starting material, compounds 8-1 and 8-2 were prepared in an analogous manner as described by the synthesis of compound 8. Compound 8-1: Acid [3,5-dibromo-4- (3 ' -iso-propyl-4 '-hydroxyphenoxy) phenoxy] methylphosphonic acid It was prepared from 4-benzoyloxy-3,5-dibromophenol according to the procedure described in compound 8. mp: 77-80 ° C; LC-MS m / z = 495, 497 [C? 6H17Br206P-H] ~; X H NMR (300 MHz, DMSO-de): d 8.99 (s, 1 H), 7.42 (s, 2 H), 6.63 (m, 2 H), 6.22 (m, 1 H), 4.21 (d, J = 9.0 Hz, 2 H), 3.11 (m, 1 H), 1.10 (d, J = 6.0 Hz, 6 H); Anal. Calculated for (C? 6H? 7Br206P + 0.2 C6H? 4): C, 40.06; H, 3.78. Found: C, 40.25, H, 3.89. Compound 8-2: [3,5-Dichloro-4- (3'-iso-propyl-4'-hydroxyphenoxy) phenoxy] methylphosphonic acid was prepared from 2,6-dichloro-4- (2-methoxyethoxy) phenol (Synth, Commu, 1997, 27, 107) according to the procedure described in compound 8. pf: 73-76 ° C; LC-MS m / z = 407 [C16H? 7Cl20eP-H] ~; X H NMR (300 MHz, DMSO-de): d 9.10 (s, 1 H), 7.34 (s, 2 H), 6.72 (m, 2 H), 6.32 (m, 1 H), 4.28 (d, J = 9.0 Hz , 2 H), 3.22 (m, 1 H), 1.17 (d, J = 6.0 Hz, 6 H); Anal. Calculated for (C? 6H? 7Cl206P + 0.2 C4H802 + 0.4 H20): C, 46.71; H, 4.53. Found: C, 46.95, H, 4.50. Example 9 Compound 9 3,5-Dichloro-4- [4 '-hydroxy-3' - (N-piperidinylsulfonamido) phenoxy] benzylphosphonic acid Step a: To a stirred solution of bis (4-methoxyphenyl) iodonium tetrafluoroborate (5.2 g , 13.5 mmol, N. Yokoyama et al., Med. Chem. 1995, 38, 695) and copper powder (1.14 g, 18.1 mmol) in CH 2 Cl 12 (30 mL) at 0 ° C was added a solution of 3.5 methyl-dichloro-4-hydroxybenzoate (39.0.0 g, 9.0 mmol) and Et3N (1.1 g, 1.5 mL, 12.0 mmol) in CH2C12 (10 mL). The reaction mixture was stirred at room temperature for 24 h and filtered through a plug of celite. The filtrate was washed with 2N HCl (20 mL) and extracted with ethyl acetate (2x100 mL). The combined organic layers were washed with brine and water, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1: 9) to provide methyl 3,5-dichloro-4- (4'-methoxyphenoxy) benzoate as a white solid ( 1.59 g, 55%): mp 82-85 ° C; 1 H NMR (300 MHz, CDC13): d 8.04 (s, 2 H), 6.85 (dd, J = 2.7, 4.8 Hz, 1 H), 6.80 (dd, J = 1.8, 4.5 Hz, 1 H), 6.78 ( t, J = 3.3 Hz, 1 H), 6.74 (d, J = 2.4 Hz, 1 H), 3.94 (s, 3 H), 3.76 (s, 3 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 4); Rf = 0.7. Step b: To a stirred solution of methyl 3,5-dichloro-4- (4'-methoxyphenoxy) benzoate (1.5 g, 4.5 mmol) in CH 2 C 12 (50 mL) at -78 ° C was added BBr3 (11.4 mL, 11.4 mmol, solution 1 M in CH2C12). The reaction mixture was stirred at room temperature for 14 h, emptied in ice water (100 mL) and stirred for 1 h. The reaction mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with water and brine, dried over MgSO, filtered and concentrated under reduced pressure. The crude product was recrystallized from CH2C12, filtered and dried under reduced pressure to provide 3,5-dichloro-4- (4'-hydroxyphenoxy) benzoic acid as a brown solid (1.02 g, 75%): mp 163- 165 ° C; X H NMR (300 MHz, DMSO-d 6): d 9.02 (bs, 1 H), 8.0 (s, 2 H), 6.67 (m, 4 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (2: 3); Rf = 0.3. Step c: To a cold stirred solution of CH3OH (35 mL) and acetyl chloride (7 mL, 86.0 mmol) at 0 ° C was added dropwise a solution of 3,5-dichloro- (4'-hydroxyphenoxy) acid. ) benzoic acid (1.3 g, 4.3 mmol) in CH3OH (5 mL). The reaction mixture was heated under reflux for 5 h and cooled to room temperature. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (100 mL). The resulting solution was washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was triturated with hexane-ether (8: 2), filtered and dried under reduced pressure to provide methyl 3,5-dichloro-4- (4'-hydroxyphenoxy) benzoate as a brown solid (1.22 g, 90 %): mp 152-155 ° C; 1 H NMR (300 MHz, DMSO-d 6): d 9.22 (s, 1 H), 8.08 (s, 2 H), 6.77 (t, J = 3.0 Hz, 1 H), 6.74 (t, J = 2.7 Hz, 1 H), 6.72 (t, J = 2.7 Hz, 1 H), 6.68 (d, J = 2.7 Hz, 1 H), 3.87 (s, 3 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (2: 3); Rf = 0.5 Step d: To a stirred solution of methyl 3,5-dichloro-4- (4'-hydroxyphenoxy) benzoate (1.2 g, 3.8 mmol) in CHC13 (10 mL) at 0 ° C was added chlorosulfonic acid (3.9 mL, 38.3 mmol). The reaction mixture was stirred at 0 ° C for 1 h and allowed to warm to room temperature. The reaction mixture was stirred for 2 h, emptied in ice water and extracted with ethyl acetate, (3 x 100 mL). The combined organic layers were washed with water, dried over MgSO4 and concentrated under reduced pressure to provide the crude product, which was used in the next step without purification. The crude product (1.1 g, 2.6 mmol) was dissolved in THF (10 mL) and a solution of piperidine (0.68 g, 1 mL) in THF (5 mL) was added thereto. The reaction mixture was stirred at room temperature for 16 h and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and washed with water and brine. The organic layer was dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (3: 7) to provide 3,5-dichloro-4- [4'-hydroxy-3 '- (N-piperidinylsulfonamido) methyl phenoxy] benzoate as a white solid (0.78 g, 60%): mp 122-125 ° C; X H NMR (300 MHz, CDC13): d 8.58 (s, 1 H), 7.04-7.10 (m, 2 H), 6.85 (d, J = 2.7 Hz, 2 H), 3.96 (s, 3 H), 3.02 (t, J = 5.1 Hz, 4 M, 1.63- 1.59 (m, 4 H), 1.50-1.40 (m, 2 H); CCD Conditions: Silica gel uniplaca, 250 microns; Mobile phase = ethyl acetate- hexanes (3: 7); Rf = 0.35 Step e: To a stirred solution of 3,5-dichloro-4- [4 '-hydroxy-3' - (N-piperidinylsulfonamido) phenoxy] benzoate methyl (0.95 g, 2. 0 mmol) in CH2C12 (15 mL) at -78 ° C was added DIBAL-H (6.1 mL, 6. 1 mmol, 1 M solution in CH2C12). The reaction mixture was stirred at room temperature for 5 h, cooled to 0 ° C, quenched with saturated aqueous NaF solution (20 mL) and stirred at room temperature for 1 h. The reaction mixture was filtered and the filtrate was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1: 4) to give 3,5-dichloro-4- [4'-hydroxy-3'- (N-) alcohol. piperidinylsulfonamido) phenoxy] benzyl as a white solid (0.66 g, 75%): mp 142-145 ° C; E NMR (300 MHz, DMS0-d6): d 8.54 (s, 1 H), 7.40 (s, 2 H), 7.09 (dd, J = 3.0, 9.3 Hz, 1 H), 6.98 (dd, J = 3.0, 9.3 Hz, 1 H), 6.84 (d, J = 2.4 Hz, 1 H), 4.70 (d, J = 3.9 Hz, 2 H), 3.02 (t, J = 2.4 Hz, 4 H), 1.70-1.50 (m, 4 H), 1.47-1.50 (m, 2 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (2: 3); Rf = 0.4. Step f: To a stirred solution of 3,5-dichloro-4- [4 '-hydroxy-3' - (N-piperidinylsulfonamido) phenoxy] benzyl alcohol (0.40 g, 0.92 mmol) in ethyl ether-DME (9) : 1, 10 mL) at 0 ° C was added phosphorus tribromide (1.2 g, 0.5 mL, 4.64 mmol). The reaction mixture was stirred at 0 ° C for 5 h, quenched with ice (10 g) and stirred at 0 ° C for 30 min. The reaction mixture was extracted with ether (100 mL) and washed with brine. The organic layer was dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1: 4) to provide 3,5-dichloro-4- [4'-hydroxy-3 '- (N-) bromide. piperidinylsulfonamido) phenoxy] benzyl as a colorless oil (0.34 g, 75%): XH NMR (300 MHz, CDC13): d 8.57 (s, 1 H), 7.42 (s, 2 H), 7.0 (dd, J = 3.0 , 9.3 Hz, 1 H), 6.97 (d, J = 9.3 Hz, 1 H), 6.86 (d, J = 2.7 Hz, 1 H), 4.41 (s, 2 H), 3.02 (t, J = 5.1 Hz , 4 H), 1.65-1.55 (m, 4 H), 1.50-1.45 (m, 2 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (3: 7); Rf = 0.75. Step g: To a stirred solution of 3,5-dichloro-4- [4 '-hydroxy-3' - (N-piperidinylsulfonamido) phenoxy] benzyl bromide (0.12 g, 0.25 mmol) in toluene (5 mL) at room temperature At room temperature, triethylphosphite (0.42 g, 2.5 mmol) was added. The reaction mixture was heated at 130 ° C for 8 h and cooled to room temperature. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1: 1) to provide 3,5-dichloro-4- [4'-hydroxy-3 '- (N-piperidinyl sulfonamido) phenoxy] benzylphosphonate diethyl as a white solid (0.12 g, 90%): mp 132-135 ° C; E NMR (300 MHz, CDC13): d 8.55 (s, 1 H), 7.33 (d, J = 2.7 Hz, 2 H), 7.05 (dd, J = 3.0, 9.3 Hz, 1 H), 6.97 (d , J = 9.3 Hz, 1 H), 6.83 (d, J = 3.3 Hz, 1 H), 4.09 (q, J = 6.9 Hz, 4 H), 3.07 (d, J = 21.6, 2 H), 3.02 ( t, J = 6.0 Hz, 4 H), 1.67-1.57 (m, 4 H), 1.50-1.42 (m, 2 H), 1.30 (t, J = 9.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 1); Rf = 0.4. Step h: To a stirred solution of 3,5-dichloro-4- [4'-hydroxy-3 '- (N-piperidinylsulfonamido) phenoxy] benzylphosphonate diethylate (0.1 g, 0.18 mmol) in CH2C12 (5 mL) TMSBr (0.27 g, 0.3 mL, 1.8 mmol) was added at 0 ° C. The reaction mixture was stirred at 0 ° C for 30 min, allowed to warm to room temperature and stirred for 16 h. The solvent was removed under reduced pressure and the residue was dissolved in CH 3 OH (3 mL). The solvent was removed under reduced pressure. The residue was triturated with water (3 mL). The mixture was filtered and dried under reduced pressure to give 3,5-dichloro-4- [4'-hydroxy-3 '- (N-piperidinylsulfonamido) phenoxy)] benzylphosphonic acid as a white solid (0.07 g, 78 %): mp 68-72 ° C; LC-MS m / z = 496 [C? 8H20Cl2NO7PS + H] +; Anal Calculated for (C20H16C12F05P + 0.5 CH2C12): C, 41.28; H, 3.93; N, 2.60; S, 5.96. Found: C, 41.27; H, 3.86; N, 2.84; S, 5.84. Example 10 Compound 10: 3,5-Dichloro-4- [4 '-hydroxy-3' - (N-exo-2-norbornylsulfonamido) phenoxy] benzylphosphonic acid Step a: 3,5-dichloro-4- [4 '- Methyl hydroxy-3 '- (N-exo-2-norbornylsulfonamido) phenoxy] benzoate was synthesized as a white solid (0.89 g, 55%) from methyl-3,5-dichloro-4- (4'-hydroxy) ) phenoxybenzoate (1.3 g, 3.1 mmol) by following the procedure described in example 9, step d: mp 142-145 ° C; XH NMR (300 MHz, CDC13): d 8.43 (s, 1 H), 8.05 (s, 2 H), 7.06 (dd, J = 3.0, 8.7 Hz, 1 H), 6.98 (d, J = 9.3 Hz, 1 H), 6.92 (d, J = 3.0 Hz, 1 H), 4.53 (d, J = 7.5 Hz, 1 H), 3.95 (s, 3 H), 3.12 (m, 1 H), 2.20 (bs, 1 H), 2.04 (bs, 1 H), 1.66-1.58 (m, 2 H), 1.46-1.40 (m, 2 H), 1.28-1.24 (m, 2 H), 1.20-1.16 (m, 1 H) ), 1.02 (dd, J = 1.8, 7.8 Hz, 2 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (2: 3); Rf = 0.3. Step b: 3,5-Dichloro-4- [4 '-hydroxy-3' - (N-exo-2-norbornylsulfonamido) phenoxy] benzyl alcohol was prepared as a white solid (0.46 g, 85%) from Methyl 3, 5-dichloro-4- [4 '-hydroxy-3' - (N-exo-2-norbornylsulfonamido) phenoxy] benzoate (0.5 g, 0.97 mmol) by following the procedure described in example 9, step e: mp 130-132 ° C; X H NMR (300 MHz, DMSO-d 6): d 7. 51 (s, 2 H), 7.03 (dd, J = 3.3, 9.0 Hz, 1 H), 6.89 (d, J = 8.7 Hz, 1 H), 6.81 (d, J = 3.0 Hz, 1 H), 4.51 (s, 2 H), 2.90 (dd, J = 4.2, 8.1 Hz, 1 H), 2.06 (bs, 1 H), 1.86 (bs, 1 H), 1. 37 (dd, J = 10.2, 24.3 Hz, 2 H), 1.30-1.22 (m, 2 H), 0.98- 0.90 (m, 2 H), 0.85-0.79 (m, 2 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (2: 3); Rf = 0.3. Step c: 3,5-Dichloro-4- [4 '-hydroxy-3' - (N-exo-2-norbornylsulfonamido) phenoxy] benzyl bromide was prepared as a colorless oil (0.08 g, 75%) from of 3, 5-dichloro-4- [4 '-hydroxy-3- (N-exo-2-norbornylsulfonamido) phenoxy] benzyl alcohol (0.1 g, 0.20 mmol) by following the procedure described in example 9, step f. XH NMR (300 MHz, CDC13): d 8.33 (s, 1 H), 7.34 (s, 2 H), 7.0 (dd, J = 3.0, 8.7 Hz, 1 H), 6.90 (d, J = 9.0 Hz, 1 H), 6.85 (d, J = 3.0 Hz, 1 H), 4.33 (s, 2 H), 3.05 (m, 1 H), 2.14 (bs, 1 H), 1.97 (bs, 1 H), 1.59 -1.49 (m, 2 H), 1.38-1.32 (m, 2 H), 1.21-1.16 (m, 2 H), 1.12-1.06 (m, 1 H), 0.95 (dd, J = 1.8, 8.1 Hz, 1 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (2: 3); Rf = 0.75.

Step d: Diethyl 3,5-dichloro-4- [4 '-hydroxy-3' - (N-exo-2-norbornylsulfonamido) phenoxy] benzylphosphonate was prepared as a colorless oil (0.2 g, 83%) from of 3,5-dichloro-4- [4 '-hydroxy-3- (N-exo-2-norbornylsulfonamido) phenoxy] benzyl bromide (0.22 g, 0.40 mmol) by following the procedure described in Example 9, step g 1 H NMR (300 MHz, CDC13): d 8.47 (s, 1 H), 7.33 (d, J = 2.7 Hz, 2 H), 7.09 (dd, J = 2.7, 8.7 Hz, 1 H), 6.97 (dd) , J = 2.7, 9.0 Hz, 1 H), 6.88 (d, J = 3.0 Hz, 1 H), 4.75 (d, J = 7.2 Hz, 1 H), 4.09 (q, J = 6.9 Hz, 2 H) , 3.49 (s, 1 H), 3.14 (d, J = 21.6 Hz, 2 H), 3.11-3.05 (m, 1 H), 2.2 (bs, 1 H), 2.05 (d, J = 3.3 Hz, 1 H), 1.44-1.22 (m, 6 H), 1.20-1.15 (m, 1 H), 1.14-1.02 (m, 1 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (2: 3); Rf = 0.3. Step e: 3,5-Dichloro-4- [3 '- (N-exo-2-norbornylsulfonamido) -4'-hydroxyphenoxy] benzylphosphonic acid was prepared as a white solid (50 mg, 75%) from 3 Diethyl 5-dichloro-4- [3 '- (N-exo-2-norbornylsulfonamido) -4'-hydroxyphenoxy] benzylphosphonate (0.075 g, 0.40 mmol) by following the procedure described in example 9, step h: mp 210-212 ° C; LC-MS m / z = 522 [C20H22Cl2NO7PS] +; Anal Calcd for (C20H22Cl2NO7PS + 0.7 CH2C12): C, 42.78; H, 4.06; N, 2.41. Found: C, 42.77; H, 4.17; N, 2.62.

Example 11 Compound 11: 3,5-Dichloro-4- [3 '- (4-fluorobenzyl) -4'-hydroxyphenoxy] benzylphosphonic acid Step a: To a stirred solution of 3,5-dichloro- (4'-hydroxyphenoxy) methyl benzoate (0.5 g, 1.52 mmol) and p-fluorobenzoyl chloride (0.69 g, 0.45 mL 3.8 mmol) in CH2C12 (50 mL) at room temperature was added TiCl4 (7.6 mL, 7.6 mmol, 1 M solution in CH2C12) . The reaction mixture was stirred at room temperature for 8 days, quenched with saturated aqueous NH 4 Cl (25 mL) and stirred for 2 h. The reaction mixture was extracted with CH2C12 (2 x 100 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude product was triturated with hexanes-ethyl ether (8: 2), filtered and dried under reduced pressure to provide 3,5-dichloro-4- [3 '- (4-fluorobenzoyl) -4-methoxyphenoxy] benzoate. methyl as a yellow solid. (0.39 g, 62%): mp 112-115 ° C; aH NMR (300 MHz, CDC13): d 8.04 (s, 2 H), 7.81 (dd, J = 5.7, 9.0 Hz, 2 H), 7.09 (t, J = 8.4 Hz, 2 H), 6.93 (d, J = 2.7 Hz, 1 H), 6.92 (s, 1 H), 6.81 (d, J = 3.0 Hz, 1 H), 3.94 (s, 3 H), 3.69 (s, 3 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 4); Rf = 0.75.

Step b: To a stirred solution of methyl 3,5-dichloro-4- [3 '- (4-fluorobenzoyl) -4'-methoxyphenoxy] benzoate (350 mg0.78 mmol) and TFA (2 mL) in CH2C12 (50 mL) at room temperature added triethylsilane (0.5 mL, 3.1 mmol). The reaction mixture was stirred at room temperature for 16 h, quenched with water (25 mL) and extracted with ether (100 mL). The organic layer was dried over Na 2 SO, filtered and concentrated under reduced pressure. The crude product was triturated with hexanes, filtered and dried under reduced pressure to provide methyl 3,5-dichloro-4- [3 '- (4-fluorobenzyl) -4'-methoxyphenoxy] benzoate as a brown solid (0.31 g). , 92%): mp 108-110 ° C; XH NMR (300 MHz, CDC13): d 7.98 (s, 2 H), 7.06 (dd, J = 6.0, 9.0 Hz, 2 H), 6.88 (t, J = 8.7 Hz, 2 H), 6.70 (d, J = 9.0 Hz, 1 H), 6.58 (d, J = 3.0 Hz, 1H), 6.48 (dd, J = 3.3, 9.0 Hz, 1H), 3.89 (s, 3 H), 3.83 (s, 2 H) 3.71 (s, 3 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (2: 8); Rf = 0.8. Step c: To a stirred suspension of LiAlH (0.26 g, 6.95 mmol) in THF (40 mL) at 0 ° C was added slowly a solution of 3,5-dichloro-4- [3 '- (4-fluorobenzyl) Methyl 4'-methoxyphenoxy] benzoate (1.2 g, 2.76 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 20 h and cooled to 0 ° C. The reaction mixture was quenched with 15% aqueous NaOH (1.5 mL), diluted with H20 (3.0 mL) and stirred for 1 h. The reaction mixture was filtered through a plug of celite and the filtrate was extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1: 1) to provide 3,5-dichloro-4- [3 '- (4-fluorobenzyl) -4' alcohol. -methoxyphenoxy] benzyl as an oil (0.78 g, 70%): XH NMR (300 MHz, CDC13): d 7.47 (s, 2 H), 7.16 (dd, J = 6.0, 8.7 Hz, 2 H), 7.04 ( t, J = 8.7 Hz, 2 H), 6.84 (d, J = 9.0 Hz, 1 H), 6.67 (d, J = 3.0 Hz, 1 H), 6.45 (dd, J = 5.4, 9.3 Hz, 1 H ), 5.45 (t, J = 5.7 Hz, 1 H), 4.48 (d, J = 5.7 Hz, 2 H), 3.82 (s, 2 H), 3.69 (s, 3 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (2: 3); Rf = 0.45. Step d: To a stirred solution of 3,5-dichloro-4- [3 '- (4-fluorobenzyl) -4'-methoxyphenoxy] benzyl alcohol (0.53 g, 1.29 mmol) in CH2C12 (20 mL) at -78 ° C BBr3 (0.82 g, 3.2 mmol) was added. The reaction mixture was stirred at room temperature for 16 h, emptied in ice water (100 mL) and extracted with CH2C12 (200 L). The organic layer was washed with brine, dried over Na 2 SO, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1: 4) to provide 3,5-dichloro-4- [3 '- (4-fluorobenzyl) -4' bromide. -hydroxyphenoxy] benzyl as a colorless oil (0.4 g, 67%): 1 H NMR (300 MHz, CDC13): d 7.39 (s, 2 H), 7.14 (dd, J = 5.4, 8.7 Hz, 2 H), 6.95 (t, J = 8.7 Hz, 2 H), 6.66 (d, J = 9.0 Hz, 1 H), 6.62 (d, J = 2.7 Hz, 1 H), 6.53 (dd, J = 3.0, 8.7 Hz, 1 H), 4.04 (s, 2 H), 3.90 (s, 2 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 4); Rf = 0.8. Step e: To a stirred solution of 3,5-dichloro-4- [3 '- (4-fluorobenzyl) -4-hydroxyphenoxy] benzyl bromide (0.25 g, 0.55 mmol) in toluene (5 mL) at room temperature was added. added triethylphosphite (0.91 g, 5.5 mmol). The reaction mixture was heated at 120 ° C for 8 h and cooled to room temperature. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1: 1) to provide 3,5-dichloro-4- [3 '- (4 -fluorobenzyl) -4'-hydroxyphenoxy] benzyl phosphonate diethyl ester as a colorless oil (0.2 g, 68%): 1 H NMR (300 MHz, CDC13): d 7.29 (d, J = 2.7 Hz, 2 H), 7.15 ( dd, J = 5.4, 9.0 Hz, 2 H), 6.95 (t, J = 8.7 Hz, 2 H), 6.66 (d, J = 4.8 Hz, 1 H), 6.65 (s, 1 H), 6.46 (dd) , J = 3.0, 8.7 Hz, 1 H), 4.07 (q, J = 7.2 Hz, 4 H), 3.89 (s, 2 H), 3.04 (d, J = 21.3 Hz, 2 H), 1.27 (t, J = 7.2 Hz, 3 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 1); Rf = 0.3. Step f: To a stirred solution of diethyl 3,5-dichloro-4- [3 '- (4-fluorobenzyl) -4'-hydroxyphenoxy] benzyl phosphonate (0.09 g, 0.18 mmol) in CH 2 Cl 12 (5 mL) at 0 ° C TMSBr (0.28 g, 0.3 mL) was added. The reaction mixture was stirred at 0 ° C for 30 min, allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 16 h and the solvent was removed under reduced pressure. The residue was dissolved in CH3OH (5 mL) and the solvent was removed under reduced pressure. The residue was triturated with water (3 mL), filtered and dried under reduced pressure to give 3,5-dichloro-4- [3 '- (4-fluorobenzyl) -4'-hydroxyphenoxy] benzylphosphonic acid as a white solid ( 0.075 g, 94%): mp 207-210 ° C; LCMS m / z = 457 [C20H16Cl2FO5P + H] +; Anal Calculated for (C20H? 6Cl2FO5P + 0.8 CH2C12): C, 47.78; H, 3.39. Found: C, 47.78; H, 3.39. Example 12 Compound 12-1: di (pivaloyloxymethyl) [3, 5-Dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy] methylphosphonate To a mixture of [3,5-dimethyl-4-acid] (4 '-hydroxy-3'-iso-propylbenzyl) -phenoxy] methylphosphonic acid (0.2 g, 0.5 mmol) and N, N-diisopropylethylamine (0.57 mL, 3.0 mmol) in CH3CN (5.0 mL) at 0 ° C was added iodide of pivaloyloxymethyl (0.6 mL, 3.0 mmol).

The reaction mixture was stirred at room temperature during 16 h and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with acetone-hexanes (1: 3) to give the title compound as a white solid. (0.22 g, 76%): H NMR (300 MHz, CD3OD): d 6.79 (d, J = 3.0 Hz, 1 H), 6.68 (s, 2 H), 6.45-6.60 (m, 2 H), 5.75 (m, 4 H), 4.44 (d, J = 9.9 Hz, 2 H), 3.88 (s, 2 H), 3.20 (m, 1 H), 2.20 (s, 6) H), 1.20 (s, 18 H), 1.12 (d, J = 7.2 Hz, 6 H); LC-MS m / z = 593 [C3? H4509P + H] +; Anal. Calculated for (C31H45O9P + 0.3 H20): C, 62.26; H, 7.69. Found: C, 62.15; H, 7.77. Using the appropriate starting material, compounds 12-2 and 12-9 were prepared in an analogous manner as described by the synthesis of compound 12-1.

Compound 12-2: Di (ethoxycarbonyloxymethyl) [3, 5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy] methylphosphonate: 1 H NMR (300 MHz, DMSO-d 6): d 9.01 (s, 1 H), 6.86 (s, 1 H), 6.73 (s, 2 H), 6.63-6.61 (m, 1 H), 6.47-6.45 (m, 1 H), 5.72 (s, 2 H) , 5.68 (s, 2 H), 4.51-4.48 (d, J = 7.5 Hz, 2 H), 4.17-4.12 (m, 4 H), 3.82 (s, 2 H), 3.13 (m, 1 H), 2.18-2.16 (m, 6 H), 1.23-1.18 (m, 6 H), 1.12-1.10 (d, J = 6.0 Hz, 6 H); LC-MS m / z = 569 [C27H370nP + H] +; Anal. Calculated for (C27H370nP): C, 57.04; H, 6.56. Found: C, 56.60, H, 6.14.

Compound 12-3: Di (isopropoxycarbonyloxymethyl) [3, 5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy] methylphosphonate: aH NMR (300 MHz, DMSO-d6): d 8.97 (s, 1 H), 6.81 (s, 1 H), 6.69 (s, 2 H), 6.59-6.56 (m, 1 H), 6.43-6.40 (m, 1 H), 5.68 (s, 2 H) , 5.63 (s, 2 H), 4.81-4.73 (m, 2 H), 4.46-4.43 (d, J = 7.5 Hz, 2 H), 3.78 (s, 2 H), 3.12-3.07 (, 1 H) , 2.14 (s, 6 H), 1.21-1.16 (, 12 H), 1.08-1.06 (d, J = 6.0 Hz, 6 H); LC-MS m / z = 597 [C 29 H 4? OnP + H] +; Anal. Calculated for (C29H4? OnP): C, 58.38; H, 6.93. Found: C, 58.10, H, 7.54. Compound 12-4: Di- (pivaloyloxymethyl) [3, 5-dimethyl-4- (4'-hydroxy-3'-sec-butylbenzyl) phenoxy] methylphosphonate: XH NMR (300 MHz, DMS0-d6): d 8.95 ( s, 1H), 6.76 (s, 1H), 6.72 (s, 2H), 6.64-6.61 (d, 1H), 6.65-6.47 (d, 1H), 5.73 (s, 2H), 5.68 (s, 2H) , 4.48-4.45 (d, 2H), 3.81 (s, 2H), 2.93-2.90 (q, 1H), 2.17 (s, 6H), 1.52-1.44 (m, 2H), 1.17-1.11 (m, 18H) , 1.08-1.06 (d, 3H), 0.78-0.73 (t, 3H); LC-MS m / z = 607.2 [C32H4709P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (3: 7); Rf = 0.56; Anal. Calculated for (C32H4709P + 0.25 C3H60): C, 63.32; H, 7.87. Found: C, 63.72; H, 8.19. Compound 12-5: Di- (pivaloyloxymethyl) [3, 5-dibromo-4- (4'-hydroxy-3'-iso-propylphenoxy) benzyl] phosphonate: mp: 90-91 ° C; aH NMR (300 MHz, DMSO-d6): d 9.07 (s, 1H), 7.66 (s, 1H), 6.68-6.66 (m, 2H), 6.26-6.22 (d, 1H), 5.67-5.58 (q, 4H), 3.56-3.48 (d, 2H), 3.19-3.14 (m, 1H), 1.19-1.11 (m, 24H); LC-MS m / z = 709.4 [C28H37Br209P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (3: 7); Rf = 0.50; Anal. Calculated for (C28H37Br209P): C, 47.48; H, 5.26. Found: C, 47.09; H, 4.87. Compound 12-6: Di- (pivaloyloxymethyl) [3, 5-dimethyl-4- (3 '- (4-fluorobenzyl) -4'-hydroxy-benzyl) phenoxy] methylphosphonate: 1 H NMR (300 MHz, DMSO-d 6) : d 9.17 (1H, s), 7.18-7.02 (m, 3H), 6.71-6.64 (m, 4H), 6.54 (, 1H), 4.45 (d, 2H, J = 10Hz), 3.76 (s, 4H), 2.12 (s, 6H), 1.13 (s, 18H); LC-MS m / z = 633 [C33H 09P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 50% ethyl acetate in hexane; Rf = 0.48; Anal. Calculated for (C33H44F09P + 0.5 H20): C, 62.99; H, 6.90. Found: C, 62.99; H, 6.90. Compound 12-7: Di (pivaloyloxymethyl) [3, 5-diiodo-4- (4'-hydroxy-3'-iso-propylphenoxy) phenoxy] methylphosphonate mp: 144-147 ° C; a H NMR (300 MHz, DMSO-d 6): d 8.99 (s, 1 H), 7. 59 (s, 2 H), 6.68 (m, 1 H), 6.56 (m, 1 H), 6.25 (m, 1 H), 5.73 (d, J = 12.0 Hz, 2 H), 4.64 (d, J) = 10.5 Hz, 2 H), 3.16 (, 1 H), 1.17 (m, 18 H), 1.12 (d, J = 6.0 Hz, 6 H); LC-MS m / z = 819 [C 28 H 37 O 10 I 2 P + H] +; CLAR conditions: Column = Agilent Zorbax SB-Aq RP-18 filter, 150 x 3.0; Mobile Phase = Solvent A (Acetonitrile) = Acetonitrile grade CLAR; Solvent B (buffer) = 20 M ammonium phosphate buffer solution (pH 6.1, 0.018 M NH4H2PO4 / 0.002 M (NH) 2HP04). Flow ratio = 1.0 mL / min; UVT255 nm. Retention time in minutes, (rt = 14.66 / 25.00, 93% purity); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 1); Rf = 0.39. Compound 12-8: Di (pivaloyloxymethyl) [3,5-dichloro-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy a H NMR (200 MHz, DMSO-d 6): d 9.09 (s, 1 H ), 7.21 (s, 2 H), 6.94 (s, 1 H), 6.64 (s, 2 H), 5.72 (d, J = 21.0 Hz, 2 H), 4.64 (d, J = 15 Hz, 2 H), 4.00 (s, 2 H), 3.15 (m, 1 H), 1.25 (m, 18 H), 1.11 (d, J = 4.5 Hz, 6 H); LC-MS m / z = 633 [C29H3909C12P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (3: 2); Rf = 0.62. Anal. Calculated for (C29H3909C12P + 0.3 H20 + 0.2 CH3C02CH2CH3): C, 54.49; H, 6.32. Found: C, 54.52, H, 6.33; Compound 12-9: Di (pivaloyloxymethyl [4,6-dichloro-3-fluoro-5- (4'-hydroxy-3'-iso-propylphenoxy) -pyrid-2-ylamino] methylphosphonate The title compound was prepared in accordance with the procedure described for the synthesis of example 12 using [4,6-dichloro-3-fluoro-5- (4'-hydroxy-3'-iso-propylphenoxy) -pyrid-2-ylamino] methylphosphonic acid (US 6747048 B2) : X H NMR (200 MHz, DMSO-d 6): d 9.20 (s, 1 H), 7.54 (t, J = 6.0 Hz, 1 H), 6.80 (d, J = 3.4 Hz, 1 H), 6.68 (d , J = 8.8 Hz, 1 H), 6.44 (dd, J = 3.4, 8.8 Hz, 1 H), 5.62 (d, J = 12.4 Hz, 4 H), 3.97 (, 2 H), 3.22 (m, 1 H), 1.07-1.17 (m, 24 H); CCD Conditions: Silica gel uniplaca, 250 microns; Mobile phase = ethyl acetate-hexanes (3: 2); Rf = 0.51; LC-MS m / z = 654 [C27H36C12FN209P + H] + Anal Calculated for (C27H36C12FN209P + 0.2Et2? Ac): C, 49.76; H, 5.65; N, 4.17. Found: C, 50.02; H, 6.02; N, 4.07.Example 13 Cis and Trans (S) -2- [(3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy) methyl] -4- (3-chlorophenyl) ) -2-oxo-2? 5- [1,3,2] -dioxaphosphonane To a mixture of [4- (4'-hydroxy-3'-iso-propylbenzyl) -3,5-dimethylphenoxy] methylphosphonic acid (0.2 g, 0.55 mmol), 1- (3-chlorophenyl) -1,3-propane diol (0.31 g, 1.6 mmol) and pyridine (1 mL) in DMF (5 mL) at room temperature was added 1,3-dicyclohexylcarbodiimide ( 0.34 g, 1.6 mmol). The reaction mixture was heated at 70 ° C for 4 h, cooled to room temperature and filtered through a plug of celite. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel, eluting with 4% methanol in CH2C12 to give Cis (0.06 g, 15%) and Trans (S) -2- [3, 5-Dimethyl-4- (4 '-hydroxy-3' -isopropylbenzyl) phenoxy] methyl 1-4- (3-chlorophenyl) -2-oxo-1,3,2-dioxaphosphonane (0.05 g, 12%) as white solids. Compound 13-1-cis: mp 77-82 ° C; LC-MS m / z = 516 [C28H32C105P + H] +; Anal. Calculated for (C 28 H 32 ClO 5 P + 0.2 H 20): C, 64.85; H, 6.30. Found: C, 64.93; H, 6.65. P.F: 77-82.0 ° C. Improved alternative method for the preparation of the compound: Compound 13-1-cis: Cis (S) -2- [(3,5-Dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy) ethyl] -4- (3-Chlorophenyl) -2-oxo-2? 5- [1,3,2] -dioxaphosphinan: A solution of cis (S) -2- [(4- (4'-acetoxy-3 '- iso-propylbenzyl) -3, 5-dimethylphenoxy) methyl] -4- (3-chlorophenyl) -2-oxo-2? 5- [1, 3, 2] -dioxaphosphonane (compound 59-cis, 2.5 g, 4.49 mmol) and 4.0 M HCl in dioxane (2.5 mL, 10.0 mmol) in methanol (25 mL) was stirred at 20 ° C for 3.5 hrs. The solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with acetone-dichloromethane (1: 4) to give cis (S) -2- [(3,5-dimethyl-4- (4'-hydroxy-3 '-iso-propylbenzyl) phenoxy) methyl-4- (3-chlorophenyl) -2-oxo-2? 5- [l, 3,2] -dioxaphosphinan (1.9 g, 83%): 1 H NMR (300 MHz, DMS0 -d6): d 8.97 (s, 1H), 7.47 (m, 1H), 7.38-7.31 (, 3H), 6.82 (d, J = 2.1 Hz, 1H), 6.73 (s, 2H), 6.59 (d, J = 8.1 Hz, 1H), 6.43 (dd, J = 8.1 and 2.0 Hz, 1H), 5.76-5.71 (m, 1H), 4. 61-4.36 (m, 4H), 3.78 (s, 2H), 3.15-3.05 (m, 1H), 2.24-2.17 (m, 2H), 2.14 (s, 6H), 1.07 (d, J = 6.9 Hz, 6H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = dichloromethane-acetone (9: 1); Rf = 0.28; Anal Calculated for (C28H32C105P + 0.2 H20): C, 64.85; H, 6.30. Found: C, 64.64; H, 6.36. water by titration KF = 0.66%. Compound 13-1-trans: mp 88-93 ° C; LC-MS m / z = 516 [C28H32C105P + H] +; Anal. Calculated for (C28H32C105P + 0.2 H20): C, 64.85; H, 6.30. Found: C, 64.93; H, 6.65.

P.F: 88-93.0 ° C. Using the appropriate starting material, the compounds 13-2 through 13-14 were prepared in an analogous manner as described by the synthesis of compound 13-1. Cis y_ Trans 2- [(3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy) methyl] -4- (3-bromophenyl) -2-oxo-2? 5- [ 1,3,2] -dioxaphosphonane: Compound 13-2-cis: mp 70-75 ° C; LC-MS m / z = 559, 561 [C28H32Br05P + H] +; Anal. Calculated for (C28H32Br05P): C, 60.12; H, 5.77. Found: C, 60.03, H, 5.76; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 3: 2 hexanes-acetone; rf = 0.31. Compound 13-2-trans: mp 80-85 ° C; LC-MS m / z = 559, 561 [C28H32Br05P + H] +; Anal. Calculated for (C28H32Br05P): C, 60.12; H, 5.77. Found: C, 59.76, H, 5.72; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 3: 2 hexanes-acetone; rf = 0.49.

Cis y_ Trans 2- [(3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy) methyl] -4- (3-fluorophenyl) -2-oxo-2? 5- [ 1,3,2] -dioxaphosphonane: Compound 13-3-cis: mp 75-80 ° C; LC-MS m / z = 499 [C28H32F05P + H] +; Anal. Calculated for (C28H32F05P + 0.2 EtOAc): C, 67.02; H, 6.56. Found: C, 67.01, H, 6.58; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile Phase = 3: 2 acetone-hexanes; rf = 0.19. Compound 13-3-trans: mp 80-85 ° C; LC-MS m / z = 499 [C28H32F05P + H] +; Anal. Calculated for (C28H32F05P + 0.2 EtOAc): C, 67.02; H, 6.56. Found: C, 66.93, H, 6.61; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile Phase = 3: 2 acetone-hexanes; rf = 0.52. Cis and Trans 2- [(3,5-dimethyl-4- (4 '-hydroxy-3'-iso-propylbenzyl) phenoxy) methyl] -4- (pyrid-3-yl) -2-oxo-2? 5 - [1,3,2] -dioxaphosphonane: Compound 13-4-trans: mp 75-78 ° C: LC-MS m / z = 482 [C27H32N05P + H] +; Anal Calculated for C27H32N05P: C, 67.35; H, 6.70; N, 2.91. Found: C, 67.17; H, 6.89; N, 2.62; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = CH2Cl2-MeOH (2%); Rf = 0.3. Compound 13-4-cis: (108 mg, 50%): mp 75-78 ° C; LC-MS m / z = 482 [C27H32N05P + H] +; Anal Calculated for C27H32N05P: C, 67.35; H, 6.70, N, 2.91. Found: C, 67.78; H, 6.76; N, 2.63; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = CH2Cl2-MeOH (2%); Rf = 0.27. Cis and Trans 2- [(3,5-dimethyl-4- (4 '-hydroxy-3'-iso-propylbenzyl) phenoxy) methyl] -4-pyrid-4-yl) -2-oxo-2? 5- [1,3,2] -dioxaf osf onan: Compound 13-5-trans: (52%), mp 75-77 ° C; LC-MS m / z = 482 [C27H32N05P + H] +; Anal Calculated for (C27H32N05P + 0.4 H20): C, 66.35; H, 6. 76; N, 2.87. Found: C, 66.08; H, 6.55; N, 2.74; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = CH2Cl2-MeOH (2%); Rf = 0.3. Compound 13-5-cis: (20%), mp 75-77 ° C; LC-MS m / z = 482 [C27H32N05P + H] +; Calculated Analysis: (MF: C27H32N05P) Calculated: C: 67.35, H: 6.70, N: 2.91; Found: C: 67.02, H: 6.78, N: 2.81; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = CH2Cl2-MeOH (2%); Rf = 0.25. Cis and Trans 2- [(3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy) methyl] -4- (4-chlorophenyl) -2-oxo-2? 5- [ 1, 3, 2] -dioxaf osf onan: Compound 13-6-trans: mp 77-80 ° C; LC-MS m / z = 515 [C28H32C105P] +; Anal Calculated: (MF: C28H32ClO5P + 0.1 H2O + 0.4 EtOAc) Calc'd: C: 64.34, H: 6.48; Found: C: 64.56, H: 6.91; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate / hexanes (3: 2); Rf = 0.6. Compound 13-6-cis: yellow solid, mp 77-80 ° C; LC-MS m / z = 515 [C28H32C105P + H] +; Anal Calculated: (MF: C28H32ClO5P + 0.1 H2O + 0.1 CH2C12) Calculated: C: 64.65, H: 6.25; Found: C: 64.61, H: 6.66; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate / hexanes (3: 2); Rf = 0.5 Cis and Trans 2- [(3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy) methyl] -4- (3,5-dichlorofenyl) -2-oxo-2? 5- [1,3,2] -dioxaf osf onan: Compound 13-7-trans: mp 79-81 ° C; LC-MS m / z = 549 [C27H32C1205P + H] +; Anal Calculated for (C28H3? Cl205P + 0.35 H20): C, 60.45; H, 5.74; Cl, 12.87. Found: C, 60.15; H, 5.67, Cl, 11.97; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate / hexanes (3: 2); Rf = 0. 6. Compound 13-7-cis: (50%), mp 79-81 ° C; LC-MS m / z = 549 [C28H3? Cl205P] +; Anal Calculated for (C28H? Cl205P + 0.1 H20): C, 60.94; H, 5.70; Cl, 12.97. Found: C, 60.77; H, 6.18; Cl, 11. 56; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (3: 2); Rf = 0. 5. Compound 13-8: Cis- (S) -2- [(3,5-dimethyl-4- (4'-hydroxy-3'-sec-butylbenzyl) phenoxy) methyl] -4- (3-chlorophenyl) -2-oxo-2? 5- [1,3,2] -dioxaphosphonane: mp: 66-70 ° C; 2 H NMR (300 MHz, DMS0-d 6): d 8.91 (s, 1 H), 7.39-7.36 (, 3 H), 6.76 (s, 1 H), 6.75 (s, 2 H), 6.60-5.57. (d, 1H), 6.47-6.44 (d, 1H), 5.75-5.71 (m, 1H), 4.61-4.53 (m, 2H), 4.47-4.36 (m, 2H), 3.78 (s, 2H), 2.92 -2.85 (q, 1H), 2.25-2.20 (m, 2H), "2.14 (s, 6H), 1.51-1.36 (, 2H), 1.05-1.03 (d, 3H), 0.74-0.70 (t, 3H); LC-MS m / z = 529.0 [C29H34C105P + H] +; CCD Conditions: Silica gel uniplaca, 250 microns; Mobile phase = hexanes-ethyl acetate (1: 1); Rf = 0.17; Anal. (C29H34C105P + 0.3 CH3C02CH2CH3 + 0.4 H20): C, 64.47; H, 6.66. Found: C, 64.64; H, 6.82, Compound 13-9: Cis- (S) -2- [3, 5-dibromo-4- (4 '-hydroxy-3' -iso-propylphenoxy) benzyl] -4- (3-chlorophenyl) -2-oxo 2? 5- [1,3,2] -dioxaphosphonane: mp: 83-85 ° C; XH NMR (300 MHz, DMSO-d6): d 9.06 (s, 1H), 7.75 (s, 2H), 7.44-7.42 (m, 3H), 7.32-7.28 (m, 1H), 6.68-6.65 (d, 1H) , 6.58 (s, 1H), 6.31-6.27 (d, 1H), 5.69-5.65 (d, 1H), 4.59-4.51 (t, 1H), 4.37-4.28 (t, 1H), 3.61-3.53 (d, 2H), 3.18-3.07 (m, 1H), 2.29-2.17 (m, 1H), 1.84-1.77 (, 1H), 1.07-1.03 (d, 6H); LC-MS m / z = 630.8 [C25H24Br2C105P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (1: 1); Rf = 0.56; Anal. Calculated for (C25H24Br2C105P): C, 47.61; H, 3.84. Found: C, 47.88; H, 4.23. Compound 13-10: Cis (S) -2- [(3,5-diiodo-4- (4'-hydroxy-3'-iso-propylphenoxy) phenoxy) methyl] -4- (3-chlorophenyl) -2- oxo-2- [1, 3, 2] -dioxaphosphonane mp: 82-86 ° C; 2 H NMR (300 MHz, DMS0-d 6): 1 H NMR (300 MHz, DMSO-d 6): d 8.99 (s, 1 H), 7.62 (s, 1 H), 7.51 (m, 1 H), 7.44 (s) , 2 H), 7.38 (, 3 H), 6.68 (m, 1 H), 6.60 (s, 1 H), 6.25 (m, 1 H), 5.80 (m, 1 H), 4.65 (m, 3 H) ), 4.45 (m, 1H), 3.16 (m, 1 H), 2.26 (m, 1 H), 1.13 (d, J = 6.0 Hz, 6 H); LC-MS m / z = 741 [C25H24C1I206P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (4: 1); Rf = 0.17. Anal. Calculated for (C25H2 C1I206P + 0.2 CH3C02CH2CH3): C, 40.86; H, 3.40. Found: C, 41.02, H, 3.49. Compound 13-11: Cis (S) -2- [(3,5-dichloro-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy) methyl] -4- (3-chlorofenyl) -2 -oxo-2? 5- [1,3,2] -dioxaf osf onan X NMR (300 MHz, DMSO-d6): d 9.10 (s, 1 H), 7.43 (s, 1 H), 7.38-7.31 ( m, 4 H), 7.24 (m, 1 H), 6.97 (s, 1 H), 6.64 (s, 2 H), 5.75 (m, 1 H), 4.69-4.61 (m, 2 H), 4.50- 4.41 (m, 2 H), 4.05 (s, 2 H), 3.12 (m, 1 H), 2.21 (s, 2 H), 1.11 (d, J = 9.0 Hz, 6 H); LC-MS m / z 554 [C26H26C1305P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (4: 1); Rf = 0.24. Anal. Calculated for (C26H2eCl305P + 0.5 H20 + 0.2 CH3C02CH2CH3): C, 55.27; H, 4.95. Found: C, 55.21, H, 4.96. Cis and Trans 2- [4,6-dichloro-3-fluoro-5- (4 '-hydroxy-3' -iso-propyl-enoxy) -pyrid-2-ylaminomethyl] -4- (3-chlorofenyl) -2 -oxo-2? 5- [1,3,2] -dioxaphosphonane To a stirred solution of [4,6-dichloro-3-f-luoro-5- (4'-hydroxy-3'-iso-propyl-enoxy) - pyrid-2-ylamino] methylf osfonic (0.2 g, 0.47 mmol, US, 6747048 B2) and (S) -1- (3-chlorophenyl) -1,3-propandiol (0.18 g, 0.94 mmol) in DMF (6 L) at room temperature was added pyridine (0.46 mL, 5.64 mmol) and EDCI (0.27 g, 1.41 mmol). The reaction mixture was stirred at 68 ° C for 16 hrs. The solvent was removed under reduced pressure, and the residue was partitioned between EtOAc and water. The organic layer was dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate to provide: Compound 13-12-trans: (60 mg, 22%): X NMR (300 MHz, DMSO-de): d 9.20 (s, 1 H), 7.67 (t, J = 6.0 Hz, 1 H), 7.36-7.48 (m, 4 H), 6.81 (d, J = 3.0 Hz, 1 H), 6.69 (d, J = 9.0 Hz, 1 H), 6.44 (dd, J = 3.0, 9.0 Hz, 1 H), 5.78 (t, J = 7.5 Hz, 1 H), 4.71 (m, 1 H), 4.45 (m, 1 H), 4.11 (m, 2 H), 3.17 (m, 1 H), 2.19 (s, 1 H), 1.14 (d, J = 6.9 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (2: 1); Rf = 0.44; LC-MS m / z = 576 [C 24 H 23 C 13 FN 205 P + H] +; Anal Calculated for (C24H23C13FN205P + 0.2 CH2C12 + 0.3 H20): C, 48.58; H, 4.04; N, 4.68. Found: C, 48.64; H, 3.66; N, 4.83. Compound 13-12-cis: (90 mg, 33%): aH NMR (200 MHz, DMSO-d6): d 9.20 (s, 1 H), 7.67 (t, J = 6.0 Hz, 1 H), 7.21- 7.37 (m, 4 H), 6.71 (d, J = 3.0 Hz, 1 H), 6.63 (d, J = 9.0 Hz, 1 H), 6.34 (dd, J = 3.0, 9.0 Hz, 1 H), 5.65 (d, J = 10.4 Hz, 1 H), 4.21- 4.61 (, 2 H), 4.11 (, 1 H), 3.80 (, 1 H), 3.07 (m, 1 H), 2.11 (, 1 H), 1.88 (m, 1 H), 1.04 (m, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate; Rf = 0.53; LC-MS m / z = 576 [C 24 H 23 C 13 FN 205 P + H] +; Anal Calculated for (C24H23C13FN205P + 0.1 CH2C12 + 0.4H2O): C, 48.94; H, 4.09; N, 4.74. Found: C, 48.57; H, 3.69; N, 4.92. Cis and trans 2- [(3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy) methyl] -4,4-dimethyl-6- (3-chlorophenyl) -2-oxo -2? 5- [1,3,2] -dioxaphosphonane: Preparation of 1- (3-chloro-phenyl) -3-methyl-butane-1,3-diol: Step a: To a solution of diisopropyl amine ( 12.4 L, 88.2 mmol) in THF (50 mL) at -78 ° C was added n-butyllithium (35.3 mL, 88.2 mmol). The reaction mixture was stirred at -78 ° C for 30 min, at which time ethyl acetate (16.1 mL, 163.2 mmol) was added. After 1 h, 3-chloro benzaldehyde was added and the reaction mixture was allowed to warm to room temperature for 2 h. The reaction mixture was quenched with aqueous NH4C1 (20 mL) and extracted with ethyl acetate (2 x 20 mL). The organic layer was rinsed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give yellow oil. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1: 4) to provide ethyl 3- (3-chloro-phenyl) -3-hydroxypropionate as a yellow oil ( 10.0 g, 99.0%). X NMR (400 MHz, d-DMSO): d 7.43-7.30 (m, 4H), 5.66 (d, 1H), 5.01-4.95 (q, 1H), 4.14-4.04 (m, 2H), 2.71-2.58 ( m, 2H), 1.24-1.17 (t, 3H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 3); Rf = 0.50. Step b: To a solution of ethyl 3- (3-chloro-phenyl) -3-hydroxy-propionate (10.0 g, 44.1 mmol) in THF (100 L) and diethyl ether (100 mL) at -78 ° C. Magnesium methyl bromide was added (61.7 mL of a 3.0 M solution in diethyl ether, 185.1 mmol). The reaction mixture was allowed to warm to room temperature and stirring for 16 h. The reaction mixture was cooled to -50 ° C and quenched with aqueous NHC1 (20 mL), and extracted with diethyl ether (2 x 20 mL). The organic layer was rinsed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1: 3) to give l- (3-chloro-phenyl) -3-methyl-butane-1,3-diol as a yellow oil (5.65 g, 59.7%). 2 H NMR (400 MHz, d-DMSO): d 7.40-7.26 (m, 4H), 5.46 (d, 1H), 4.90-4.85 (q, 1H), 4.70 (s, 1H), 1.75-1.62 (m, 2H), 1.23-1.22 (d, 3H), 1.19-1.18 (d, 3H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 3); Rf = 0.32. Compound 13-13-cis: Cis 2- [(3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy) methyl] -4,4-dimethyl-6- (3-chlorophenyl) ) -2-oxo-2? 5- [1,3,2] -dioxaphosphonane: x NMR (400 MHz, d-DMSO): d 9.05 (s, 1 H), 7.59 (s, 1 H), 7.47-7.43 (m, 3H), 6.91 (s, 1H), 6.81 (s, 2H), 6.68-6.65 (d, 1H), 6.53-6.50 (d, 1H), 5.92-5.87 (t, 1H), 4.54-4.40 (m, 2H), 3.87 (s, 2H), 3.23-3.14 (q, 1H), 2.55-2.23 (m, 8H), 1.69 (s, 3H), 1.44 (s, 3H), 1.17-1.14 (d , 6H); LC-MS m / z = 544.8 [C 30 H 36 ClO 5 P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (1: 1); Rf = 0.16; Anal. Calculated for (C3oH3eC105P + 1.0 CH3C02CH2CH3): C, 64.70; H, 7.03; Found: C, 64.50; H, 7.32. Compound 13-13-trans: Trans 2- [(3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy) ethyl] -4,4-dimethyl-6- (3-chloro) enyl) -2-oxo-2? 5- [1,3,2] -dioxaf osf onan: LC-MS m / z = 544.8 [C3oH36C105P + H] +; 1 H NMR (400 MHz, d-DMSO): d 9.00 (s, 1 H), 7.54 (s, 1 H), 7.49-7.44 (m, 3 H), 6.86 (s, 1 H), 6.79 (s, 2 H), 6.63-6.60 (d, 1H), 6.46-6.43 (d, 1H), 5.85-5.82 (t, 1H), 4.46-4.43 (d, 2H), 3.82 (s, 2H), 3.16-3.11 (q, 1H) ), 2.28-2.25 (d, 2H), 2.18 (s, 6H), 1.62 (s, 3H), 1.47 (s, 3H), 1.12-1.10 (d, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (1: 1); Rf = 0.27; Anal. Calculated for (C30H36ClO5P + 1.4 CH3C02CH2CH3): C, 64.17; H, 7.14; Found: C, 64.06; H, 6.98. Cis and trans (S) 2- [(3,5-dimethyl-4- (3 '- (4-fluorobenzyl) -4'-hydroxybenzyl) phenoxy) methyl] -4- (3-chlorophenyl) -2-oxo- 2? 5- [1, 3, 2] -dioxaphosphonane]: Compound 13-14-cis: Cis (S) 2- [(3,5-dimethyl-4- (3 '- (4-fluorobenzyl) -4' -hydroxybenzyl) phenoxy) methyl] -4- (3-chlorophenyl) -2-oxo-2? 5- [1,3,2] -dioxaphosphonanol: (0.041 g, 14%); 2 H NMR (300 MHz, CD 3 OD): d 7.46 (s, 1 H), 7.28 (m, 3 H), 7.11-6.91 (m, 4 H), 6.63 (m, 5 H), 5.72 (d, 1 H, J = 11.4 Hz ), 4.71 (m, 1H), 4.51 (m, 3H), 3.84 (, 4H), 2.44 (m, 1H), 2.22 (m, 1H), 2.15 (s, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 25% hexane in ethyl acetate; Rf = 0.21; LC-MS m / z = 582 [C 32 H 4? ClF05P + H] +; Anal Calculated for (C32H4? ClF05P + 0.5 H20): C, 65.14; H, 5.47. Found: C, 65.31; H, 5.67. Compound 13-14-trans: Trans (S) 2- [(3,5-dimethyl-4- (3 '- (4-fluorobenzyl) -4' -hydroxybenzyl) phenoxy) methyl] -4- (3-chlorophenyl) -2-oxo-2? 5- [1,3,2] -dioxaphosphonane]: (0.030 g, 10%); X H NMR (300 MHz, CD30D): d 7.46 (s, 1H), 7.28 (m, 3H), 7.11-6.91 (m, 4H), 6.63 (m, 5H), 5.86 (d, 1H, J = 11.4 Hz ), 4.57 (m, 4H), 3.84 (m, 4H), 2.34 (m, 1H), 2.25 (, 1H), 2.15 (s, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 25% hexane in ethyl acetate; Rf = 0.41; LC-MS m / z = 582 [C32H41C1F05P + H] +; Anal Calculated for (C32H4? ClF05P + 0.5 H20): C, 65.14; H, 5.47. Found: C, 65.24; H, 5.77.

Example 14 Compound 14: di (S-acetyl-2-thioethyl) [3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl)] phenoxy] methylphosphonate A mixture of S-acetyl-2- thioethanol (0.12 g, 0.96 mmol), acid [3, 5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy] methylphosphonic acid (0.10 g, 0.25 mmol), pyridine (1.0 L) and dicyclohexylcarbodiimide (0.14 g, 0.69 mmol) in DMF (2.5 mL) ) was heated at 70 ° C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1: 1) to give di (S-acyl-2-thioethyl) [3,5-dimethyl-4- (4 ' -hydroxy-3 '-iso-propylbenzyl) phenoxy] methylphosphonate as an oil (0.09 g, 56%): LC-MS m / z = 569 [C27H3707PS2 + H] +; Anal. Calculated for (C27H3707PS2): C, 57.03; H, 6.56. Found: C, 57.02, H, 7.03; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile Phase = 2/3 hexanes / EtOAC; Phosphonic acid rf = 0.00, rf = 0.35.

Example 15 Compound 15-1: di-N- (1-1-ethoxycarbonylethylamino) [3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl)] phenoxy] methylphosphonamide To a stirred solution of acid [3,5-dimethyl-4- ('-hydroxy-3'-iso-propylbenzyl)] phenoxymethyl) phosphonic acid (1, 0.3 g, 0.8 mmol) and DMF (0.1 mL, 0.08 mmol) in 1,2-dichloroethane (10 mL) at room temperature oxalilchloride (0.55 g, 2.8 mmol) was added. The reaction mixture was heated at 50 ° C for 3 h, cooled to room temperature and concentrated under reduced pressure. To the residue at 0 ° C was added a solution of alanine ethyl ester (0.57 g, 4.3 mmol) and N, N-diispropylethylamine (0.6 mL, 4.3 mmol) in CH2C12. The reaction mixture was stirred for 14 h at room temperature and concentrated under reduced pressure. The residue was partitioned between EtOAc (50 L) and aqueous NaHCO 3 solution (100 mL). The organic layer was separated, washed with brine, dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with CH2Cl2-MeOH (95: 5) to provide Di (ethoxycarbonyl-1-ethylamino) [3,5-Dimethyl-4- (4'-hydroxy-3 '-iso-propylbenzyl)] phenoxy] methylphosphonamide as a yellow solid (175 mg, 52%): mp 48-50 ° C; LCMS miz = 563 [C29H43N207P + H] +; Analysis calculated for: (C29H43N2O7P + 0.2 CH2C12): C, 60.24; H, 7.52; N, 4.80. Found: C, 59.86; H, 8.01; N, 5.12. Using the appropriate starting material, compounds 15-2 through 15-9 were prepared in an analogous manner as described by the synthesis of compound 15-1.

Compound 15-2: di-N- (1-ethoxycarbon-l-methylethylamino) [3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) 1-phenoxy] methylphosphonamide: LC-MS m / z = 591 [C29H43N207P + H] +; Anal Calculated for (C29H43N207P + 0.2 CH2C12): C, 60.24; H, 7.52; N, 4.80.

Found: C, 59.86; H, 8.01; N, 5.12; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate / hexanes (4: 1); Rf = 0.4. Using the appropriate starting material, compound 15-3 was prepared in an analogous manner as described by the synthesis of compound 15-1.

Compound 15-3: di-N- (1-ethoxycarbonyl-2-methyl-propylamino) [3, 5-dimethyl-4- (3 '-iso-propyl-4' -hydroxybenzyl) phenoxymethylphosphonamide mp: 52-55 ° C; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (3: 1); Rf = 0.4; XH NMR (3 00 MHz, CDC13): d 6.84 (d, J = 2.1 Hz, 1 H), 6.52 (d, J = 7.2 Hz, 1 H), 6.42 (dd, J = 1.8, 4.5 Hz, 1 H ), 4.02-4.20 (, 6 H), 3.70-3.95 (m, 2 H), 3.80 (s, 2 H), 3.05- 3.35 (m, 3 H), 2.13 (s, 6 H), 1.09-1.20 (m, 9 H), 0.95 (t, J = 6.9 Hz, 3 H), 0.81 (dd, J = 2.1, 6.9 Hz, 6 H); LC-MS m / z = 619 [C33H51N207P + H] +; Analysis calculated for: (C33H5? N207P + 0.75 H20): C, 62.29; H, 8.37; N, 4.43. Found: C, 62.48; H, 8.89; N, 4.37.

Compound 15-4: di-N- (L-1-ethoxycarbonylethylamino) [3, 5-dimethyl-4- (4'-hydroxy-3'-sec-butylbenzyl) phenoxy] methylphosphonamide: XH NMR (300 MHz, DMSO- d6): d 8.94 (s, 1H), 6.77 (s, 1H), 6.64-6.61 (m, 3H), 6.51-6.48 (d, 1H), 4.87-4.75 (q, 2H), 4.09-3.99 (m , 4H), 3.81 (s, 2H), 2.95-2.88 (q, 1H), 2.17 (s, 6H), 1.57-1.37 (m, 2H), 1.31-1.29 (d, 6H), 1.26-1.16 (m , 4H), 1.08-1.06 (d, 3H), 0.78-0.73 (t, 3H); LC-MS m / z = 577.6 [C 30 H 45 N 2 O 7 P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (1: 1); Rf = 0.58; Anal. Calculated for (C30H45N2O7P + 1.1H20): C, 60.41; H, 7.98; N, 4.70. Found: C, 60.12; H, 7.58; N, 4.49.

Compound 15-5: di-N- (L-1-ethoxycarbonylethylamino) [3, 5-dibromo-4- (4'-hydroxy-3'-iso-propylphenoxy) benzyl] phosphonamide: XH NMR (300 MHz, DMSO- d6): d 9.08 (s, 1H), 7.68 (s, 2H), 6.69-6.66 (d, 1H), 6.63 (s, 1H), 6.31-6.28 (d, 1H), 4.76-4.61 (q, 2H) ), 4.09-4.01 (m, 8H), 3.17-3.08 (q, 1H), 1.27-1.10 (m, 18H); LC-MS m / z = 679.4 [C26H35Br2N207P + H +; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = dichloromethane-ethyl acetate (1: 1); Rf = 0.34; Anal. Calculated for (C26H35Br2N207P + 0.6 CF3C02H): C, 43.92; H, 4.84; N, 3.78. Found: C, 43.51; H, 4.78; N, 4.26.

Compound 15-6: di-N- (L-1-ethoxycarbonylethylamino) [4,6-dichloro-3-fluoro-5- (4'-hydroxy-3'-iso-propylphenoxy) -pyrid-2-ylamino] methylphosphonamide To a stirred suspension of [4,6-dichloro-3-fluoro-5- (4'-hydroxy-3'-iso-propylphenoxy) -pyrid-2-ylamino] methylphosphonic acid (0.11 g, 0.26 mmol, US 6747048 B2) and L-alanine (0.16 g, 10.4 mmol) at room temperature in pyridine (2 mL) was added TEA (0.14 mL, 1.04 mmol), followed by a fresh prepared solution of aldritium-2 (0.25 g, 1.12 mmol) and PPh3 (0.29 g, 1.12 mmol) in pyridine (2 mL). The reaction mixture was stirred at 85 ° C for 16 hrs. The solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate to give the title compound as a yellow foam (40 mg, 25%): X H NMR (300 MHz, DMSO-d 6): d 9.20 (s, 1 H), 6.99 (t, J = 6.0 Hz, 1 H), 6.78 (d, J = 3.0 Hz, 1 H), 6.68 (d, J = 9.0 Hz, 1 H), 6.46 (dd, J = 3.0, 9.0 Hz, 1 H), 4.86 (m, 1 H), 4.66 (m, 1 H), 4.07 (m, 4 H), 3.83 (m, 2 H), 3.44 (m, 2 H) , 3.16 (m, 1 H), 1.11-1.27 (m, 18 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate; Rf = 0.54; LC-MS m / z = 624 [C25H34C12FN407P + H] +; Anal Calculated for (C25H34C12FN407P): C, 48.16; H, 5.50; N, 8.99. Found: C, 47.99; H, 5.26; N, 8.77.

Compound 15-7: Di-N- (1-1-ethoxycarbonylethylamino) [3,5-dichloro-4- (4'-hydroxy-3'-iso-propylbenzyl)] phenoxy] methylphosphonamide 1H NMR (300 MHz, DMSO- d6): d 9.11 (s, 1 H), 7.12 (s, 2 H), 6.97 (m, 1 H), 6.66 (m, 2 H), 4.89 (m, 2 H), 4.22 (m, 2 H) ), 4. 05-3.93 (m, 8 H), 3.14 (m, 1 H), 1.28 (m, 6 H), 1.16 (m, 12 H); LC-MS m / z = 603 [C 27 H 33 C 12 N 207 P + H] +; Anal. Calculated for (C27H33C12N207P + 0.5 H20): C, 52.95; H, 6.25; N, 4.57.

Found: C, 52.97; H, 6.32; N, 4.71; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (4: 1); Rf = 0.26.

Compound 15-8: Di-N- (1-1-ethoxycarbonylethylamino) [3, 5-diiodo-4- (4'-hydroxy-3'-iso-propyl-f-enoxy)] phenoxy] methyl-1-phenamide-1H-NMR (300 MHz , DMSO-d6): d 8.99 (s, 1 H), 7.50 (s, 2 H), 6.68 (m, 1 H), 6.56 (m, 1 H), 6.25 (m, 1 H), 4.87 (m , 2 H), 4.18 (m, 2 H), 4.06-3.95 (m, 6 H), 3.17 (m, 1 H), 1.32 (m, 6 H), 1.21-1.11 (m, 12 H); LCMS m / z = 789 [C26H35I2N208P + H] +; Anal. Calculated for (C26H35I2N208P + 0.1H20): C, 39.52; H, 4.49; N, 3.55. Found: C, 39.49; H, 4.50; N, 3.46; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (1: 1); Rf = 0.13. Compound 15-9: Di-N- (1-1-ethoxycarbonylethylamino) [3, 5-dimethyl-4- (3 '- (4-fluorobenzyl) -4' -hydroxybenzyl)] phenoxylmethylphosphonamide XH NMR (300 MHz, CD3OD) : d 7.12 (m, 2H), 7.89 (, 2H), 6.61 (m, 5H), 4.19 (dd, 2H, J = 2.4 Hz and J = 14 Hz), 4.08 (m, 5H), 3.84 (s, 2H), 3.81 (s, 2H), 2.15 (s, 6H), 2.25 (m, 1H), 2.15 (s, 6H), 1.40 (d, 6H, J = 7.5 Hz), 1.21 (m, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate; Rf = 0.18; LC-MS m / z = 629 [C33H42FN207P + H] +, Anal Calculated for (C33H42FN207P +1.1 H20): C, 61.12; H, 6.87, N, 4.32. Found: C, 60.85; H, 6.78, N, 4.72. Example 16 Compound 16: 3,5-Dichloro-4- (4'-hydroxy-3'-iso-propylphenoxy) benzylphosphonic acid Step a: To a solution of 3,5-dichloro-4- (4'-hydroxy) alcohol 3'-iso-propylphenoxy) benzyl in CH2C12 (5.0 mL) at -78 ° C is added BBr3. The reaction mixture is stirred at room temperature for 16 h, emptied in ice water and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with acetone-hexanes to provide 3,5-dichloro-4- (4'-hydroxy-3'-iso-propylphenoxy) benzyl bromide. Step b: 3, 5-Dichloro-4- (4'-hydroxy-3'-iso-propylphenoxy) benzylphosphonate diethyl was prepared from 3,5-dichloro-4- (4'-hydroxy-3 'bromide -iso-propylphenoxy) benzyl by following the procedure described in example 9, stage g. Step c: 3,5-dichloro-4- (4'-hydroxy-3'-iso-propylphenoxy) benzylphosphonic acid was prepared from 3,5-dichloro-4- (4'-hydroxy-3'-iso- diethyl propylphenoxy) benzylphosphonate following the procedure described in example 9, step h. Compound 17: [3,5-Dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy] acetic acid Compound 17 was synthesized by a literature method (G. Chiellini et al., Bioorg Med. Chem. Lett., 2000, 10, 2607) Compound 18: 3,5-dichloro-4- [4'-hydroxy-3'-iso-propyl phenoxybenzeneacetic acid Example 19 Compound 19: [3,5-Dichloro-4- (4'-hydroxy-3'-iso-propylphenoxy)] benzylphosphonic acid Step a: To a mixture of bis (4-methoxy-3-iso-propylphenyl) tetrafluoroborate ), iodonium (4.55 g, 8.88 mmol) and copper powder (0.88 g, 13.80 mmol) in CH2C12 (40.0 mL) at 0 ° C was added a solution of TEA (1.06 mL, 3.71 mmol) and 3, 5-dichloro- Methyl 4-hydroxybenzoate (1.65 g, 6.90 mmol) in dichloromethane (20.0 L). The reaction mixture was stirred at room temperature for 3 d and filtered through a plug of celite. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with acetone-hexanes (1:19) to provide 3,5-dichloro-4- (3'-iso-propyl-4). methyl methoxyphenoxy) benzoate as an orange oil (2.02 g, 80%): X NMR (300 MHz, DMS0-d6): d 8.10 (m, 1 H), 6.85 (m, 2 H), 6.50 (, 1 H), 3.90 (s, 3 H), 3.76 (s, 3 H), 3.21 (m, 1 H), 1.14 (d, J = 6.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-acetone (17: 3); Rf = 0.51. Step b: To a mixture of methyl 3,5-dichloro-4- (3'-iso-propyl-4'-methoxyfenoxy) -benzoate (1.40 g, 3.37 mmol) in THF (10.0 mL) at 0 ° C added a solution of DIBAL-H (8.12 mL, 8.12 mmol, 1.0 M solution in THF). The reaction mixture was stirred at room temperature for 16 h, quenched with cold 1N HCl and diluted with ethyl acetate. The organic layer was washed with 1 N HCl and brine, dried over MgSO, filtered and concentrated under reduced pressure to provide 4- (3'-iso-propyl-4'-methoxyphenoxy) -3,5-dichlorobenzyl alcohol as a Off white solid (0.94 g, 100%): a H NMR (300 MHz, DMSO-de): d 7.54 (s, 2 H), 6.81 (m, 2 H), 6.40 (m, 1 H), 5.51 (m , 1 H), 4.54 (d, J = 6.0 Hz, 2 H), 3.75 (s, 3 H), 3.21 (m, 1 H), 1.13 (d, J = 6.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-acetone (17: 3); Rf = 0.27. Step c: To a stirred solution of triphenylphosphine (0.42 g, 1.61 mmol) and CBr4 (0.534 g, 1.61 mmol) in diethyl ether (15.0 mL) at room temperature was added 4- (3'-iso-propyl-4) alcohol. '-methoxyphenoxy) -3,5-dichlorobenzyl (0.50 g, 1.46 mmol). The reaction mixture was stirred at room temperature for 16 h, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with acetone-hexanes (1: 9) to provide 3,5-dichloro-4- (3'-iso-propyl-4'-methoxyphenoxy) benzyl bromide. (0.320 g, 54%): 2 H NMR (300 MHz, DMSO-de): d 7.77 (s, 2 H), 6.82 (m, 2 H), 6.38 (m, 1 H), 4.75 (s, 2 H) ), 3.75 (s, 3 H), 3.22 (m, 1 H), 1.13 (d, J = 6.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-acetone (1: 4); Rf = 0.46. Step d: A mixture of 3,5-dichloro-4- (3'-iso-propyl-4'-methoxyphenoxy) benzyl bromide (0.61 g, 1.51 mmol) and triethylphosphite (0.61 g, 3.56 mmol) in DMF (2.0 mL) was heated under reflux for 4 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and brine. The organic layer was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with acetone-hexanes (3: 7) to provide 3,5-dichloro-4- (3'-iso-propyl). 4'-methoxyphenoxy) enylphosphonate diethyl ester as an oil (0.59 g, 85%): X H NMR (300 MHz, DMSO-d 6): d 7.55 (s, 2 H), 6.88 (d, J = 9.0 Hz, 1 H ), 6.75 (d, J = 3.0 Hz, 1 H), 6.43 (m, 1 H), 4.01 (m, 4 H), 3.75 (s, 3 H), 3.41 (m, 2 H), 3.22 (m , 1 H), 1.20 (m, 6 H), 1.12 (d, J = 6.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (4: 1); Rf = 0.22. Step e: To a solution of diethyl 3,5-dichloro-4- (3'-iso-propyl-4'-methoxyphenoxy) benzylphosphonate (0.59 g, 1.28 mmol) in CH 2 Cl 12 (10.0 mL) at -30 ° C added bromotrimethylsilane (2.53 mL, 19.2 mmol). The reaction mixture was stirred at room temperature for 16 h and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (25.0 mL), it was cooled to -78 ° C and to this was added BBr3 (19.0 mL, 19.0 mmol, 1.0 M solution in CH2C12). The reaction mixture was stirred at -78 ° C for 10 min, allowed to warm to room temperature and stirred for 16 h. The reaction mixture was emptied on ice, concentrated and extracted with ethyl acetate. The organic layer was washed with water (20 mL x 2), dried over MgSO and filtered. The solvent was removed under reduced pressure to provide 3,5-dichloro-4- (3'-iso-propyl-4'-hydroxyphenoxy) benzylphosphonic acid as a brown solid (0.20 g, 40%): mp: 178-181 ° C; LC-MS m / z = 391 [C 16 H 7 Cl 2? 5 P-H] "; E NMR (300 MHz, DMSO-d 6): d 9.08 (s, 1 H), 7.48 (s, 2 H), 6.72 (m, 2 H), 6.25 (m, 1 H), 3.18 (m, 1 H), 3.00 (d, J = 21.0 Hz, 2 H), 3.11 ( m, 1 H), 1.14 (d, J = 6.0 Hz, 6 H); Anal. Calculated for (C16H17C1205P + 0.2 C4H802 + 0.5 H20): C, 48.30; H, 4.73. Found: C, 48.69, H, 5.16. Using the appropriate starting material, compounds 1971 to 19-3 were prepared in an analogous manner as described by the synthesis of compound 19. Compound 19-1: [3,5-dibromo-4- (4-hydroxy-3 '-iso-propylphenoxy)] diethyl benzylphosphonate It was prepared from methyl 3,5-dibromo-4-hydroxybenzoate (J. Med. Chem. 2003, 46, 1580) according to the procedure described for the synthesis of the compound 19. MP: 145 ° C .; LCMS m / z = 536 [C2oH25Br205P + H] +; E NMR (300 MHz, CD30D): d 7.53 (s, 2 H), 6.50 (, 2 H), 6.23 (, 1 H), 3.98 (m, 4 H), 3.11 (m, 1 H), 1.21 ( m, 6 H), 1.02 (d, J = 6.0 Hz, 6 H); Anal. Calculated for (C20H25Br2O5P): C, 44.80; H, 4.70. Found: C, 45.19, H, 4.80. Compound 19-2: [3,5-dibromo-4- (4'-hydroxy-3'-iso-propylphenoxy) benzylphosphonic acid was prepared from compound 19-1 according to the procedure described for the synthesis of compound 19 stage e. mp: 76-79 ° C; LC-MS m / z = 480 [C? 6H? 7Br205P + H] +; XR NMR (300 MHz, CD3OD): d 7.52 (s, 2 H), 6.55 (m, 2H), 6.20 (m, 1 H), 3.14 (m, 1 H), 3.00 (d, J = 21.0 Hz, 2 H), 1.06 (d, J = 6.0 Hz, 6 H); CLAR conditions: Column = 3 Chromolith SpeedRODs RP-18e, 100 x 4.6 mm; Mobile Phase = Solvent A (Acetonitrile) = Acetonitrile grade CLAR; Solvent B (buffer) = 20 mM ammonium phosphate buffer solution (pH 6.1, 0.018 M NH4H2PO4 / 0.002 M (NH4) 2HP04) with 5% acetonitrile. Flow ratio = 4 mL / min; UVT255 nm. Retention time in minutes. (rt = 5.80, 96% purity). Compound 19-3: [3,5-Dimethyl-4- (4'-hydroxy-3'-iso-propylphenoxy] benzylphosphonic acid) Prepared from methyl 3,5-dimethyl-4-hydroxybenzoate in accordance with the procedure described for the synthesis of compound 19. mp: 79-82 ° C; LC-MS m / z = 351 [C18H2305P + H] +; aH NMR (300 MHz, CD3OD): d 6.93 (s, 2 H), 6.51 (m, 2 H), 6.13 (m, 1 H), 3.13 (m, 1 H), 2.98 (d, J = 21.0 Hz, 2 H), 1.96 (s, 6 H), 1.04 (d, J = 6.0 Hz, 6 H); Anal.Calcd for (C? 8H2305P + 1.2 H20): C, 58.12; H, 6.88. Found: C, 58.01; H, 7.00 Example 20 Compound 20 Acid [3,5-dimethyl- 4-N- (4 '-hydroxy-3-iso-propylphenylamino) phenoxy Step a: A solution of 4-amino-3,5-dimethylphenol (5.0 g, 36.46 mmol, Fieser, LF Organic Syntheses, Collect Vol II, 1943 , 39), imidazole (6.21 g, 77.37 mmol) and triisopropylsilyl chloride (7.70 g, 40.1 mmol) in CH2C12 (80 mL) was stirred at room temperature for 1 h.The reaction mixture was diluted with CH2C12 (100.0 mL) and washed with water and s The organic layer was dried over MgSO, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1:19) to provide 2,6-dimethyl-4-triisopropylsilanyloxyphenylamine (8.46 g, 79%): a H NMR (300 MHz , CDC13): d 6.57 (s, 2 H), 2.19 (s, 6 H), 1.23 (m, 3 H), 1.12 (m, 18 H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 9); Rf = 0.51. Step b: A mixture of Pd2 (dba) 3 (800 mg, 0.87 mmol) and BINAP (1.09 g, 1.75 mmol) in toluene (70 mL) at 100 ° C in a sealed tube was heated for 30 min. The reaction mixture was cooled to room temperature and thereto was added 2,6-dimethyl-4-triisopropylsilanyloxyphenylamine (6.15 g, 20.98 mmol) followed by 4-bromo-2-iso-propyl-l-methoxymethoxybenzene (4.0 g, 17.48 mmol. ) and potassium tert-butoxide (2.18 g, 22.72 mmol). The reaction mixture was heated at 110 ° C in a sealed tube for 16 h, cooled to room temperature and filtered through a plug of Celite. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1: 9) to give N, N- (2,6-dimethyl-4-triisopropylsilanyloxyphenyl) ) - (3-iso-propyl-4-methoxy ethoxyphenyl) amine as a yellow solid (4.8 g, 58%): XR NMR (300 MHz, CDC13): d 6.88 (d, J = 8.7 Hz, 1 H), 6.67 (s, 1 H), 6.41 (d, J = 2.7 Hz, 1 H), 6.22 (m, 1 H), 5.11 (s, 2 H), 3.52 (s, 3 H), 3.28 (m, 1 H), 2.17 (s, 6 H), 1.28 (m, 3 H), 1.15 (m, 24 H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 9); Rf = 0.70. Step c: To a solution of N, N- (2,6-dimethyl-4-triisopropylsilanyloxyphenyl) - (3-isopropyl-4-methoxymethoxyphenyl) amine (800 mg, 1.70 mmol) in THF (10.0 mL) a 0 ° C TBAF (2.55 mmol, 1.0 M in THF) was added. The reaction mixture was stirred at room temperature for 16 h, diluted with ethyl acetate (10.0 mL) and quenched with H20. (10.0 mL). The aqueous layer was extracted with ethyl acetate (10.0 mL) and the combined organic layers were dried over MgSO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1: 4) to provide 3,5-dimethyl-4-N- (3-iso -propyl-4'-methoxymethoxyphenylamino) phenol (280 mg, 52%): XH NMR (300 MHz, CDC13): d 6.88 (d, J = 8.1 Hz, 1 H), 6.63 (s, 2 H), 6.47 ( m, 1 H), 6.21 (m, 1 H), 5.12 (s, 2 H), 3.52 (s, 3 H), 3.30 (m, 1 H), 2.19 (s, 6 H), 1.2 (d, 6 H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 9); Rf = 0.45. Step d: To a solution of sodium hydride (22 mg, 0.86 mmol) in DMF at 0 ° C was added a solution of 3,5-dimethyl-4-N- (3-iso-propyl-4'-methoxymethoxyphenylamino) phenol (270 mg, 0.86 mmol) in DMF (2.0 mL). The reaction mixture was stirred at room temperature for 1 h and a solution of diethyl tosyloxymethylphosphonate (0.34 g, 1.03 mmol) in DMF (1.0 mL) was added thereto. The reaction mixture was stirred at room temperature for 16 h and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (10.0 mL) and saturated aqueous NaHCO3 (10.0 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (10.0 mL). The combined organic layers were dried over MgSO, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1: 1) to provide [3,5-dimethyl-4-N- (3-iso-propyl-4'-methoxymethoxyphenylamino ) phenoxy] diethyl methylphosphonate (160 mg, 52%): R NMR (300 MHz, CDC13): d 6.88 (d, J = 8.4 Hz, 1 H), 6.75 (s, 2 H), 6.46 (m, 1 H), 6.20 (m, 1 H), 5.12 (s, 2 H), 4.25 (m, 6 H), 3.52 (s, 3 H), 3.28 (, 1 H), 2.21 (s, 6 H), 1.40 (m, 6 H), 1.20 (d, J = 6.9 Hz, 6 H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 9); Rf = 0.29. Step e: To a solution of diethyl [3, 5-dimethyl-4-N- (3-iso-propyl-4'-methoxymethoxyphenylamino) phenoxy] methylphosphonate (150 mg, 0.32 mmol) in CH2C12 (10 mL) at room temperature TMSBr (0.51 mL, 3.88 mmol) was added. The reaction mixture was stirred at room temperature for 16 h and the solvent was removed under reduced pressure. The residue was treated with water (5.0 mL), stirred for 2 h and extracted with ethyl acetate (10.0 mL x 2). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative LC-MS to provide [3,5-dimethyl-4-N- (4'-hydroxy-3-iso-propylphenylamino) phenoxy] methylphosphonic acid as a blue solid (40 mg, 33.9%). aH NMR (300 MHz, CDC13): d 8.3 (s, 1 H), 6.74 (s, 2 H), 6.49 (d, J = 8.4 Hz, 1 H), 6.36 (d, J = 2.4 Hz, 1 H), 5.92 (m, 1 H), 4.05 (d, J = 10.5 Hz, 2 H), 3.11 (m, 1H), 2.10 (s, 6 H), 1.10 (d, J = 6.9 Hz, 6 H ). pf > 200 ° C; LC-MS m / z = 366 [C18H24N05P + H] +; Anal. Calculated for (C18H24N05P + 0.5 H20 + 0.2 HCl): C, 56.65; H, 6.66; N, 3.67. Found: C, 56.45; H, 6.73; N, 3.71. Using the appropriate starting material, compound 20-1 was prepared in an analogous manner as described by the synthesis of compound 20.

Compound 20-1 [3,5-dimethyl-4- (4'-hydroxy-3-iso-propylphenylmethylamino) phenoxy] methylphosphonic acid was prepared by standard reductive amination (J. Org. Chem. 1972, 37, 1673) of N , N- (2,6-dimethyl-4-triisopropylsilanyloxyphenyl) - (3-iso-propyl-4-methoxymethoxyphenyl) amine with formaldehyde followed by the same procedure described for compound synthesis 20. E NMR (300 MHz, CDCl 3): d 8.28 (s, 1 H), 6.76 (s, 2 H), 6.54 (d, J = 8.8 Hz, 1 H), 6.15 (m, 1 H), 5.94 (m, 1 H), 4.05 (d, J = 10.2 Hz, 2 H), 3.13 (m, 1 H), 3.02 (s, 3 H), 1.97 (s, 6 H), 1.06 (d, J = 7.0 Hz, 6 H). pf > 200 ° C. LC-MS m / z = 379 [C? 9H26N05P + H] ~; Anal. Calculated for (C19H26N05P + 0.3 HBr + 0.1 CH2C12): C, 55.41; H, 6.46; N, 3.38. Found: C, 55.35; H, 6.55; N, 3.43. Example 21 Compound 21: 2- [3,5-Dichloro-4- (4'-hydroxy-3'-iso-propylphenoxy) phenyl] -2-oxoethylphosphonic acid Step a: To a stirred solution of diethyl methylphosphonate (0.4 g) , 2.6 mmol) in anhydrous THF (15 L) at -78 ° C was added n-BuLi (1.95 L, 1.95 mmol, 1 M solution in hexanes). The reaction mixture was stirred at -78 ° C for 1 h and a solution of methyl 3,5-dichloro-4- (3'-iso-propyl-4'-methoxyphenoxy) benzoate (0.24 g, 0.65 mmol. , step a, example 19) in THF (5 mL). The reaction mixture was stirred at -78 ° C for 1 h, quenched with 10% AcOH (10 L) and H20 (50 mL) and extracted with ethyl acetate (50 L x 2). The combined organic layers were washed with water and brine, dried over Na 2 SO 4, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1: 1) to give 2- [3,5-dichloro-4- (3'-iso-propyl-4 '- methoxyphenoxy)] -2-oxoethylphosphonate diethyl as a colorless oil (0.28 g, 63%): X H NMR (300 MHz, CDC13): d 8.05 (s, 2 H), 6.85 (d, J = 3.3 Hz, 1 H ), 6.71 (d, J = 9.0 Hz, 1 H), 6.40 (dd, J = 3.3, 9.0 Hz, 1 H), 4.08 (q, J = 6.3 Hz, 1 H), 3.81 (s, 3 H), 3.60 (d, J = 23.1 Hz, 2 H), 3.35-3.25 (m, 1 H), 1.32 (t, J = 6.9 Hz, 6 H), 1.19 (d, J = 6.9 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (2: 3); Rf = 0.2. Step b: To a stirred solution of diethyl 2- [3,5-dichloro-4- (3'-iso-propyl-4'-methoxyphenoxy)] -2-oxoethylphosphonate (0.26 g, 0.54 mmol) in CH2C12 (7 mL) at 0 ° C TMSBr (0.83 g, 0.8 mL, 5.4 mmol) was added. The reaction mixture was stirred at 0 ° C for 30 min, allowed to warm to room temperature and stirred for 16 h. The solvent was removed under reduced pressure and the residue was dissolved in CH 3 OH (3 L). The solvent was removed under reduced pressure to provide 2- [3,5-dichloro-4- (3'-iso-propyl-4'-methoxyphenoxy) phenyl] -2-oxoethylphosphonic acid as a white solid (0.2 g, 83% ): "" "H NMR (300 MHz, CD30D): d 8.09 (s, 2 H), 6.83 (d, J = 3.3 Hz, 1 H), 6.71 (d, J = 9.0 Hz, 1 H), 6.40 (dd, J = 3.3, 9.0 Hz, 1 H), 3.81 (s, 3 H), 3.60 (d, J = 22.1 Hz, 2 H), 3.35-3.25 (m, 1 H), 1.19 (d, J = 6.9 Hz, 6 H) . Step c: To a stirred solution of 2- [3,5-dichloro-4- (3'-iso-propyl-4'-methoxyphenoxy) phenyl] -2-oxoethylphosphonic acid (0.17 g, 0.40 mmol) in CH2C12 (5 mL) at -78 ° C was added BBr3 (1.0 mL, 1.0 mmol, 1.0 M in CH2C12). The reaction mixture was stirred at room temperature for 14 h, emptied in ice water (25 mL) and stirred for 1 h. The reaction mixture was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with water and brine, dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude product was recrystallized from CH2C12, filtered and dried to give 2- [3,5-dichloro-4- ('-hydroxy-3'-iso-propylphenoxy) phenyl] -2-oxoethylphosphonic acid as a yellow solid ( 0.14 g, 92%, mp: 83-85 ° C, 98% pure): XR NMR (300 MHz, CD3OD): d 8.18 (s, 2 H), 6.71 (d, J = 3.0 Hz, 1 H), 6.65 (d, J = 8.7 Hz, 1 H) 6.37 (dd, J = 3.0, 8.7 Hz, 1 H), 3.65 (d, J = 37.8 Hz, 2 H) 3.30-3.20 (m, 1 H), 1.18 (d, J = 6.9 Hz, 6 H); LC-MS = 420 [C? 7H? 7Cl206P + H] +; CLAR conditions: ODSAQ column AQ-303-5; Mobile phase = CH3OH: TFA (7: 3) flow ratio = 1.0 mL / min; detection = UV @ 254 nm retention time in min: 13.26; Anal Calculated: (C17H? 7Cl206P) Calculated: C: 48.09; H: 4.18. Found: C, 47.97; H: 4.39. Example 22 Compound 22: [3,5-Dichloro-4- (4'-hydroxy-3'-iso-propylphenoxy) phenylamino] methylphosphonic acid Step a: To a solution of 4-amino-2,6-dichlorophenol (4.0 g 22.5 mmol) in THF (25 mL) was added t-BOC anhydride (5.88 g, 27.0 mmol). The reaction mixture was heated under reflux for 2.5 h and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with acetone-hexanes (1: 9) to give 3,5-dichloro-4-hydroxyphenylcarbamic acid t-butyl ester as an off white solid (5.80 g. 93%): XR NMR (300 MHz, DMSO-d5): d 9.70 (s, 1 H), 9.44 (s, 1 H), 7.46 (s, 2 H), 1.48 (s, 9 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (3: 7); Rf = 0.39. Step b: To a mixture of bis (4-methoxy-3-iso-propylphenyl) iodonium tetrafluoroborate (2.76 g, 5.39 mmol) and copper powder (0.46 g, 7.18 mmol) in CH2C12 (20.0 mL) at 0 ° C A solution of TEA (0.55 mL, 3.95 mmol) and 3,5-dichloro-4-hydroxyphenylcarbamic acid tert-butyl ester (1.00 g, 3.59 mmol) in dichloromethane (10.0 mL) was added. The reaction mixture was stirred at room temperature for 14 h and filtered through a plug of celite. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with acetone-hexanes (1:19) to provide 3,5-dichloro-4- (3'-iso-propyl-4'-methoxyphenoxy) phenylcarbamic acid tert-butyl ester as an off white solid (1.45 g, 95%): XH NMR (300 MHz, DMSO-de): d 9.81 (s, 1 H), 7.68 (m, 2 H), 6.79 (m, 2 H), 6.42 (m, 1 H), 3.75 (s, 3 H) , 3.20 (m, 1 H), 1.51 (s, 9 H), 1.33 (d, J = 6.0 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (3: 7); Rf = 0.64. Step c: To a tert-butyl ester mixture of 3,5-dichloro-4- (3'-iso-propyl-4'-methoxyphenoxy) phenylcarbamic acid (0.400 g, 0.94 mmol) in THF (12.0 L) a 0 ° C was added sodium hydride (0.064 g, 1.22 mmol, 60% oil dispersion). The reaction mixture was stirred at room temperature during 1 h and cooled to 0 ° C. To the stirred mixture was added diethyl trifluoromethanesulfonyloxymethylphosphonate (0.18 g, 0. 94 mmol). The reaction mixture was stirred at room temperature for 2 h, quenched with water and diluted with ethyl acetate. The organic layer was washed with water and brine and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (2: 3) to give N-tert-butoxycarbonyl- [3,5-dichloro-4- (3-iso-propyl) 4'-methoxyphenoxy) phenylamino] methylphosphonate diethyl as an oil (0.34 g, 63%): 1 H NMR (300 MHz, DMSO-d 6): d 7. 64 (s, 2 H), 6.90 (m, 1 H), 6.76 (s, 1 H), 6.45 (m, 1 H), 4. 95 (d, J = 9.0 Hz, 2 H); 4.01 (m, 4 H); 3.76 (s, 3 H), 3.21 (m, 1 H), 1.43 (s, 9 H), 1.20 (m, 6 H), 1.13 (d, J = 6.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; . 07 Mobile phase = ethyl acetate-hexanes (2: 3); Rf = 0.15 Step d: To a solution of diethyl N-tert-butoxycarbonyl- [3,5-dichloro-4- (3-iso-propyl-4'-methoxy-phenoxy) phenylamino] methyl) phosphonate (0.25 g, 0.43 mmol) in CH2C12 (6.0 mL) at 0 ° C was added bromotrimethylsilane (0.86 mL, 6.50 mmol). The reaction mixture was stirred at room temperature for 16 h and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (5.0 mL), cooled to -78 ° C and to this was added BBr3 (2.84 L, 2.84 mmol, 1.0 M solution in CH2C12). The reaction mixture was stirred at -78 ° C for 10 min, allowed to warm to room temperature and stirred for 16 h. The reaction mixture was emptied on ice, diluted with ethyl acetate and washed with water. The organic layer was dried over MgSO 4 and concentrated under reduced pressure to provide [3,5-dichloro-4- (4'-hydroxy-3-iso-propylphenoxy) phenylamino] methylphosphonic acid as an off white solid (0.15 g, 85% during two stages): mp: 97-100 ° C; LCMS m / z = 405, 407 [C? 6H? 8Cl2N05P + H] +; X H NMR (300 MHz, DMSO-d 6): d 9.02 (s, 2 H), 6.90 (m, 2 H), 6.71 (m, 2 H), 6.32 (m, 2 H), 3.36 (m, 2 H) ), 3.21 (m, 1 H), 1.17 (d, J = 6.0 Hz, 6 H); Anal. Calculated for (C16H? 8Cl2N05P + 0.1 C4H802 + 0.3 H20): C, 46.85; H, 4.65; N, 3.33. Found: C, 47.09; H, 4.94; N, 3.50.

Example 23 Compound 23: N- [3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylphenoxy) benzamido] methyl phosphonic acid Step a: To a solution of 3,5-dimethyl-4- ( 3'-Isopropyl-4'-methoxyphenoxymethylbenzoate (8.53 g, 16.7 mmol, intermediate for the synthesis of Example 19-3) in methanol (60.0 mL) at 0 ° C was added a solution of 1 N NaOH (28.15 mL, 28.15 mmol). The reaction mixture was stirred at room temperature for 16 h and acidified with cold concentrated HCl. The reaction mixture was extracted with ethyl acetate (10.0 mL) and the organic layer was dried over MgSO4. The solvent was removed under reduced pressure to provide 4- (3'-iso-propyl-4'-methoxyphenoxy) -3,5-dimethylbenzoic acid as a pink solid (1.38 g, 78%): aH NMR (300 MHz, DMSO -d6): d 12.88 (s, 1 H), 7.76 (s, 2 H), 6.85 (m, 1 H), 6.75 (m, 1 H), 6.34 (m, 1 H), 3.73 (s, 3H), 3.20 (m, 1 H), 2.11 (s, 6 H), 1.12 (d, J = 6.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-acetone (17: 3); Rf = 0.00 Step b: To a mixture of 4- (3 '-iso-propyl-4'-methoxyphenoxy) -3,5-dimethylbenzoic acid (0.20 g, 0.63 mmol), diethyl aminomethylphosphonate (0.19 g, 0.76 mmol) and triethylamine in CH2C12 (10.0 mL) at 0 ° C was added EDCI (0.18 g, 0.763 mmol) followed by 1-hydroxy-7-azabenzotriazolo (0.09 mg, 0.63 mmol). The reaction mixture was stirred at room temperature for 16 h, concentrated and diluted with ethyl acetate (10.0 mL). The organic layer was washed with water (10 mLx3) and brine, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by preparative CCD to give N- [3,5-dimethyl-4- (3'-iso-propyl-4'-methoxyphenoxy) -benzamido] methylphosphonate diethyl as an oil (0.20 g, 68%) : E NMR (300 MHz, DMSO-d6): d 8.77 (m, 1 H), 7.69 (s, 2 H), 6.84 (d, J = 9.0 Hz, 1 H), 6.75 (m, 1 H), 6.36 (m, 1 H), 4.05 (, 4 H), 3.76 (m, 5 H), 3.21 (m, 1 H), 2.11 (s, 6 H), 1.21 (m, 6 H), 1.13 (d) , J = 6.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-acetone (1: 1); Rf = 0.28. Step c: To a solution of diethyl N- [4- (3'-iso-propyl-4'-methoxyphenoxy) -3,5-dimethylbenzamido] methyl] phosphonate (0.20 g, 0.43 mmol) in CH2C12 (4.3 mL) At -30 ° C bromotrimethylsilane was added (0.56 mL, 4.31 mmol). The reaction mixture was stirred at room temperature for 16 h and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (5.0 mL), cooled to -78 ° C, and to this was added BBr3 (1.29 mL, 1.29 mmol, 1.0 M solution in CH2C12). The reaction mixture was stirred at -78 ° C for 3 h, allowed to warm to room temperature and stirred for 16 h. The reaction mixture was emptied on ice, extracted with ethyl acetate (10.0 mL) and washed with 2% HCl (20 mL x 2) and water (20 mL x 2). The organic layer was dried over MgSO 4, filtered and concentrated under reduced pressure to provide N- [3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylphenoxy) benzamido] methylphosphonic acid as a pink solid (0.08 g, 47% during two stages): mp: 163-166 ° C; LC-MS m / z = 394 [C? 9H24N06P + H] +; 2 H NMR (300 MHz, CD30D): d 7.52 (s, 2 H), 6.51 (m, 2 H), 6.19 (m, 1 H), 3.70 (d, J = 12.0 Hz, 2 H), 3.14 (m , 1 H), 2.04 (s, 6 H), 1.01 (d, J = 6.0 Hz, 6 H); Anal. Calculated for (C? 9H24N06P + 1.0 H20): C, 55.47; H, 6.37; N, 3.40. Found: C, 55.30; H, 6.32; N, 3.12.

Example 24 Compound 24: 2- [3,5-Dimethoxy-4- (4'-hydroxy-3 '-iso propylbenzyl) phenyl] ethylphosphonic acid Step a: To a solution of 3,5-dimethoxy-4- (3') -iso-propyl-4'-methoxymethoxybenzyl) phenol (0.6 g, 1.73 mmol, intermediate for the synthesis of Example 7-2) and DMAP (0.85 g, 6.92 mmol) in CH2C12 (20 mL) at 0 ° C was added slowly trifluoromethanesulfonyl anhydride (0.44 mL, 2.6 mmol). The reaction mixture was stirred at 0 ° C for 2 h and quenched by water (10.0 mL). The organic layer was dried over Na 2 SO, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1: 9) to provide 3,5-dimethoxy-4- (3'-iso-propyl-4'-methoxymethoxybenzyl) - 1-trifluoromethanesulfonyloxyphenyl as a light yellow oil (0.83 g, 100%):? E NMR (300 MHz, DMS0-d6): d 7.09 (s, 1 H), 6.87 (s, 2 H), 6.80 (s, 2 H), 5.15 (s, 2 H), 3.84 (s, 6 H), 3.81 (s, 2 H), 3.36 (s, 3 H), 3.20 (m, 1 H), 1.14 (d, J = 6.6 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 9); Rf = 0.73. Step b: A mixture of 3,5-dimethoxy-4- (3 '-iso-propyl-4' -methoxymethoxybenzyl) -1-trifluoromethanesulfonyloxyphenyl (0.83 g, 1.73 mmol), triethylamine (0.96 mL, 6.92 mmol), Pd ( PPh3) 2Cl2 (0.12 g, 0.17 mmol) and diethyl vinylphosphonate (0.37 L, 2.43 mmol) in DMF (8 mL) was heated at 80 ° C for 16 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and saturated aqueous NaHCO 3. The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-CH2Cl2 (1: 1) to provide 2- [4- (3'-iso-propyl-4'-methoxymethoxybenzyl) -3.5 diethyl dimethoxyphenyl] vinylphosphonate as a light yellow oil (0.1 g, 12%): XR NMR (300 MHz, CDC13): d 7.50 (d, J = 17.4 Hz, 1 H), 7.29 (s, 1 H), 7.11 (m, 2 H), 6.72 (s, 2 H), 6.22 (t, J = 17.1 Hz, 1 H), 5.17 (s, 2 H), 4.21 (m, 4 H), 3.96 (s, 2 H), 3.87 (s, 6 H), 3.49 (s, 3 H), 3.31 (m, 1 H), 1.40 (t, J = 6.9 Hz, 6 H), 1.23 (d, J = 6.6 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-CH2Cl2 (1: 3); Rf = 0.4. Step c: A mixture of diethyl 2- [3,5-dimethoxy-4- (3'-iso-propyl-4'-methoxymethoxybenzyl) phenyl] vinylphosphonate (0.1 g, 0.2 mmol) and Pd / C (20 mg, 10%) in MeOH (20 mL) was stirred under an atmosphere of hydrogen at room temperature for 16 h. The mixture was filtered through a plug of celite. The solvent was removed under reduced pressure and the residue (90 mg) was dissolved in CH2C12 (5 mL). Deprotection with TMSBr as described for the synthesis of compound 7, step b to provide 2- [3,5-dimethoxy-4- (4'-hydroxy-3'-iso-propylbenzyl) phenyl] ethylphosphonic acid as light pink foam (73 mg, 91%). E NMR (200 MHz, DMSO-d6): d 8.88 (s, 1 H), 7.01 (d, J = 1.8 Hz, 1 H), 6.71 (dd, J = 1.8 Hz, J = 8.0 Hz, 1 H) , 6.55 (d, J = 8.4 Hz, 1 H), 6.5 (s, 2 H), 3.76 (s, 6 H), 3.69 (s, 2 H), 3.08 (m, 1 H), 2.72 (m, 2 H), 1.82 (m, 2 H), 1.08 (d, J = 7.0 Hz, 6 H), LC-MS m / z = 395 [C20H27? 6P + H] +; Anal Calculated for (C20H27O6P + 1.3 H20): C, 57.49; H, 7.14. Found: C, 57.24; H, 7.24. Using the appropriate starting material, compounds 24-1 to 24-4 were prepared in an analogous manner as described by the synthesis of compound 24.

Compound 24-1: 2- [3,5-Dimethyl-4- (4f-hydroxy-3'-iso-propylbenzyl) phenyl] ethylphosphonic acid Prepared from 3,5-dimethyl-4- (3'-iso) -propyl-4'-methoxymethoxybenzyl) phenol (G. Chiellini et al., Biorg, Med. Chem. Lett., 2000, 10, 2607). mp: 65-68 ° C; XR NMR (300 MHz, CD30D): d 6.93 (s, 2 H), 6.86 (d, J = 1.8 Hz, 1 H), 6.60 (d, J = 8.4 Hz, 1 H), 6.54 (dd, J = 1.8 Hz, J = 8.0 Hz, 1 H), 3.94 (s, 2 H), 3.24 (m, 1 H), 2.82 (m, 2 H), 2.23 (s, 6 H), 2.01 (m, 2 H), 1.15 (d, J = 7.0 Hz, 6 H), LC-MS m / z = 363 [C20H27O4P] +; Anal Calculated for (C20H27O4P + 0 .6 H20 + 0 4 CH30H): C, 63. 47; H, 7 78 Found: C, 63. 39; H, 8 06 Compound 24-2: Trans-2- [3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenyl] vinylphosphonic acid Was prepared from 3,5-dimethyl-4- (3 '-iso-propyl-4' -methoxymethoxybenzyl) phenol (G. Chiellini et al., Biorg, Med. Chem. Lett., 2000, 10, 2607). mp: 82-84 ° C; XH NMR (300 MHz, CD30D): d 7.38 (m, 1 H), 7.27 (s, 2 H), 6.84 (d, J = 1.8 Hz, 1 H), 6.62 (d, J = 8.4 Hz, 1 H ), 6.54 (dd, J = 1.8 Hz, J = 8.0 Hz, 1 H), 6.42 (m, 1 H), 4.00 (s, 2 H), 3.24 (m, 1 H), 2.28 (s, 6 H) ), 1.15 (d, J = 7.0 Hz, 6 H), LC-MS m / z = 361 [C2oH2504P + H] +; Anal Calculated for (C20H25O4P + 0.3 H20): C, 65.67; H, 7.05. Found: C, 65.43; H, 7.13.

Compound 24-3: 2- [4- (3 '-sec-Butyl-4'-hydroxy-benzyl) -3,5-dimethyl-phenyl] -ethylphosphonic acid The title compound was prepared from intermediate intermediate 4- (3 '-sec-butyl-4'-methoxymethoxybenzyl) -3,5-dimethyl-phenol was prepared from 4-bromo-2-ethyl-phenol according to the procedure described in G. Chiellini et al. Biorg. Med. Chem. Lett. 2000, 10, 2607, and was transformed into the title compound by the procedure used for the synthesis of compound 24 as a light yellow foam; 2 H NMR (200 MHz, DMS0-d 6): d 8.88 (s, 1 H), 6.86 (s, 2 H), 6.80 (s, 1 H), 6.61 (d, J = 8.0 Hz, 1 H), 6.46 (d, J = 8.0 Hz, 1 H), 3.81 (s, 2 H), 2.88 (m, 1 H), 2.65 (m, 2 H), 2.15 (s, 6 H), 1.75 (m, 2 H) ), 1.46 (m, 2 H), 1.06 (d, J = 7.0 Hz, 3 H), 0.74 (t, J = 7.4 Hz, 3 H), LC-MS m / z = 377 [C2? H2904P + H ] +; Anal Calculated for (C21H2904P + 1.6 H20): C, 62.24; H, 8.01. Found: C, 61.87; H, 7.82.

Compound 24-4: 2- [3,5-Dimethyl-4- (3'-Ethyl-4'-hydroxybenzyl) phenyl] ethylphosphonic acid The intermediate 4- (3'-ethyl-4'-methoxybenzyl) -3,5 -dimethylphenol, was prepared according to the procedure described in G. Chiellini et al. Biorg. Med. Chem. Lett. 2000, 10, 2607, was transformed into the title compound by the procedure used for the synthesis of compound 24 as a foam (94 mg, 19%); LC-MS m / z = 347 [C? 8H2305P-H]; X H NMR (300 MHz, DMS0-d 6): d 8.98 (s, 1 H), 6.86 (d, 1 H, J = 3 Hz), 6.72 (d, 1 H, J = 1.8 Hz), 6.60 (s, 2 H), 6.49 (dd, 1H, J = 2. 8 Hz, J = 8.4 Hz), 3.82 (s, 2H), 2.71 (m, 2H), 2.26 (s, 3H), 2. 09 (s, 3H), 1.66 (m, 2H), 1.06 (t, 3H, J = 9 Hz); Uniplaca of silica gel, 250 microns; Mobile phase = isopropyl alcohol / ammonium hydroxide / water [7: 2: 1]; Rf = 0.22; Anal. Calculated for (C? 9H2504P + 1.1 H20): C, 61.98; H, 7.45; Found: C, 61.88, H, 7.19.

Example 25 Compound 25: [3,5-dimethyl-4- (3'-iso-propyl-4'-hydroxybenzoyl) phenoxymethylphosphonic acid Step a: To a stirred solution of (2,6-dimethyl-4-triisopropylsilanyloxyphenyl) - ( 3'-iso-propyl-4'-methoxymethoxyphenyl) methanol (0.620 g, 1.27 mmol), (G. Chiellini et al., Bioorg, Med.Chem. Lett., 2000, 10, 2607) in THF (10.0 mL) at 0 ° C tetrabutylammonium fluoride (1.91 mL, 1.91 mmol, 1.0 M solution in THF) was added. The reaction mixture was stirred at room temperature for 20 minutes, diluted with diethyl ether and washed with water (20 mL x 2) and brine. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (1: 4) to provide 3,5-dimethyl-4- (3'-iso). propyl-4'-methoxymethoxybenzylhydroxy) phenol as an oil (0.370 g, 88%): 1 H NMR (300 MHz, DMSO-d 5): d 9.07 (s, 1 H), 7.20 (m, 1 H), 6.90 (m , 1 H), 6. 78 (m, 1 H), 6.39 (s, 2 H), 5.98 (d, J = 3.0 Hz, 1 H), 5.52 (d, J = 3.0 Hz, 1 H) 5.18 ( s, 2H), 3.38 (s, 3 H), 3.25 (m, 1 H), 2.12 (s, 6 H), 1.16 (m, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (4: 1); Rf = 0.15. Step b: To a mixture of 3,5-dimethyl-4- (3'-iso-propyl-4'-methoxymethoxybenzylhydroxy) phenol (0.380 g, 1.15 mmol) in DMF (10.0 mL) at 0 ° C was added Cs2CO3 (1.87 g, 5.75 mmol). After minutes, diethyl trifluoromethanesulfonyloxymethyl phosphonate (0.24 g, 1.15 mmol) was added. The reaction mixture was stirred at 0 ° C for 5 hours, allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with 1 N HCl, diluted with ethyl acetate, and washed with water (10 mLx4) and brine. The organic layer was concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel, eluted with acetone-hexanes (1: 4) as mobile phase to provide [3,5-dimethyl-4- (3 '-iso-propyl-4'-methoxymethoxybenzylhydroxy) phenoxy] methylphosphonate diethyl as an oil (0.41 g, 74%):? E NMR (300 MHz, DMSO-d6): d 7.20 (m, 1 H), 6.92 ( m, 1 H), 6.78 (m, 1 H), 6.67 (s, 2 H), 6.03 (d, J = 3.0 Hz, 1 H), 5.64 (d, J = 3.0 Hz, 1 H), 5.18 ( s, 2H), 4.38 (d, J = 9.0 Hz, 2 H), 4.11 (m, 4 H), 3.38 (s, 3 H), 3.25 (m, 1 H), 2.19 (s, 6 H), 1.24 (m, 6 H), 1.16 (m, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-acetone (6: 4); Rf = 0.35. Step c: To a stirred solution of [3, 5-dimethyl-4- (3'-iso-propyl-4'-methoxymethoxybenzylhydroxy) phenoxymethylphosphonate diethyl ester (0.32 g, 0.66 mmol) in dichloromethane (8.0 mL) at 0 ° C was added Dess-Martin periodinone (2.08 mL, 0.99 mmol, 0.48 M solution in CH2C12). The reaction mixture was stirred at room temperature for 16 h, concentrated, diluted with diethyl ether (10.0 L). To the solution was added a solution of 580 mg of Na2S203 pentahydrate in 60 mL of saturated NaHCO3). After minutes, the reaction mixture was diluted with ethyl acetate and water and washed with saturated NaHCO 3 and brine. The organic layer was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (1: 1) to provide [3,5-dimethyl-4- (3'-iso-propyl-4'-methoxymethoxybenzoyl) ) phenoxy] methylphosphonate diethyl as an oil (0.285 g, 89%): 1 H NMR (300 MHz, DMSO-d 6): d 7.22 (m, 1 H), 7.43 (m, 1 H), 7.13 (m, 1 H), 6.85 (s, 2 H), 5.35 (s, 2 H), 4. 49 (d, J = 7.5 Hz, 2 H), 4.16 (m, 4 H), 3.43 (s, 3 H), 3.27 (m, 1 H), 2.02 (s, 6 H), 1.29 (m, 6 H), 1.20 (m, 6 H);; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = dichloromethane-methanol (3:97); Rf = 0.52. Step d: To a solution of diethyl [3, 5-dimethyl-4- (3'-iso-propyl-4'-methoxymethoxybenzoyl) phenoxy] methylphosphonate (0.075 g, 0.16 mmol) in CH2C12 (3.0 mL) at -30 ° C was added bromotrimethylsilane (0.31 mL, 2.4 mmol). The reaction mixture was stirred at room temperature for 16 h and the solvent was removed under reduced pressure. The residue was treated with acetonitrile-water (4: 1, 5.0 mL) and sonicated. The solvents were removed under reduced pressure. The residue was dissolved in 1N NaOH and extracted with dichloromethane and ethyl acetate. The aqueous layer was acidified with 2 N HCl and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give [3,5-dimethyl-4- (4'-hydroxy-3-iso-propylbenzoyl) phenoxy] methylphosphonic acid as a pink solid ( 0.05 g, 84%): mp 138 ° C; LC-MS m / z = 379 [C19H2306P + H] +; X H NMR (300 MHz, DMSO-de): d 10.50 (s, 1 H), 7.64 (s, 1 H), 7.27 (m, 1 H), 6.87 (m, 1 H), 6.78 (m, 1 H ), 4.18 (m, 2 H), 3.18 (m, 1 H), 2.00 (s, 6 H), 3.11 (m, 1 H), 1.17 (d, J = 6.0 Hz, 6 H); CLAR conditions: Column = 3 Chromolith SpeedRODs RP-18e, 100x4.6 mm; Mobile phase = Solvent A (Acetonitrile) = Acetonitrile grade CLAR; Solvent B (buffer) = 20 mM ammonium phosphate buffer (pH 6.1, 0.018 M NH4H2PO4 / 0.002 M (NH4) 2HP04) with 5% acetonitrile. Flow ratio = 4 mL / min; UV @ 255 nm. Retention time in minutes, (tr = 5.30, 95% purity).

Example 26 Compound 26: 2- [3,5-dimethyl-4- (3'-iso-propyl-4'-hydroxybenzyl) phenoxy) ethylphosphonic acid Step a: To a stirred solution of 3,5-dimethyl-4- ( 3 '-iso-propyl-4' -methoxymethoxymethylbenzyl) phenol (1.00 g), 3.18 mmol, G. Chiellini et al. Biorg. Med. Chem. Lett. 2000, 10, 2607) in DMF (30.0 mL) was added Cs2CO3 (5.18 g, 15.90 mmol) followed by 1,2-dibromoethane (1.64 g, 19.08 mmol). The reaction mixture was stirred at 60 ° C for 2 d, diluted with ethyl acetate and washed with water (20 mLx4) and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by Columnar chromatography on silica gel, eluted with ethyl acetate-hexanes (1:19) to give l- (2-bromoethoxy) -4- (3'-iso-propyl-4 '- methoxymethoxybenzyl) -3,5-dimethylbenzene as an oil (0.26 g, 16%): XR NMR (300 MHz, CDC13): d 6.94 (m, 2 H), 6.67 (m, 3 H), 5.18 (s, 2 H), 4.32 (m, 2 H), 3.95 (s, 2 H), 3.68 (m, 2 H), 3.51 (s, 3 H), 3.37 (s, 3 H), 3.32 (m, 1 H) , 2.26 (s, 6 H), 1.22 (d, J = 6.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (4: 1); Rf = 0.91. Step b: A mixture of 1- (2-bromoethoxy) -4- (3 '-iso-propyl-4' -methoxymethoxybenzyl) -3,5-dimethylbenzene (0.15 g, 0.36 mmol) and triethylphosphite (0.18 g, 1.07 mmol ) in DMF (2.0 mL) was heated under reflux for 4 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and extracted with water (10 mLx4) and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by Column chromatography on silica gel, eluted with acetone-hexanes (1: 1) to provide 2- [3,5-dimethyl-4- (3 '-iso-propyl-4'-methoxymethoxybenzyl) diethyl phenoxy] ethylphosphonate as an oil (0.085 g, 50%): 1 H NMR (300 MHz, DMS0-d 6): d 6.96 (m, 1 H), 6.89 (m, 1 H), 6.62 (m, 3 H) ), 5.16 (s, 2 H), 4.12 (m, 2 H), 4.07 (m, 4 H) 3.86 (s, 2 H), 3.37 (s, 3 H), 3.22 (m, 1 H), 2.30 (m, 2 H), 2.17 (s, 6 H), 1.25 (m, 6 H), 1.12 (d, J = 6.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (3: 7); Rf = 0.10.

Step c: Deprotection of diethyl 2- [3,5-dimethyl-4- (3'-iso-propyl-4'-methoxymethoxybenzyl) phenoxy] ethylphosphonate with bromotrimethylsilane afforded 2- [3,5-dimethyl-4-acid] (4'-Hydroxy-3'-iso-propylbenzyl) phenoxy] ethylphosphonic acid as a brown oil (0.055 g, 87%): mp: 58-61 ° C; LC-MS m / z = 379, [C20H27O5P + H] +; XR NMR (300 MHz, CD3OD): d 6.84 (s, 1 H), 6.66 (s, 2 H), 6.56 (m, 2 H), 4.26 (m, 2 H), 3.90 (s, 2 H), 3.22 (m, 1 H), 2.30 (m, 1 H), 2.22 (s, 6 H), 1.15 (d, J = 6.0 Hz, 6 H); Analysis calculated for (C20H27O5P + 0.6 H20): C, 61.72; H, 7.30. Found: C, 61.96, H, 7.73.

Example 27 Compound 27: [3,5-dimethyl-4- (4'-fluoro-3'-iso-propylbenzyl) phenoxymethyl] phosphonic acid Step a: To a solution of 2-bromopropene (6.0 g, 49.60 mmol) in diethyl ether (200 mL) at -78 ° C was added t-butyllithium (36.0 mL). The reaction mixture was stirred at -78 ° C for 3 h and to this was added tributyltin chloride (16.1 g, 49.60 mmol). The reaction mixture was allowed to warm to room temperature and was stirred for 16 h. The reaction mixture was filtered through a plug of Celite and the filtrate was washed with saturated NH 4 Cl. The organic layer was dried over MgSO, filtered and concentrated to give the crude product as a colorless oil which was used by the next step without further purification. Step b: To a solution of 3-bromo-4-fluorobenzaldehyde (1.23 g, 6.04 mmol) in dioxane (20 L) was added the product obtained from step a followed by Pd (Ph 3) 2 Cl 2. The reaction mixture was heated at 110 ° C for 16 h, cooled to room temperature and filtered through a plug of Celite. Solvent was removed under reduced pressure and the crude product was purified by Column chromatography on silica gel, eluted with ethyl acetate-hexanes (1:19) to provide 4-fluoro-3-isopropenylbenzaldehyde (500 mg, 50% ): X H NMR (300 MHz, CDC13): d 7.89 (, 1 H), 7.82 (m, 1 H), 7.24 (m, 1 H), 5.36 (s, 2 H), 2.21 (s, 3 H) . CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1:19); Rf = 0.60. Step c: To a solution of 4-bromo-3,5-dimethyl-triisopropylsilane-benzene (1.29 g, 3.6 mmol, G. Chiellini et al., Biorg, Med. Chem. Lett., 2000, 10, 2607) in THF at -78. ° C n-butyllithium (1.58 mL, 3.96 mmol, 2.5 M in THF) was added. After 30 min, a solution of 4-fluoro-3-isopropenylbenzaldehyde (500 mg, 3.0 mmol) in THF was added. The reaction mixture was stirred at -78 ° C for 1 h, allowed to warm to room temperature, diluted with EtOAc and quenched with water. The organic layer was dried over MgSO, filtered and concentrated to give crude 1- (2,6-dimethyl-4-triisopropylsilanyloxyphenyl) -1- (4'-fluoro-3'-isopropenylphenyl) methanol as an oil: "" "H NMR (200 MHz, CDC13): d 7.18 (m, 1 H), 7.02 (m, 1 H), 6.94 (m, 1 H), 6. 56 (s, 2 H), 6.22 (s, 1 H), 5.18 (m, 2 H), 2.20 (s, 6 H), 2. 08 (s, 3 H), 1.25 (m, 3 H), 1.11 (m, 18). Step d: A solution of 1- (2,6-dimethyl-4-triisopropylsilanyloxyphenyl) -1- (4 '-fluoro-3' -isopropenylphenyl) methanol (1.2 g, 2.71 mmol) and Pd / C (0.1 g, 10 g) %) in EtOH / HOAc (9: 1, 10 mL) was stirred under an H2 atmosphere for 16 h. The reaction mixture was filtered through a plug of Celite and concentrated to give crude 3,5-dimethyl-4- (4'-fluoro-3'-iso-propylbenzyl) triisopropylsilane-benzene which was used by the next step without additional purification. Step e: To a solution of 3,5-dimethyl-4- (4'-fluoro-3'-iso-propylbenzyl) triisopropylsilane-benzene in THF (10 L) at 0 ° C was added TBAF (1M, 4.0 mL). The reaction mixture was stirred for 3 h, diluted with ethyl acetate 920 mL) and quenched with water (10 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (1: 9) to provide 3,5-dimethyl-4- (4'-fluoro-3'-iso-propylbenzyl) phenol (450 mg, 61% over two steps): XR NMR (300 MHz, CDC13): d 6.97 (d, J = 7.4 Hz, 1 H), 6.86 (m, 1 H), 6.69 (m, 1 H) , 6.60 (s, 2 H), 3.95 (s, 2 H), 3.20 (m, 1 H), 2.22 (s, 6 H), 1.25 (d, J = 6.4 Hz, 6 H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 9); Rf = 0.50. Step f: [3,5-Dimethyl-4- (4'-fluoro-3'-iso-propylbenzyl) phenoxymethylphosphonic acid was prepared from 3,5-dimethyl-4- (4'-fluoro-3 '- iso-propylbenzyl) phenol following the same procedure as described in compound 7, step b: XE NMR (300 MHz, DMSO-d6): d 7.03 (, 1 H), 6.93 (m, 1 H), 6.71 (s) , 2 H), 6.64 (m, 1 H), 4.03 (d, J = 10.2 Hz, 2 H), 3.89 (s, 2 H), 3.09 (m, 1 H), 2.15 (s, 6 H), 1.16 (d, J = 6.6 Hz, 6 H). pf: > 200 ° C; LC-MS m / z = 367 [C? 9H24F04P + H] +; Analysis calculated for (C? 9H24F04P + 0.4 H20): C, 61.09; H, 6.69. Found: C, 60.85; H, 6.32. Using the appropriate starting material, compound 27-1 was prepared in a manner analogous to that described by the synthesis of compound 27.

Compound 27-1: 5-dichloro-4- (4'-fluoro-3'-iso-propylbenzyl) -phenoxymethylphosphonic acid The intermediate (2,6-dichloro-4-triisopropylsilanyloxy-phenyl) - (4-fluoro-3-) iso-propyl-phenyl) -methanol was prepared by the procedure described by the synthesis of compound 27, steps a, b, c, d as an oil (520 mg, 98%): 1 H NMR (300 MHz, CDC13): d 7.24 (m, 1H), 6.98 (, 2H), 6.91 (s, 2H), 6.52 (s, 1H), 4.48 (s, 1H), 3.24 (m, 1H), 1.25 (m, 3H), 1.15 ( s, 24H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1:19); Rf = 0.86. Step d: To a solution of (2,6-dimethyl-4-triisopropylsilanyloxy-phenyl) - (4-fluoro-3-iso-propyl-phenyl) -methanol (520 mg, 1.08 mmol) in CH2C12 (10 mL) was added TFA (1.53 M, 0.7 mL) followed by triethylsilane (0.6 mL, 3.77 mmol) at room temperature. After being stirred for 2 h, the reaction mixture was diluted with EtOAc and water and the layers were separated. The aqueous layer was further extracted with EtOAc. The combined organic layers were washed with saturated NaHCO3, water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, hexanes) to provide 3,5-dichloro-4- (4'-fluoro-3'-iso-propyl-benzyl) -phenoxy] -triisopropylsilane as a colorless liquid ( 360 mg, 72%): XH NMR (300 MHz, CDC13): d 7.11 (m, 1H), 6.91 (m, 4H), 4.21 (s, 2H), 3.19 (m, 1H), 1.24 (m, 3H ), 1.17 (m, 24H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes; Rf = 0.68. The intermediate 3, 5-dichloro-4- (4'-fluoro-3'-iso-propyl-benzyl) -phenoxy] -triisopropylsilane was transformed into the title compound by the procedure described by the synthesis of compound 35, steps e , f and h to give a white solid (55 mg, 35%): X H NMR (300 MHz, DMSO-d 6): d 7.22 (s, 2H), 7.18 (m, 1H), 7.04 (m, 1H), 6.87 (, 1H), 4.22 (d, J = 9.6 Hz, 2H), 6.60 (s, 2H), 3.12 (m, 1H) ), 1.19 (d, J = 6.9) Hz, 6H). mp = 132-135, LC-MS m / z = 408 [C? 7H? 8Cl2F04P + H] +; Analysis calculated for (C? 7H18Cl2F04P + 0.2 H2O): C, 49.70; H, 4. 51. Found: C, 49.58; H, 4.24.

Example 28 Compound 28: trans-2- [3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylphenoxy) phenyl] vinylphosphonic acid Step a: To a mixture of bis (4-methoxy) tetrafluoroborate 3-iso-propylphenyl) iodide (4.80 g, 9.38 mmol) and copper powder (0.79 g, 12.52 mmol) in CH2C12 (15.0 mL) at 0 ° C was added a solution of triethylamine (0.96 mL, 6.89 mmol) and 3 , 5-dimethyl-4-hydroxybenzaldehyde (0.94 g, 6.26 mmol) in dichloromethane (15.0 mL). The reaction mixture was stirred at room temperature for 3 days and filtered through a plug of celite. Solvent was removed under reduced pressure and the residue was purified by column, chromatography on silica gel, eluted with acetone-hexanes (1:19) to provide 3,5-dimethyl-4- (3'-iso-propyl). 4'-methoxyphenoxy) benzaldehyde as an oil (2.00 g, 100%): XR NMR (300 MHz, DMSO-d6): d 9.96 (s, 1 H), 7.75 (s, 2 H), 6.85 (m , 1 H), 6.73 (m, 1 H), 6.36 (m, 1 H), 3.74 (s, 3 H), 3.19 (m, 1 H), 2.15 (s, 6 H), 1.12 (d, J = 6.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-acetone (17: 3); Rf = 0.51. Step b: To a mixture of tetraethy methylene diphosphonate (0.20 mL, 0.80 mmol) and THF (7.0 mL) at 0 ° C was added sodium hydride (0.033 g, 0.804 mmol, 60% dispersion in oil). The reaction mixture was stirred at room temperature for 30 minutes and thereto was added 3,5-dimethyl-4- (3'-iso-propyl-4'-methoxyphenoxy) benzaldehyde (0.20 g, 0.67 mmol). The reaction mixture was stirred at room temperature for 1 h, quenched with a cold aqueous solution of NH4C1, diluted with ethyl acetate and washed with water and brine. The solvent was removed under reduced pressure and the residue was purified by preparative CCD on silica gel, eluted with acetone-hexanes (1: 4) to give trans-2- [3,5-dimethyl-4- (3 '- diethyl iso -propyl-4'-methoxyphenoxy) phenyl] vinylphosphonate as an oil (0.21 g, 74%): X H NMR (300 MHz, DMSO-d 6): d 7.53 (s, 2 H), 7.32 (m, 2 H), 6. 84 (m, 1 H), 6.74 (m, 1 H), 6.59 (m, 2 H), 6.36 (m, 1 H), 4.00 (m, 4 H), 3.73 (s, 3 H), 3.20 (m, 1 H), 2.07 (s, 6 H), 1.27 (m, 6 H), 1.10 (d, J = 6.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-acetone (4: 1); Rf = 0.13. Step c: To a solution of diethyl trans-2- [3,5-dimethyl-4- (3'-iso-propyl-4'-methoxyphenoxy) phenyl] vinylphosphonate (0.22 g, 0.50 mmol) in CH2C12 (5.0 mL ) at -30 ° C was added bromotrimethylsilane (0.66 mL, 5.00 mmol). The reaction mixture was stirred at room temperature for 16 h and the Solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (5.0 mL) and cooled to -78 ° C. To this was added BBr3 (1.49 mL, 1. 49 mmol, 1.0 M solution in CH2C12). The reaction mixture was stirred at -78 ° C for 3 h, allowed to warm to room temperature and stirred for 16 h. The reaction mixture was emptied on ice, concentrated, and extracted with ethyl acetate. The organic solution was washed with 2% HCl (20 mL) and water (20 mLx3), dried over MgSO4 and filtered. Solvent was removed under reduced pressure to provide trans-2- [3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylphenoxy) phenyl] vinylphosphonic acid as an opaque white solid (0.08 g, 44% during two stages): mp 92-94 ° C; LC-MS m / z = 363 [C19H2305P + H] +; 1 H NMR (300 MHz, CD 3 OD): d 7.35 (s, 2 H), 7.10 (s, 1 H), 6.65 (s, 2 H), 6.32 (m, 2 H), 3.21 (m, 1 H), 2.12 (s, 6 H), 1.15 (d, J = 6.0 Hz, 6 H); CLAR conditions: Column = 3 Chromolith SpeedRODs RP-18e, 100x4.6 mm; Mobile phase = Solvent A (Acetonitrile) = Acetonitrile grade CLAR; Solvent B (buffer) = 20 M ammonium phosphate buffer solution (pH 6.1, 0.018 M NH4H2PO4 / 0.002 M (NH4) 2HP04) with 5% acetonitrile. Flow ratio = 4 mL / min; UV @ 255 nm. Retention time in minutes, (tr = 5.71, 98% purity). Example 29 Compound 29: 3- [3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylphenoxy) phenyl) propylphosphonic acid Step a: To a mixture of triethyl phosphonoacetate (0.16 mL, 0.80 mmol) in THF (7.0 mL) at 0 ° C was added NaH (0.033 g, 0.804 mmol, 60% dispersion in oil). The reaction mixture was stirred at room temperature for 30 minutes and thereto was added 3,5-dimethyl-4- (3-iso-propyl-4-methoxyphenoxy) benzaldehyde (0.20 g, 0.67 mmol, Example 28, step a). The reaction mixture was stirred at room temperature for 1 h, quenched with cold saturated NHC1, diluted with ethyl acetate and washed with water and brine. Solvent was removed under reduced pressure and the residue was purified by preparative CCD on silica gel, eluted with acetone-hexanes (3:17) to provide trans-3- [3,5-dimethyl-4- (3 '- iso-propyl-4'-methoxyphenoxy) phenyl] ethyl acrylate as an oil (0.24 g, 97%): X H NMR (300 MHz, DMS0-d 6): d 7.60 (m, 3 H), 6.83 (m, 1 H), 6.76 (m, 1 H), 6.60 (m, 1 H), 6.36 (m, 1 H), 4.21 (m, 4 H), 3.73 (s, 3 H), 3.21 (m, 1 H), 2.08 (s, 6 H), 1.27 (, 6 H), 1.12 (d, J = 6.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-acetone (4: 1); Rf = 0.62. Step b: To a mixture of trans-3- [3,5-dimethyl-4- (3'-iso-propyl-4'-methoxyphenoxy) phenyl] ethyl acrylate (1.10 g, 3.35 mmol) in THF (20.0 mL ) at 0 ° C DIBAL-H (4.68 mL, 4.68 mmol, 1.0 M solution in THF) was added. The reaction mixture was stirred at room temperature for 2 h, quenched with cold IN HCl, diluted with ethyl acetate and washed with water and brine. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluted with acetone-hexanes (1: 9) to give trans-3- [3,5-dimethyl-4- (3 '- iso-propyl-4 '-methoxyphenoxy) phenyl] -prop-2-en-l-ol as an oil (0.50 g, 81%): 1 H NMR (300 MHz, DMSO-de): d 7.22 (s, 2 H ), 6.97 (m, 0.5 H), 6.84 (m, 1.5 H), 6.73 (m, 1 H), 6.36 (m, 2 H), 4.87 (m, 1 H), 4.14 (m, 2 H), 3.73 (s, 3 H), 3.21 (m, 1 H), 2.05 (s, 6 H), 1.11 (d, J = 6.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-acetone (17: 3); Rf = 0.11. Step c: To a mixture of trans -3- [3,5-dimethyl-4- (3'-iso-propyl-4'-methoxyphenoxy) phenyl] -prop-2-en-l-ol (0.50 g, 1.53 mmol ) in methanol (15.0 L) was added 10% Pd / C (0.10 g, 20% w / w). The reaction mixture was stirred under H2 (balloon) at room temperature for 6 h and filtered through a plug of Celite. Solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluted with acetone-hexanes (3: 7) to provide 3- [3,5-dimethyl-4- (3'-iso-propyl-4'-methoxyphenoxy) phenyl] propanol as an oil (0.36 g, 72%): 1 H NMR (300 MHz, DMSO-d 6): d 6.97 (s, 2 H), 6.82 (m, 1 H), 6.74 (m, 1 H), 6.30 (m, 1 H), 4.49 (m, 1 H), 3.73 (s, 3 H), 3.43 (m, 2 H), 3.21 (m, 1 H), 2.57 (m, 2 H), 2.03 (s, 6 H), 1.73 (m, 2 H), 1.11 (d, J = 6.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-acetone (17: 3); Rf = 0.26. Step d: To a stirred solution of triphenylphosphine (0.36 g, 1.39 mmol) and CBr4 (0.46 g, 1.39 mmol) in diethyl ether (12.0 L) at room temperature was added 3- [3,5-dimethyl 4- (3 ' -iso-propyl-4 '-methoxyphenoxy) phenyl] propanol (0.35 g, 1. 06 mmol). The reaction mixture was stirred for 16 h, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluted with acetone-hexanes (1: 9) to give l-bromo-3- [3,5-dimethyl-4- (3'-iso-propyl-4 '-methoxyphenoxy) phenyl] propane as an oil (0.30 g, 72%): 1 H NMR (300 MHz, DMSO-d 6): d 7.00 (s, 2 H), 6.83 (m, 1 H), 6. 80 ( m, 1H), 6.31 (m, 1 H), 3.73 (s, 3 H), 3.53 (m, 2 H), 3.20 (, 1 H), 2.70 (m, 2 H), 2.12 (m, 2 H) ), 2.03 (s, 6 H), 1.11 (d, J = 6.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-acetone (4: 1); Rf = 0.75. Step e: A mixture of l-bromo-3- [3,5-dimethyl-4- (3'-iso-propyl-4 '-methoxyphenoxy) phenyl] propane (0.30 g, 0.77 mmol) and triethylphosphite (0.39 g, 2.31 mmol) in DMF (7.0 mL) was heated under reflux for 2.5 h and cooled to room temperature. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was concentrated under reduced pressure and the residue was purified by Column chromatography on silica gel, eluted with acetone-hexanes (1: 3) to provide 3- [3,5-dimethyl-4- (3'-iso diethyl-propyl-4'-methoxyphenoxy) phenyl] propylphosphonate as an oil (0.11 g, 32%): 1 H NMR (300 MHz, DMSO-de): d 6.97 (s, 2 H), 6.83 (d, J = 9.0 Hz, 1 H), 6.72 (d, J = 3.0 Hz, 1 H), 6.32 (m, 1 H), 3.99 ( m, 4 H), 3.73 (s, 3 H), 3.35 (m, 2 H), 3.17 (m, 1 H), 2.62 (m, 2 H), 2. 02 (s, 6 H), 1.75 (m, 4 H), 1.23 (m, 6 H), 1.10 (d, J = 6. 0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (1: 4); Rf = 0.17.

Step f: To a solution of diethyl 3- [3,5-dimethyl-4- (3'-iso-propyl-4'-methoxyphenoxy) phenyl] propylphosphonate (0.10 g, 0.22 mmol) in CH 2 Cl 12 (5.0 mL) a - 30 ° C was added bromotrimethylsilane (0.30 mL, 2.23 mmol). The reaction mixture was stirred at room temperature for 16 h and the Solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (3.0 mL) and cooled to -78 ° C. To this was added BBr3 (0.66 mL, 0.66 mmol, 1.0 M solution in CH2C12). The reaction mixture was stirred at -78 ° C for 3 h, allowed to warm to room temperature and stirred for 16 h. The reaction mixture was emptied on ice, concentrated and extracted with ethyl acetate (10 mL). The organic solution was washed with 0.5 M HCl (20 mL × 2) and water (20 mL × 2), dried over MgSO0, filtered and concentrated under reduced pressure to provide 3- [3,5-dimethyl-4- (4 '- hydroxy-3'-iso-propylphenoxy) phenyl] propylphosphonic acid as a white solid (0.50 g, 60% over two steps): mp: 60-63 ° C; LC-MS m / z = 379 [C 20 H 27 O 5 P + H] +; ? NMR (200 MHz, DMSO-d6): d 8.80 (s, 1 H), 6.85 (s, 2 H), 6.56 (m, 2 H), 6.10 (m, 1 H), 3.05 (m, 1 H), 2.40 (m, 2 H), 1.90 (s, 6 H), 1.49 (m, 2 H), 1.33 (s, 2 H), 1. 03 (d, J = 6. 0 Hz, 6 H); Analysis calculated for (C20H27O5P + 1. 1H20): C, 60. 32; H, 7 39 Found: C, 60 19 H, 7 32 EXAMPLE 30 Compound 30: 2- [3,5-dimethyl-4- (3'-iso-propyl-4'-methoxyphenoxy) phenyl] ethylphosphonic acid Step a: A solution of trans-2- [3, 5-dimethyl- 4- (3'-Isopropyl-4'-methoxyphenoxy) phenyl] vinylphosphonate diethyl ester (1.77g, 4.10 mmol, Example 28, step b) and Pd / C (177mg) in EtOH / HOAc (10 mL, 9: 1)) was stirred under an H2 atmosphere for 5 h. The reaction mixture was filtered through a plug of Celite and the Solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (1: 1) to provide diethyl 2- [3,5-dimethyl-4- (3'-iso-propyl-4'-methoxyphenoxy) phenyl] ethylphosphonate (1.29 g, 74 %): 1 H NMR (300 MHz, CDC13): d 6.94 (s, 2 H), 6.81 (d, J = 3.0 Hz, 1 H), 6.68 (d, J = 8.7 Hz, 1 H), 6.36 (m , 1 H), 4.15 (m, 4 H), 3.30 (m, 1 H), 2.88 (m, 2 H), 2.13 (s, 6 H), 2.05 (m, 2 H), 1.37 (m, 6 H), 1.21 (d, J = 6.9 Hz, 6 H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 9); Rf = 0.35. Step b: Deprotection of diethyl 2- [3,5-dimethyl-4- (3'-iso-propyl-4'-methoxyphenoxy) phenyl] ethylphosphonate with bromotrimethylsilane gave 2- [3,5-dimethyl-4-acid] (3 '-iso-propyl-4' -methoxyphenoxy) phenyl] ethylphosphonic acid: - "? NMR (300 MHz, DMSO-de): d 6.98 (s, 2 H), 6.78 (d, J = 9.3 Hz, 1 H ), 6.72 (d, J = 2.7 Hz, 1 H), 6.26 (m, 1 H), 3.70 (s, 3 H), 3.16 (m, 1 H), 2.71 (m, 2 H), 2.00 (s) , 6 H), 1.81 (m, 2 H), 1.10 (d, J = 6.6 Hz, 6 H) LC-MS m / z = 379 [C20H27O5P + H] +, Analysis calculated for (C20H27O5P + 0.7 H20) : C, 61.43; H, 7.32, Found: C, 61.59; H, 7.60.

Example 31 Compound 31: [3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylphenoxy) phenoxymethylphosphonic acid To a solution of 3,5-dimethyl-4- (3'-iso-propyl-4) '-methoxyphenoxy) benzaldehyde (0.18 g, 0.60 mmol, Example 28, step a) in dichloromethane (6.0 mL) at 0 ° C was added m-chloroperoxybenzoic acid (0.22 g, 0.905 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate. The organic solution was washed with saturated sodium bicarbonate (2xl0mL) and water. Solvent was removed under reduced pressure and the residue was dissolved in methanol (5 mL). To the solution was added 1 N NaOH (1.81 mL, 1.81 mmol) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate, acidified with 2 N HCl and washed with brine. The solvent was evaporated and the residue was purified by preparative CCD eluted with acetone-hexanes (1: 4) to provide 3,5-dimethyl-4- (3'-iso-propyl-4'-methoxyphenoxy) phenol as an oil. (0.08 g, 47%): XH NMR (200 MHz, DMSO-de): d 9.17 (s, 1 H), 6.82 (m, 1 H), 6.70 (, 1 H), 6.51 (s, 2 H), 6.32 (m, 1 H), 3.71 (s) , 3 H), 3.18 (m, 1 H), 1.95 (s, 6 H), 1.12 (d, J = 6.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-acetone (4: 1); Rf = 0.44. The intermediate 3,5-dimethyl-4- (3'-iso-propyl-4'-methoxyphenoxy) phenol was converted to [3,5-dimethyl-4- (3 '-iso-propyl-4'-methoxyphenoxy) acid) phenoxy] methylphosphonic following the procedure described by the synthesis of compound 8: mp 60-64 ° C; LC-MS = 367 [C18H2306P + H] +; NMR (200 MHz, DMSO-de): d 8.88 (s, 1 H), 6.76 (s, 2 H), 6.60 (m, 2 H), 6.17 (m, 1 H), 4.04 (d, J = 15.0 Hz, 2 H), 3.13 (m, 1 H), 2.01 (s, 6 H), 1.10 (d, J = 6.0 Hz, 6 H); Analysis calculated for (C? 8H2306P + 0.7 H20): C, 57.05; H, 6.49. Found: C, 57.10 H, 6.63. Example 32: Compound 32: 3- [3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylphenoxy)] phenyl-2-oxopropylphosphonic acid Step a: To a stirred solution of 3,5-dimethyl -4- (3 '-iso-propyl-4' -methoxyphenoxy) benzaldehyde (4.1 g, 15.2 mmol, Example 28, step a) in methanol (35 mL) at 0 ° C was slowly added NaBH (1.16 g,, 30.5 mmol). The reaction mixture was stirred at room temperature for 5 h and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (150 mL), washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (2: 4) to give the alcohol 3,5-dimethyl-4- (3'-iso-propyl-4 '- methoxyphenoxy) benzyl with a white solid (3.4 g, 83%, mp: 78-80 ° C): XH NMR (300 MHz, CDC13): d 7.12 (s, 2 H), 6.80 (d, J = 3.3 Hz, 2 H), 6.67 (d, J = 9.0 Hz, 1 H), 6.36 (dd, J = 3.0, 8.7 Hz, 1 H), 4.68 (s, 2 H), 3.80 (s, 3 H), 3.35- 3.25 (m, 1 H), 2.16 (s, 6 H), 1.19 (d, J = 7.2 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (2: 4); Rf = 0.5 Step b: To a stirred solution of 3,5-dimethyl-4- (3'-iso-propyl-4'-methoxyphenoxy) benzyl alcohol (1.0 g, 3.4 mmol) in DME (10 mL) at 0 ° C was added phosphorus tribromide (1.8 g, 0.5 mL, 6.8 mmol). The reaction mixture was stirred at 0 ° C for 5 h, quenched with methanol (2 mL) and stirred for 30 min. The reaction mixture was poured into ice water and extracted with ether (100 L). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide crude 3,5-dimethyl-4- (3'-iso-propyl-4'-methoxyphenoxy) benzyl bromide as a oil (1.02 g, 82%): 1 H NMR (300 MHz, CDC13): d 7.15 (s, 2 H), 6.81 (d, J = 3.0 Hz, 1 H), 6.67 (d, J = 9.0 Hz, 1 H), 6.34 (dd, J = 3.0, 8.7 Hz, 1 H), 4.51 (s, 2 H), 3.80 (s, 3 H), 3.40-3.25 (, 1 H), 2..15 (s, 6 H), 1.20 (d, J = 7.2 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (2: 4); Rf = 0.7. Step c: To a stirred solution of sodium cyanide (0.23 g, 4.69 mmol) in H20 (2 L) at room temperature was added a solution of 3,5-dimethyl-4- (3'-iso-propyl) bromide. 4'-methoxyphenoxy) benzyl (0.85 g, 2.34 mmol) in ethanol (5 mL). The reaction mixture was heated at 80 ° C for 2 h, cooled to room temperature, and poured into ice water (100 mL). The mixture was stirred for 1 h and extracted with ethyl acetate (2x100 mL). The combined organic layers were washed with water and brine, dried over Na 2 SO, filtered and concentrated under reduced pressure. The crude product was purified by Column chromatography on silica gel, eluted with ethyl acetate-hexanes (1: 4) to give 3,5-dimethyl-4- (3'-iso-propyl-4'-methoxyphenoxy) phenylacetonitrile as a brown solid (0.64 g, 85%, mp: 56-58 ° C): XH NMR (300 MHz, CDC13): d 7.07 (s, 2 H), 6.78 (d, J = 3.3 Hz, 1 H ), 6.68 (d, J = 9.0 Hz, 1 H), 6.35 (dd, J = 3.0, 8.7 Hz, 1 H), 3.80 (s, 3 H), 3.73 (s, 2 H), 3.40-3.25 ( m, 1 H), 2.16 (s, 6 H), 1.19 (d, J = 7.2 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 4); Rf = 0.5 Step d: To a stirred solution of 3,5-dimethyl-4- (3 '-iso-propyl-4'-methoxyphenoxy) phenylacetonitrile (0.75 g, 2.42 mmol) in acetic acid (7 mL) was added at 50% strength. a solution of H2SO4 (14 mL). The reaction mixture was heated at 105 ° C, for 3 h, cooled to room temperature and emptied into ice water (100 mL). The mixture was stirred for 1 h and extracted with ethyl acetate (3x50 L). The combined organic layers were washed with water and brine, dried over Na 2 SO, filtered and concentrated under reduced pressure to provide 3,5-dimethyl-4- (3'-iso-propyl-4'-methoxyphenoxy) phenylacetic acid as a brownish solid (0.62 g, 85%, mp: 118-120 ° C): XE NMR (300 MHz, CDC13): d 7.11 (s, 2 H), 6.82 (d, J = 2.7 Hz, 1 H), 6.80 (d, J = 8.7 Hz, 1 H), 6.37 (dd, J = 3.3, 8.7 Hz, 1 H), 3.80 (s, 3 H), 3.61 (s, 2 H), 3.38-3.25 (m, 1 H), 2.11 (s, 6 H), 1.17 (d, J = 7.2 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 1); Rf = 0.2. Step e: To a stirred cold solution of methanol (15 mL) and acetyl chloride (3 mL, 86.0 mmol) at 0 ° C was added dropwise a solution of 3,5-dimethyl-4- (3 '- iso-propyl-4'-methoxyphenoxy) phenylacetic acid (0.7 g, 4.3 mmol) in methanol (5 mL). The reaction mixture was heated under reflux for 5 h and cooled to room temperature. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (100 mL). The organic solution was washed with water and brine, dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude product was triturated with hexane, filtered and dried under reduced pressure to give methyl 3,5-dimethyl-4- (3'-iso-propyl-4'-methoxyphenoxy) phenylacetate as a yellow solid (0.69 g, 95%): 1 H NMR (300 MHz, CDC13): d 7.02 (s, 2 H), 6.82 (d, J = 2.7 Hz, 1 H), 6.66 (d, J = 8.7 Hz, 1 H), 6.38 (dd, J = 3.3, 8.7 Hz, 1 H), 3.79 (s, 3 H), 3.75 (s, 3 H), 3.60 (s, 2 H), 3.28-3.25 (m, 1 H), 2. 14 (s, 6 H), 1.20 (d, J = 7.2 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 1); Rf = 0.6. Step f: 3- [3,5-Dimethyl-4- (4'-hydroxy-3'-iso-propylphenoxy) phenyl] -2-oxopropylphosphonic acid was prepared from methyl-3,5-dimethyl-4- (3 '-iso-propyl-4'-methoxyphenoxy) phenylacetate following the same procedure as described in compound 21: mp: 80-82 ° C; 1 H NMR (300 MHz, CDC13): d 6.85 (s, 2 H), 6.51 (d, J = 2.1 Hz, 1 H), 6.48 (d, J = 8.4 Hz, 1 H), 6.14 (dd, J = 3.0, 9.0 Hz, 1 H), 4.80 (s, 2 H), 3.80 (s, 2 H), 3.20-3.10 (m, 1 H), 2.99 (d, J = 22.5 Hz, 1 H), 1.97 (s, 6 H), 1.03 (d, J = 6.9 Hz, 6 H); LCMS ME / z = 393 [C2oH2506P + H] +; CLAR conditions: ODSAQ AQ-303-5 Column; Mobile phase = CH3OH: 5% TFA (7: 3) flow ratio = 1.0 mL / min; detection = UVT254 nm retention time in minutes: 11.19; Analysis calculated for (C20H25O6P + 0.2 CH2C12): C, 58.82; H, 6.22. Found: C, 58.75; H, 6.30.

Example 33: Compound 33: [3,5-dimethyl-4- (4'-Hydroxy-3'-iso-propyl-phenyl) methoxymethyl] -phenoxy] methylphosphonic acid Step a: To a solution of (2,6-dimethyl) -4-triisopropylsilanyloxyphenyl) - (3-iso-propyl-4-methoxymethoxyphenyl) methanol (1.60 g, 3.29 mmol, G. Chiellini et al., Biorg.Med Chem. Lett., 2000, 10, 2607) in THF (30.0 L ) at 0 ° C TBAF (4.93 L, 4.93 mmol, 1.0 M solution in THF) was added. The reaction mixture was stirred at room temperature for 60 min, diluted with diethyl ether (10.0 L) and washed with water (20 mLx2). The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (1: 4) to provide 3,5-dimethyl-4- [(3'-iso-propyl-4'-methoxymethoxyphenyl) ) -hydroxymethyl] phenol as a white solid (1.00 g, 92%): 1 H NMR (300 MHz, DMSO-de): d 9.05 (s, 1 H), 7.17 (m, 1 H), 6.90 (m, 1 H), 6.77 (m, 1 H), 6.37 (s, 2 H), 5.97 (d, J = 6.0 Hz, 1 H), 5.51 (d, J = 6.0 Hz, 1 H) 5.15 (s, 2H) , 3.36 (s, 3 H), 3.23 (m, 1 H), 2.10 (s, 6 H), 1.16 (, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (4: 1); Rf = 0.17. Step b: To a mixture of 3,5-dimethyl-4- [(3'-iso-propyl-4'-methoxymethoxyphenyl) -hydroxymethyl] phenol (0.380 g, 1.15 mmol) in DMF (10.0 mL) at 0 ° C Cs2C03 (1.87 g, 5.75 mmol) was added. After 5 minutes, trifluoromethanesulfonic acid diethoxyphosphoryl methyl ester (0.24 g, 1.15 mmol) was added. The reaction mixture was stirred at room temperature for 16 h, quenched with 1 N HCl, diluted with ethyl acetate and extracted with water (10 mLx4). The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by Column chromatography on silica gel, eluted with acetone-hexanes (1: 4) to provide [3,5-dimethyl-4- [(3'-iso-propyl-4'-methoxymethoxyphenyl) diethyl-hydroxymethyl] phenoxymethylphosphonate as an oil (0.41 g, 74%): XR NMR (300 MHz, DMSO-d6): d 7.20 (, 1 H), 6.92 (m, 1 H), 6.78 (m, 1 H ), 6.67 (s, 2 H), 6.03 (d, J = 3.0 Hz, 1 H), 5.64 (d, J = 3.0 Hz, 1 H), 5.18 (s, 2 H), 4.38 (d, J = 9.0 Hz, 2 H), 4.11 (m, 4 H), 3.38 (s, 3 H), 3.25 (m, 1 H), 2.19 (s, 6 H), 1.24 (m, 6 H), 1.16 (m , 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-acetone (6: 4); Rf = 0.35.

Step c: To a solution of diethyl [3, 5-dimethyl-4- [(3'-iso-propyl-4'-methoxymethoxyphenyl) -hydroxymethyl] phenoxymethylphosphonate (0.200 g, 0.42 mmol) in MeOH (6.0 mL) a 0 ° C was added 2 M HCl (2.1 mL, 4.20 mmol). The reaction mixture was stirred at 0 ° C for 3 h and at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (10.0 mL) and washed with water (20 mL x 2). The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluted with acetone-hexanes (1: 1) to provide [3,5-dimethyl-4- [(4'-hydroxy-3'-iso-propylphenyl) diethyl methoxymethyl] phenoxy] methylphosphonate as an oil (0.125 g, 69%): 1 H NMR (300 MHz, DMS0-d 6): d 9.16 (s, 1 H), 7.03 (s, 1 H), 6.71 (s, 2 H), 6.59 (m, 2 H), 5.63 (s, 2 H), 4.41 (d, J = 15.0 Hz, 2 H), 4.11 (, 4 H) 3.20 (s, 3H), 2.17 (s, 6 H), 1.21 (m, 6 H), 1.11 (m, 6 H); Terms CCD: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-acetone (1: 1); Rf = 0.50. Step d: To a solution of diethyl [3, 5-dimethyl-4- [(4'-hydroxy-3'-iso-propylphenyl) ethoxymethyl] phenoxy] methylphosphonate (0.065 g, 0.15 mmol) and 1.1.1. , 3, 3, 3-hexamethyldisilazane (0.38 mL, 1.80 mmol) in CH2C12 (3.0 mL) at -30 ° C was added bromotrimethylsilane (0.12 mL, 0.90 mmol). The reaction mixture was stirred at room temperature for 16 h and the solvent was removed under reduced pressure. The residue was treated with acetonitrile-water (4: 1, 5.0 mLx3) and sonicated. The solvent was removed under reduced pressure and the residue was dissolved in 1 M NaOH (5 mL). The aqueous solution was extracted with ethyl acetate (5mLx2) and acidified with 2 M HCl. The mixture was diluted with ethyl acetate and washed several times with water. The organic layer was dried over MgSO4 and concentrated under reduced pressure to provide the title compound as a red powder (0.035 g, 62%):? R NMR (300 MHz, D20): d 7.03 (s, 1 H), 6.78-6.67 (m, 4 H), 6.14 (s, 1 H), 4.02 (d, J = 10.5 Hz, 2 H), 3.21 (s, 3 H), 2.09 (s, 6 H), 1.01 (m , 6 H); CLAR conditions: Column = 3 Chromolith SpeedRODs RP-18e, 100x4.6 mm; Mobile phase = Solvent A (Acetonitrile) = Acetonitrile grade CLAR; Solvent B (buffer) = 20 mM ammonium phosphate buffer (pH 6.1, 0.018 M NH4H2PO4 / 0.002 M (NH4) 2HP04) with 5% acetonitrile. Flow ratio = 4 mL / min; UV @ 255 nm. Retention time in minutes, (tr = 5.70, 93% purity).

Example 34: Compound 34: [3,5-dimethyl-4- (4'-hydroxy-3'-iodobenzyl) phenoxy] methylphosphonic acid Step A: A mixture of diethyl [3,5-dimethyl-4- (4'-methoxymethoxybenzyl) phenoxy] methylphosphonate (0.26 g, 0.61 mmol, was prepared from commercially available 4-bromophenol according to the procedure described in compound 7) in methanol (3.0 mL) at 0 ° C was added 2 N HCl (1.0 mL). The reaction mixture was stirred at room temperature for 24 h, quenched with water (10.0 mL) and extracted with ethyl acetate (10.0 mL). The organic layer was dried over MgSO, filtered and concentrated under reduced pressure to give [3, 5-dimethyl-4- (4'-hydroxybenzyl) phenoxy] methyl-diethylphosphonate (0.22 g, 95%) as a colorless oil: R NMR (300 MHz, DMSO-d6): d 9.11 (s, 1 H), 6.60-6.80 (m, 6 H), 4.35 (d, J = 14.7 Hz, 2 H), 4.11 (, 4 H), 3.80 (s, 2 H), 2.15 (s, 6 H), 1.25 (t, J = 10.5 Hz, 2, H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (1: 1); Rf = 0.40. [3,5-Dimethyl-4- (4'-hydroxy-3'-iodobenzyl) phenoxy] methylphosphonic acid was prepared from diethyl [3,5-dimethyl-4- (4'-hydroxybenzyl) phenoxy] ethylphosphonate] according to the procedure described in compound 2 steps f and g: 1 H NMR (300 MHz, CD 3 OD): d 7.27 (d, J = 2.4 Hz, 1 H), 6.83 (dd, J = 8.1, 2.1 Hz, 1 H), 6.76 (s, 2 H), 6.72 (d, J = 8.1 Hz, 1 H), 4.23 (d, J = 10.2 Hz, 2 H), 3.91 (s, 2 H), 2.23 (s, 6 H); LC-MS m / z = 449 [C16H? 8I05P + H] +; Analysis calculated for (C? 6H? 8I05P + 0.7 H20): C, 41.70; H, 4.24. Found: C, 41.73; H, 4.56. Example 35: Compound 35: [3,5-dimethyl-4- (3'-carboxy-4 '-hydroxybenzyl) phenoxy] methylphosphonic acid Step a: To the suspension of NaH (3.25 g, 0.135 mol) in DMF (150 mL ) 4-hydroxy-benzaldehyde (15.0 g, 0.123 mol) in DMF (10 mL) was added at 0 ° C, 5 min. Later the reaction mixture became a cake. The heterogeneous mixture was stirred at 0 ° C for 30 min. MOMCI (9.96 g, 0.123 mol) was added slowly and the reaction mixture was allowed to warm to room temperature. After being stirred at room temperature for 16 h, the volatiles were removed under vacuum. The residue was partitioned between ethyl acetate and water and the water layer was further extracted with ethyl acetate. The combined ethyl acetate extracts were dried over MgSO 4, filtered and concentrated. The residue was purified by Column chromatography on silica gel (ethyl acetate-hexanes: 1: 4) to give 4-methoxymethoxy-benzaldehyde (19.0 g, 93%): R NMR (300 MHz, CDC13): d 9.94 (s, 1 H), 7.88 (m, 2 H), 7.18 (m, 2 H), 5.29 (s, 2 H), 3.53 (s, 2 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 4); Rf = 0.86. Step b: To a solution of (4-bromo-3,5-dimethyl-phenoxy) triisopropylsilane (8.0 g, 23.30 mmol) in THF (50 mL) was added a solution of n-butyllithium (2.5 M in THF, 90 mL ) at -78 ° C. The heterogeneous mixture was stirred at -78 ° C for 1 h. A solution of 4-methoxymethoxy-benzaldehyde (3.09 g, 18.58 mmol) in THF (5 mL) was added and the mixture was stirred at -78 ° C for 1 h then it was warmed to room temperature. The reaction was then diluted with ethyl acetate and water, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried (MgSO 4), filtered and concentrated to provide crude (2,6-dimethyl-4-triisopropylsilanyloxyphenyl) - (4-methoxymethoxyphenyl) methanol. It was carried out in the next step without further purification. Step c: A degassed solution of crude (2,6-dimethyl-4-triisopropylsilanyloxyphenyl) - (4-methoxymethoxyphenyl) methanol (12.0 g, 26.84 mmol) and Pd / C (1.2 g) in EtOAc / HOAc (19/1) was stirred under a hydrogen atmosphere (1 atom) at room temperature. After 5 h, the catalyst was filtered through a pad of celite, rinsed with ethyl acetate and the combined filtrates were concentrated under reduced pressure. The residue was purified by Column chromatography on silica gel (ethyl acetate-hexanes: 1: 9) to give 4- (2,6-dimethyl-4-triisopropylsilanyloxybenzyl) -methoxymethoxybenzene (4.0 g, 41.5% over two steps) : R NMR (300 MHz, CDC13): d 6.93 (s, 4 H), 6.63 (s, 2 H), 5.16 (s, 2 H), 3.94 (s, 2 H), 3.50 (m, 3 H) , 1.58 (s, 6 H), 1.29 (m, 3 H), 1.13 (m, 18 H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1:19); Rf = 0.80. Step d: To a solution of 4- (2,6-dimethyl-4-triisopropylsilanyloxybenzyl) -methoxymethoxybenzene (2.0 g, 4.66 mmol) in ether was added TMEDA (1.05 mL, 6.99 mmol), followed by nBuLi (2.5 M in THF). , 2.8 mL) at -20 ° C. The reaction mixture was warmed to 0 ° C and stirred for 1 h DMF (0.72 mL, 9.32 mmol) then added and after stirring at 0 ° C for 2 h, the reaction mixture was quenched with a saturated solution of NHC1 and was diluted with EtOAc. The water layer was extracted with EtOAc and the combined organic extracts were dried (MgSO 4), filtered and concentrated to give the crude product 5- (2,6-dimethyl-4-triisopropylsilanyloxybenzyl) -2-methoxymethoxy-benzaldehyde (2.1 g, 98%): X H NMR (300 MHz, d 6 -DMS0): d 10.33 (s, 1 H), 7.24 (m, 3 H), 6.58 (s, 2 H), 5.31 (s, 2 H), 3.91 (s, 2 H), 3.33 (s, 6 H), 1.23 (m, 3 H), 1.06 (m, 18 H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 9); Rf = 0.55. Step e: To a solution of 5- (2,6-dimethyl-4-triisopropylsilanyloxybenzyl) -2-methoxymethoxy-benzaldehyde (1.4 g, 3.07 mmol) in THF (15 L) was added TBAF (1 M, 3.68 L) at 0 ° C. After being stirred at room temperature for 2 h, the reaction mixture was diluted with EtOAc and water. The water layer was extracted with EtOAc and the combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by Column chromatography on silica gel (ethyl acetate-hexanes: 1: 9) to give 5- (4-hydroxy-2,6-dimethylbenzyl) -2-methoxymethoxybenzaldehyde (590 mg, 64% over two hours). steps): XH NMR (200 MHz, CDC13): d 10.45 (s, 1 H), 7.54 (s, 1 H), 7.27 (m, 1 H), 7.09 (m, 1 H), 6.56 (s, 2 H), 5.25 (s, 2 H), 3.92 (s, 2 H), 3.50 (s, 3 H), 2. 16 (s, 6 H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 9); Rf = 0.68.

Step f: To a solution of 5- (4-hydroxy-2,6-dimethylbenzyl) -2-methoxymethoxybenzaldehyde (590 mg, 1.97 mmol) in DMF (10 mL) was added CsC03 (3.2 g, 9.83 mmol), followed by trifluoromethanesulfonic acid diethoxy phosphorylmethyl ester (649 mg, 2.16 mmol) at room temperature. After being stirred at room temperature for 16 h, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc and water. The water layer was extracted with EtOAc and the combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate-hexanes; 1: 1) to provide [diethyl 4- (3'-formyl-4'-methoxymethoxybenzyl) -3,5-dimethylphenoxy] ethylphosphonate (650 g, 72%): XR NMR (300 MHz, CDC13): d 10.42 ( s, 1 H), 7.51 (s, 1 H), 7.09 (m, 2 H), 6.67 (s, 2 H), 5.25 (s, 2 H), 4.26 (m, 6 H), 3.94 (s, 2 H), 3.50 (s, 3 H), 2.19 (s, 6 H), 1.37 (m, 6 H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 1); Rf = 0.55. Step g: To a solution of [4- (3 '-formyl-4' -methoxymethoxybenzyl) -3,5-dimethylphenoxy] methylphosphonate (650 mg, 1.44 mmol) in THF (1.0 mL) at room temperature, a solution was added NaH2P04 (52 mg, 0.43 mmol) in water (0.2 L), 30% H202 (30%, 0.16 mL) followed by a solution of sodium chloride (245 mg, 2.17 mmol) in water (1.0 mL). After being stirred at room temperature for 30 minutes, the reaction mixture was diluted with EtOAc and water. The water layer was extracted with EtOAc and the combined organic extracts were washed with water, brine, dried (MgSO), filtered and concentrated to provide [3, 5-dimethyl-4- (3'-carboxy-4 ' diethylhydroxybenzyl) phenoxy] methylphosphonate as a yellow solid (585 mg, 86.9%): 1 H NMR (300 MHz, CDC13): d 7.91 (m, 1 H), 7.11 (m, 2 H), 6.68 (s, 2 H), 4.25 (m, 6 H), 3.96 (s, 2 H), 3.54 (s, 3 H), 2.19 (s, 6 H), 1.37 (m, 6 H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = MeOH-ethyl acetate (1: 9); Rf = 0.2. Step h: To the solution of diethyl [3, 5-dimethyl-4- (3'-carboxy-4'-hydroxybenzyl) phenoxy] methylphosphonate (100 mg, 0.21 mmol) in CH2C12 (10 mL) was added TMSBr (0.28). mL, 2.10 mmol) at room temperature. After being stirred at room temperature for 16 h, the reaction mixture was concentrated and the residue was suspended in MeOH. After stirring for 2 h, the volatiles were removed and the residue was azeotroped with CH2C12 twice to give [3,5-dimethyl-4- (3'-carboxy-4 '-hydroxybenzyl) phenoxy] methylphosphonic acid as a white solid (48 mg, 61.5%): mp. > 200 ° C; X H NMR (200 MHz, DMS0-d 6): d 7.38 (d, J = 2.1 Hz, 1 H), 7.17 (m, 1 H), 6.87 (d, J = 8.4 Hz, 1 H), 6.74 (s, 2 H), 4.06 (d, J = 10.2 Hz, 2 H), 3.89 (s, 2 H), 2.18 (s, 6 H). pf > 200, LC-MS m / z = 367 [C17H? 907P + H] +; Analysis calculated for (C17H? 907P + 0.4 H20): C, 54.67; H, 5.34. Found: C, 54.57; H, 5.60.

Example 36: Compound 36: [3,5-dimethyl- (4'-hydroxy-3'-iso-propylcarbamoylbenzyl) -phenoxy] methylphosphonic acid Step a: To a solution of [3,5-dimethyl-4- (3 diethyl-carboxyl-4 '-hydroxy-benzyl) phenoxy] methylphosphonate (compound 35, step f, 122 mg, 0.262 mmol) in DMF (5.0 mL) was added EDCI (60 mg, 0.314 mmol), HOAT (53 mg) , 0.393 mmol), diisopropylethylamine (0.23 mL, 1.31 mmol) and isopropylamine (0.03 mL, 0.288 mmol). After being stirred at room temperature for 16 h, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc and a saturated solution of NaHCO 3. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water, brine, dried (MgSO 4), filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate-hexanes: 1: 1) to give [3,5-dimethyl-4- (4'-hydroxy-3 '-isopropylcarba oilbenzyl) acid - diethyl phenoxy] ethyl phosphonic acid as a yellowish liquid (40 mg, 30%). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 1); Rf = 0.45. Step b: The title compound was prepared by the procedure described by the synthesis of compound 35, step f as an opaque white solid (30 mg, 93.7%); mp: 90 ° C, dec; XR NMR (300 MHz, DMSO-de): d 8.52 (d, J = 7.5 Hz, 1 H), 7.77 (d, J = 1.5 Hz, 1 H), 6.73 (m, 4 H), 4.14 (m, 1 H), 4.06 (d, J = 10.2 Hz, 2 H), 3.88 (s, 2 H), 2.18 (s, 6 H), 1.21 (d, J - 6.9 Hz, 6 H). mp: decomposition at 90, LC-MS m / z = 408 [C2oH26NOeP + H] +; Analysis calculated for (C20H26NO5P + 0.26 acetone + 1.4 HBr): C, 46.58; H, 5.45; N, 2.61. Found: C, 46.49; H, 5.84; N, 2.93.

Example 37: Compound 37: [3,5-dimethyl-4- (4'-hydroxy-3'-phenethylcarbamoylbenzyl) enoxy] methylphosphonic acid Step a: 5- (2,6-dimethyl-4-triisopropylsilanyloxybenzyl) -2- methoxymethoxybenzaldehyde (example 35, step e) was converted to 5- (2,6-dimethyl-4-triisopropylsilanyloxybenzyl) -2-methoxymethoxybenzoic acid by the procedure used for the synthesis of compound 35, step g: yellow solid (360 mg, 86.9 %); aH NMR (200 MHz, CDC13): d 7.94 (s, 1H), 7.08 (m, 2H), 6.60 (s, 2H), 5.36 (s, 2H), 3.95 (s, 2H), 3.53 (s, 3H ), 2.14 (s, 6H), 1.26 (m, 3H), 1.14 (m, 18H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = MeOH- ethyl acetate (1: 9); Rf = 0.45. Step b: The 5- (2,6-dimethyl-4-triisopropylsilanyloxybenzyl) -2-methoxymethoxybenzamide of N-phenethyl was prepared by the procedure used for the synthesis of compound 36, step a: colorless liquid (330 mg, 75%); 1 H NMR (300 MHz, CDC13): d 8.05 (d, J = 2.4 Hz, 1 H), 7.84 (, 1 H), 7.82 (m, 5 H), 6.97 (d, J = 9.0 Hz, 1 H), 6.64 (m, 1 H), 6.61 (s, 2 H), 5.01 (s, 2 H), 3.97 (s, 2 H), 3.82 (, 2 H), 3.30 (s, 3 H), 2.97 (m, 2 H), 2.18 (s, 6 H), 1.28 (, 3 H), 1.14 (m, 18 H). Terms CCD: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 1); Rf = 0.55. Step c: The 5- (2,6-dimethyl-4-hidoxybenzyl) -2-methoxymethoxybenzamide of N-phenethyl was prepared by the procedure used for the synthesis of compound 35, step e: (170 mg, 70%); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 1); Rf = 0.45. Step d: Diethyl [3, 5-dimethyl-4- (4'-methoxymethoxy-3'-phenethylcarbamoylbenzyl) phenoxy] methylphosphonate was prepared by the procedure used for the synthesis of compound 35, step f: (185 mg, 80 %); 2 H NMR (300 MHz, CDC13): d 7.98 (d, J = 2.1 Hz, 1 H), 7.85 (m, 1 H), 7.32 (, 5 H), 7. 01 (d, J = 5.4 Hz, 1 H), 6.91 (m, 1 H), 6.69 (s, 2 H), 4.29 (m, 4 H), 3.98 (s, .2 H), 3.81 (, 2 H), 3.31 (s, 3 H), 2.96 (m, 2 H), 2.22 (s, 6 H), 1.41 (m , 6 H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 1); Rf = 0.52. Step e: The title compound was prepared by the procedure used for the synthesis of compound 35, step h: white solid (40 mg, 48.8%): mp: 100 ° C, dec; X H NMR (300 MHz, DMSO-de): d 8.85 (, 1 H), 7.67 (d, J = 2.1 Hz, 1 H), 7.32 (, 5 H), 6.86 (m, 2 H), 6.78 (s) , 2 H), 4.10 (d, J = 10.5 Hz, 2 H), 3.91 (s, 2 H), 3.57 (, 2 H), 2.92 (m, 2 H), 2.24 (s, 6 H). mp: decomposition at 100, LC-MS m / z = 470 [C25H28N06P + H] +; Analysis calculated for (C25H28NOeP + 0.9 HBr): C, 55.37; H, 5.37; N, Example 38: Compound 38: [4- (3'-benzyl-4 '-hydroxy-benzyl) -3,5-dimethylphenoxyphenylmethylphosphonic acid Step a: To a stirred solution of bromobenzene (0.45 g, 2.89 mmol) in THF (20 mL ) at -78 ° C H-BuLi (1.16 mL, 2.5 M in hexanes) was added. The mixture was stirred at -78 ° C for 1 h and a solution of 5- (2,6-dimethyl-4-triisopropylsilanyloxybenzyl) -2-methoxymethoxybenzaldehyde (Example 35, step e, 1.2 g, 2.63 mmol) was added. The reaction mixture was stirred at -78 ° C for 1 h, allowed to warm to room temperature and stirred for 1 h. The reaction mixture was quenched with saturated NH4C1 and diluted with diethyl ether. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to provide [5- (2,6-dimethyl-4-triisopropylsilanyloxy-benzyl) -2-methoxymethoxy-phenyl] -phenyl-methanol as a yellow oil ( 1.4 g, 99.6%): a H NMR (200 MHz, DMSO-de): d 7.23 (m, 6 H), 6.85 (d, J = 8.8 Hz, 1 H), 6.68 (m, 1 H), 6.56 ( s, 2 H), 5.92 (d, J = 4. 0 Hz, 1 H), 5.62 (d, J = 4.0 Hz, 1 H), 5.10 (q, J = 4.0 Hz, 2 H), 3.84 (s) , 2 H), 3.23 (s, 3 H), 2.11 (s, 6 H), 1.23 (, 3 H), 1.06 (d, J = 6.4 Hz, 18 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 15% ethyl acetate in hexanes; Rf = 0.50. Step b: To a solution of [5- (2,6-dimethyl-4-triisopropylsilanyloxy-benzyl) -2-methoxymethoxy-phenyl] -phenyl-methanol (1.4 g, 2.6 mmol) in ethyl acetate (20 mL) and Acetic acid (1.5 mL) was added Pd / C (0.15 g). The mixture was stirred under an H2 atmosphere for 16 h. The mixture was filtered through a plug of celite. Solvent was removed under reduced pressure. The residue was dissolved in CH2C12 (26 mL), ethyl-diisopropylamine (0.69 mL, 3.95 mmol) and chloromethyl methyl ether (0.26 mL, 3.42 mmol) were added. The reaction mixture was refluxed for 16 h and quenched with water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (15:75) to provide [4- (3'-benzyl-4'-methoxymethoxy-benzyl) -3,5- dimethyl-phenoxy] -triisopropylsilane as an oil (0.9 g, 66%): 1 H NMR (200 MHz, DMSO-d 6): d 7.20 (m, 5 H), 6.90 (d, J = 8.4 Hz, 1 H), 6.79 (s, 1 H), 6.70 (m, 1 H), 6.54 (s, 2 H), 5.12 (s, 2 H), 3.83 (s, 2 H), 3.81 (s, 2 H), 3.25 (s) s, 3 H), 2.09 (s, 6 H), 1.23 (m, 3 H), 1.06 (d, J = 6.6 Hz, 18 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 15% ethyl acetate in hexanes; Rf = 0.66. Step c: To a stirred solution of [4- (3'-benzyl-4'-methoxymethoxybenzyl) -3,5-dimethyl-phenoxy] -triisopropylsilane (0.9 g, 1.73 mmol) in THF (20 mL) at room temperature added tetrabutylammonium fluoride (2.3 mL, 1.0 M in THF). The reaction mixture was stirred at room temperature for 1 h, diluted with diethyl ether and washed with water (30 mL x 2). The solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (1: 1) to provide 4- (3'-benzyl-4'-methoxymethoxy-benzyl) -3,5-dimethyl. -phenol as a light yellow oil (0.6 g, 86%): XR NMR (200 MHz, DMSO-de): d 8.98 (s, 1 H), 7.16 (m, 5 H), 6.87 (m, 2 H) , 6.70 (m, 1 H), 6.43 (s, 2 H), 5.12 (s, 2 H), 3.85 (s, 2 H), 3.76 (s, 2 H), 3.24 (s, 3 H), 2.06 (s, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 20% ethyl acetate in hexanes; Rf = 0.34. Step d: Diethyl [4- (3'-benzyl-4'-methoxymethoxy-benzyl) -3,5-dimethyl-phenoxy] methylphosphonate was prepared by the procedure used for the synthesis of compound 35, step f as an oil light yellow (0.09 g, 64%): E NMR (200 MHz, DMSO-de): d 7.22 (, 5 H), 6.87 (m, 2 H), 6.70 (m, 3 H), 5.12 (s, 2 H), 4.35 (d, J = 10 Hz, 2 H ), 4.11 (m, 4 H), 3.85 (s, 2 H), 3.82 (s, 2 H), 3.24 (s, 3 H), 2.13 (s, 6 H), 1.25 (t, J = 7 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 40% ethyl acetate in hexanes; Rf = 0.27. Step e: The title compound was prepared by the procedure used for the synthesis of compound 35, step h as a white foam (32 mg, 44%): X H NMR (200 MHz, DMSO-d 6): d 9.14 (s, 1 H), 7.21 (m, 5 H), 6.67 (m, 4 H), 6.56 (m, 1 H), 4.02 (d, J = 10.2 Hz, 2 H), 3.78 (s, 2 H) ), 3.75 (s, 2 H), 2.12 (s, 6 H); LC-MS m / z = 413 [C23H2505P + H] +; Analysis calculated for (C23H2505P +0.2 Et20 + 0.6H20): C, 65. 26; H, 6 49 Found: C, 65 07; H, 6. 38.

Example 39: Compound 39: [3,5-dimethyl-4- [3 '- (4-fluoro-benzoyl) -4'-hydroxy-benzyl] phenoxy] methylphosphonic acid Step a: The [5- (2, 6- dimethyl-4-triisopropylsilanyloxy-benzyl) -2-methoxymethoxy-phenyl] - (4-fluoro-phenyl) -methanol was prepared by the procedure used by the synthesis of example 38, step a as an oil (0.68 g, 56%) : X NMR (200 MHz, DMSO-d6): d 7.26 (m, 3 H), 7.06 (m, 2 H), 6.85 (d, J = 8.4 Hz, 1 H), 6.71 (m, 1 H), 6.56 (s, 2 H), 5.91 (d, J = 4.0 Hz, 1 H), 5.68 (d, J = 4.0 Hz, 1 H), 5.10 (q, J = 3.4 Hz, 2 H), 3.84 (s) , 2 H), 3.22 (s, 3 H), 2.11 (s, 6 H), 1.23 (m, 3 H), 1.06 (d, J = 6.2 Hz, 18 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 15% ethyl acetate in hexanes; Rf = 0.26. Step b: To a stirred solution of [5- (2,6-dimethyl-4-triisopropylsilanyloxy-benzyl) -2-methoxymethoxy-phenyl] - (4-fluoro-phenyl) -methanol (0.68 g, 1.2 mmol) in dichloromethane (25 mL) at 0 ° C Dess-Martin periodinane (3.9 mL, 0.48 M solution in CH2C12) was added. The reaction mixture was stirred at room temperature, for 4 h, concentrated, diluted with ethyl acetate. To the solution was added a solution of Na2S203 pentahydrate (50 mg) in 60 mL saturated NaHCO3. After 15 minutes, the organic layer was dried over Na 2 SO 4, filtered and concentrated under reduced pressure to give crude 5- (2,6-dimethyl-4-triisopropylsilyloxy-benzyl) - (4-fluorobenzoyl) -2-methoxymethoxy-phenyl as an oil (0.68 g, 100%): 1 H NMR (200 MHz, DMSO-d 6): d 7.72 (m, 2 H), 7.33 (m, 2 H), 7.12 (m, 2 H), 6.86 (s, 1 H), 6.56 (s, 2 H ), 5.04 (s, 2 H), 3.92 (s, 2 H), 3.14 (s, 3 H), 2.13 (s, 6 H), 1.21 (m, 3 H), 1.03 (d, J = 6.2 Hz, 18 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 20% ethyl acetate in hexanes; Rf = 0.26. Step c: 15 To a stirred solution of 4- (2 ', 6'-dimethyl-4'-triisopropylsilanyloxy-benzyl) -2- (4-fluorobenzoyl) -phenol was prepared by the procedure used by the synthesis of Example 35 step c as a white solid (0.42 g, 86%): mp 140-142 ° C; XR NMR (300 MHz, DMSO-d6): d 9.05 (s, 1 H), 7.78 (, 2 H), 7.36 (m, 2 H), 7.13 (m, 2 H), 6.95 (d, J = 1.5 Hz, 1 H), 6.47 (s, 2 H), 5. 05 (s, 2 H), 3.90 (s, 2 H), 3.15 (s, 3 H), 2.12 (s, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 20% ethyl acetate in hexanes; Rf = 0.63. Step d: Diethyl [3, 5-dimethyl-4- [3 '- (4-fluoro-benzoyl) -4'-hydroxybenzyl] phenoxymethylphosphonate was prepared by the procedure used by the synthesis of Example 35 step f as a light yellow oil (0.054 g, 19%): XR NMR (300 MHz, DMSO-de): d 7.76 (, 2 H), 7.36 (m, 2 H), 7.13 (m, 2 H), 6.94 (d, J = 1.5 Hz, 1 H), 6.77 (s, 2 H), 5.05 (s, 2 H), 4.36 (d, J = 9.6 Hz, 2 H), 4.11 (m, 4 H), 3.95 (s, 2 H), 3.15 (s, 3 H), 2.20 (s, 6 H), 1.25 (m, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 67% ethyl acetate in hexanes; Rf = 0.37. Step d: The title compound was prepared by the procedure used for the synthesis of Example 35 step h as a yellow foam (22 mg, 50%): 2 H NMR (200 MHz, DMSO-de): d 10.14 (s, 1 H), 7.74 (m, 2 H), 7.31 (m, 2 H), 7.03 (m, 1 H), 6.92 (m, 2 H), 6.69 (s, 2 H), 4.02 (d, J = 10.6 Hz, 2 H), 3.87 (s, 2 H), 2.16 (s, 6 H); LC-MS m / z = 445 [C23H22F06P + H] +; Analysis calculated for (C23H22F06P +0.2 Et20 + 0.3 CF3COOH): C, 59.39; H, 4.96. Found: C, 59.62; H, 4.64.

Example 40: Compound 40: [3,5-dimethyl-4- [3 '- (4-fluoro-benzyl) -4'-hydroxy-benzyl] phenoxy] ethylphosphonic acid Step a: To a stirred solution of acid [3, 5-Dimethyl-4- [3 '- (4-fluoro-benzyl) -4'-hydroxy-benzyl] phenoxy] methylphosphonic diethyl ester (0.13 g, 0.24 mmol) in MeOH (8 mL) at 0 ° C was added NaBH 4 (90 mg, 2.4 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give [3,5-dimethyl-4- [3 '- (4-fluorophenyl-hydroxymethyl) -4'-hydroxybenzyl] phenoxy] methylphosphonic acid diethyl acid. as an oil (0.13 g, 100%). This crude product was dissolved in CH2C12 (10 mL) and Et3SiH (0.38 mL, 2.4 mmol) and TFA (0.18 mL, 2.4 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated NaHCO 3. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by Column chromatography on silica gel, eluted with ethyl acetate to provide [3,5-dimethyl-4- [3 '- (4-fluoro-benzyl) -4' -hydroxy-benzyl] diethyl phenoxy] methylphosphonate as an oil (80 mg, 69%): X H NMR (200 MHz / DMSO-d 6): d 9.18 (s, 1 H), 7.13 (m, 4 H), 6.67 (m, 5 H) ), 4.33 (d, J = 10 Hz, 2 H), 4.11 (m, 4 H), 3.76 (s, 4 H), 2.12 (s, 6 H), 1.25 (t, J = 7 Hz, 6 H) ). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate; Rf = 0.5 Step b: The title compound was prepared by the procedure used for the synthesis of Example 35 step h as a yellow solid (60 mg, 85%):? R NMR (200 MHz, DMS0-d6): d 9.11 (s, 1 H), 7.13 (m, 4 H), 6.63 (m, 5 H), 4.01 (d, J = 10.2 Hz, 2 H), 3.76 (s, 4 H), 2.12 (s, 6 H); LC-MS m / z = 431 [C23H24F05P + H] +; Analysis calculated for (C23H24F05P + 0.6 H20 + 0.2 Et20): C, 62.68; H, 6.01. Found: C, 62.31; H, 6.16; mp: 169-171 ° C.

Example 41: Compound 41: [3,5-dimethyl-4- [3'-benzyl-4'-hydroxybenzyl] benzoyl] methylphosphonic acid Step a: To a solution of 4- (3'-benzyl-4'-methoxymethoxy- benzyl) -3,5-dimethyl-phenol (example 38, step c, 0.5 g, 1.38 mmol) and DMAP (0.67 g, 5.52 mmol) in CH2C12 (20 mL) at 0 ° C was slowly added trifluoromethanesulfonyl anhydride (0.35 mL, 2.1 mmol). The reaction mixture was stirred at 0 ° C for 2 h and quenched by water (10 mL). The organic layer was dried over Na 2 SO, filtered and concentrated under reduced pressure to give trifluoromethanesulfonate of 4- (3'-benzyl-4'-methoxymethoxy-benzyl) -3,5-dimethyl-phenyl as an oil (0.5 g, 73%): XR NMR (300 MHz, DMSO-de): d 7.14-7.28 (m, 7 H), 6.94 (d, J = 8.4 Hz, 1 H), 6.85 (d, J = 2.4 Hz, 1 H), 6.70 (m, 1 H), 5.15 (s, 2 H), 3.94 (s, 2 H), 3.88 (s, 2 H), 3.27 (s, 3 H) ), 2.24 (s, 6 H); Terms CCD: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (15:75); Rf = 0.55. Step b: To a solution of 4- (3'-benzyl-4'-methoxymethoxy-benzyl) -3,5-dimethyl-phenyl trifluoromethanesulfonate (0.5 g, 1 mmol) in DMF (8 mL) in a pump apparatus MeOH was added (0.82 L, 20 mmol), Pd (OAc) 2 (23 mg, 0.1 mmol), bis- (diphenphosphino) propane (42 mg, 0.1 mmol) and TEA (0.28 L, 2 mmol). 60 psi (4.218 kg / cm2) of CO was then infused and the reaction mixture was stirred at 90 ° C for 16 h. The cold bomb was vented and the reaction mixture was poured into cold IN HCl, extracted with EtOAc twice, the combined EtOAc was washed with brine, dried over MgSO, filtered and concentrated. The residue was purified by Column chromatography on silica gel, eluted with ethyl acetate-hexanes (15:75) to provide 4- (3'-benzyl-4 '-methoxymethoxy-benzyl) -3,5-dimethyl- Methyl benzoate as a yellow oil (360 mg, 88%): XR NMR (300 MHz, DMSO-d6): d 7.66 (s, 2 H), 7.16 (m, 5 H), 6.90 (m, 2 H) , 6.71 (m, 1 H), 5.15 (s, 2 H), 3.98 (s, 2 H), 3.87 (s, 2 H), 3.85 (s, 3 H), 3.26 (s, 3 H), 2.25 (s, 6 H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (15:75); Rf = 0.50. Step c: To a stirred solution of diethyl methylphosphonate (0.39 mL, 2.67 mmol) in THF (10 mL) at -78 ° C was added n-BuLi (2.5 M in hexanes, 1.07 mL), the reaction mixture was stirred at -78 ° C for 1 h, then 4- (3'-benzyl-4'-methoxymethoxybenzyl) -3,5-dimethyl-benzoate methyl (360 mg, 0.89 mmol) in THF (10 mL) was added to the same temperature. The reaction mixture was stirred at -78 ° C for 1.5 h, then at room temperature for 1 h. The reaction mixture was quenched with saturated NH4C1 and diluted with diethyl ether. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluted with ethyl acetate to provide [3, 5-dimethyl-4- [3'-benzyl-4'-hydroxy-benzyl] benzoyl] methyl-diethylphosphonate as a Light yellow oil (350 mg, 75%): XR NMR (300 MHz, DMSO-d6): d 7.72 (s, 2 H), 7.16 (m, 5 H), 6.92 (m, 2 H), 6.71 (m , 1 H), 5.14 (s, 2 H), 4.04 (m, 6 H), 3.99 (s, 2 H), 3.82 (d, J = 22.2 Hz, 2 H), 3.26 (s, 3 H), 2.27 (s, 6 H), 1.19 (t, J = 7.5 Hz, 6 H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (2: 1); Rf = 0.35.

Step d: The title compound was prepared by the procedure described by the synthesis of example 35, step h as a white foam (55 mg, 88%): 1 H NMR (200 MHz, DMSO-d 6): d 9.21 (s, 1 H), 7.66 (s, 2 H), 7.21 (m, 5 H), 6.65 (m, 2 H), 6.55 (m, 1 H), 3.89 (s, 2 H), 3.79 (s, 2 H) ), 3.45 (d, J = 22.8 Hz, 2 H), 2.16 (s, 6 H); LC-MS m / z = 425 [C 24 H 2505 P + H] +; Analysis calculated for (C24H2505P +1.6 H20): C, 63.60; H, 6.27. Found: C, 63.87; H, 6.43. Using the appropriate starting material, compounds 41-1 to 41-3 were prepared in a manner analogous to that described by the synthesis of compound 41.

Compound 41-1: 2- [3,5-dimethyl-4- (4'-fluoro-3'-iso-propyl-benzyl) phenyl] -2-oxo-ethylphosphonic acid The title compound was prepared from , 5-dimethyl-4- (4 '-fluoro-3'-iso-propyl-benzyl) -phenol (compound 27, step e) by the procedure described by the synthesis of compound 41 as a white solid (106 mg, 81.5 %): "" "H NMR (300 MHz, DMSO-d6): d 7.70 (s, 2 H), 7.10 (m, 1 H), 6.98 (m, 1 H), 6.65 (m, 1 H), 4.00 (s, 2 H), 3.48 (d, J = 22.4 Hz, 2 H), 3.09 (m, 1 H), 2.26 (s, 6 H), 1.17 (d, J = 7.0 Hz, 6 H). mp = 138-140, LC-MS m / z = 379 [C 20 H 24 FO 4 P + H] +; Analysis calculated for (C20H24FO4P): C, 63. 49; H, 6. 39. Found: C, 63. 40; H, 6. 63.

Compound 41-3: 2- [3,5-dichloro-4- (4-fluoro-iso-propyl-benzyl) -phenyl] -2-oxo-ethylphosonic acid 3, 5-Dichloro-4- (4- fluoro-3-iso-propyl-benzyl) -phenol, the intermediate for the synthesis of compound 27-2, was transformed into the title compound by the procedure described by the synthesis of compound 41 to give a white solid (65 mg, 82%): a H NMR (300 MHz, DMSO-d 6): d 8.08 (s, 2 H), 7.25 (m, 1 H), 7.05 (m, 1 H), 6.90 (m, 1 H), 4.32 ( s, 2 H), 3.60 (d, J = 22.5 Hz, 2 H), 3.12 (, 1 H), 1.20 (d, J = 6.9 Hz, 6 H). mp = 132-134, LC-MS m / z = 417 [C? 8H? 8Cl2F04P + H] +; Analysis calculated for (C? 8H? 8Cl2F04P): C, 51.57; H, 4.33. Found: C, 51.37; H, 4.65.

Example 42: Compound 42: 2- [3,5-dimethyl-3'-benzyl-4'-hydroxybenzyl] phenyl] -ethylphosphonic acid Step a: To a stirred solution of [3,5-dimethyl-4- [3 '] diethyl benzyl-4'-hydroxy-benzyl] benzoyl] methylphosphonate (example 41, step c, 0.27 g, 0.52 mmol) in MeOH (10 mL) at 0 ° C was added NaBH (78 mg, 2.1 mmol). The reaction mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was dried over Na 2 SO 4, filtered and concentrated under reduced pressure to provide 2- [4- (3'-benzyl-4'-methoxymethoxy-benzyl) -3,5-dimethyl-phenyl] -2-hydroxy- diethyl ethyl phosphonate as an oil (0.27 g, 100%): 1 H NMR (300 MHz, DMS0-d 6): d 7.18 (m, 5 H), 7.03 (s, 2 H), 6.93 (m, 2 H), 6.70 (m, 1 H), 5.39 ( d, J = 4.5 Hz, 1 H), 5.14 (s, 2 H), 4.80 (m, 1 H), 3.85 (m, 8 H), 3.26 (s, 3 H), 2.18 (s, 6 H), 1.19 (m, 6 H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (2: 1); Rf = 0.29. Step b: To a stirred solution of diethyl 2- [4- (3'-benzyl-4'-methoxymethoxy-benzyl) -3,5-dimethyl-phenyl] -2-hydroxyethyl-phosphonate (0.24 g, 0.46 mmol) in CH2C12 (10 mL) at room temperature was added Et3SiH (0.34 mL, 2.1 mmol) and TFA (0.4 mL, 5.4 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated NaHCO 3. The organic layer was dried over Na 2 SO, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (3: 1) to give 2- [4- (3'-benzyl-4'-hydroxy-benzyl) -3, 5-dimethyl-phenyl] -ethylphosphonate as an oil (55 mg, 26%): 1 H NMR (300 MHz, DMS0-d 6): d 9.16 (s, 1 H), 7.22 (m, 5 H), 6.91 (s) , 2 H), 6.76 (s, 1 H), 6.62 (m, 2 H), 4.00 (m, 4 H), 3.80 (s, 4 H), 2.68 (m, 2 H), 2.14 (s, 6 H), 2.06 (m, 2 H), 1.23 (m, 6 H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (2: 1); Rf = 0.33. Step c: The title compound was prepared by the procedure described by the synthesis of example 35, step h as a light yellow solid (28 mg, 58%): mp: 168-170 ° C; 2H NMR (200 MHz, DMSO-de): d 9.11 (s, 1 H), 7.19 (m, 5 H), 6.85 (s, 2 H), 6.63 (m, 3 H), 3.77 (s, 4 H), 2.66 (m, 2 H), 2.12 (s, 6 H), 1. 76 (m, 2 H); LC-MS m / z = 411 [C 24 H 2 704 P + H] +; Analysis calculated for (C24H2704P +1.6 H20): C, 68. 14; H, 6. 77.

Found: C, 68.19; H, 6.55.

Compound 42-1: 2- [3,5-dimethyl-4- (4'-fluoro-3'-iso-propyl-benzyl) phenyl] ethylphosphonic acid Step a: The intermediate 2- [3,5-dimethyl-4 - (4'-Fluoro-3'-iso-propyl-benzyl) phenyl] -2-oxo-ethylphosphonate from diethyl by the synthesis of compound 41-1 was transformed into 2- [3,5-dimethyl-4- (4 '-fluoro-3' -iso-propyl-benzyl) phenyl] -2-hydroxy-ethylphosphonate of diethyl by the procedure described by the synthesis of compound 42, step a to give a yellow liquid (580 mg, 96.2%): XR NMR (300 MHz, CDC13): d 7.12 (s, 2 H), 6.99 (m, 1 H), 6.84 (m, 1 H), 6.66 (m, 1 H), 5.09 (s, 1 H), 4.19 (, 4 H), 4.01 (s, 1 H), 3.18 (, 1 H), 2.22 (s, 6 H), 2.20 (m, 2 H), 1.36 (m, 6 H), 1.25 (d, J = 6.4 Hz, 6 H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (4: 1); Rf = 0.58. Step b: A degassed solution of diethyl 2- [3,5-dimethyl-4- (4'-fluoro-3'-iso-propyl-benzyl) phenyl] -2-hydroxyethylphosphonate (500 mg, 1.15 mmol) and Pd / C (50 mg) in EtOH / HOAc (19/1) was stirred under 1 atmosphere of hydrogen at room temperature. After 5 h, the catalyst was filtered through a pad of celite and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate-hexanes: 9: 1) to provide 2- [3,5-dimethyl-4- (4'-fluoro-3'-iso-propyl-benzyl. diethyl phenyl] ethylphosphonate (450 mg, 93.5%): XR NMR (300 MHz, CDC13): d 6.99 (s, 1 H), 6.98 (s, 2 H), 6.88 (m, 1 H), 6.66 ( m, 1 H), 4.65 (, 4 H), 3.99 (s, 2 H), 3.19 (m, 1 H), 2.88 (m, .2 H), 2.24 (s, 6 H), 2.10 (m, 2 H), 1.51 (m, 6 H), 1.25 (d, J = 6.9 Hz, 6 H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 1); Rf = 0.53. Step c: Diethyl 2- [3,5-dimethyl-4- (4'-fluoro-3'-iso-propylbenzyl) phenyl] ethylphosphonate was transformed into the title compound by the procedure described by the synthesis of the compound. , step h to give a white solid (60 mg, 35%): a H NMR (300 MHz, DMSO-d 6): d 7.09 (m, 1 H), 6.98 (m, 1 H), 6.92 (s, 2 H ), 6.66 (m, 1 H), 3.94 (s, 2 H), 3.95 (s, 2 H), 3.11 (m, 1 H), 2.70 (m, 2 H), 2.18 (s, 6 H), 1.80 (m, 2 H), 1.19 (d, J = 7.2 Hz, 6 H). mp = 116-118, LC-MS m / z = 365 [C20H26FO3P + H] +; Analysis calculated for (C20H26FO3P): C, 65.92; H, 7.19. Found: C, 65.68; H, 7.19.

Example 43 Compound 43: [3,5-dimethyl-4-S- [(4'-hydroxy-3'-iso-propylphenyl) sulfanyl] phenoxymethylphosphonate: Step a: A mixture of 3,5-Dimethyl-4-iodophenol (2.0 g, 8.06 mmol), potassium carbonate (3.33 g, 24.2 mmol) and methyl iodide (602 μL, 9.67 mmol) in DMF (20 mL) under a nitrogen atmosphere was heated to 65 C, with stirring for 16 hours. The cold reaction was diluted with ethyl acetate (50 mL), filtered on a sep funnel and washed with water (2x 25 mL) then brine (25 mL). The organics were dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to give (1.68 g, 79%); a H NMR (300 MHz, DMSO-d 6): d 6.79 (s, 2 H), 3.72 (s, 3 H), 2.37 (s, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 5% ethyl acetate in hexane; Rf = 0.47. Step b: Copper iodide (70 mg, 0.37 mmol), neocuprinine (80 mg, 0.37 mmol) and potassium t-butoxide (470 mg, 4. 05 mmol) were added in this order to a solution of 4-methoxy 3-iso-propyl thiophenol (US 6,747, 048 B2, 600 mg, 2.3 mmol) and 3,5-dimethyl-4-iodoanisole (678 mg, 3.72 mmol) in toluene (10 mL).

After refluxing overnight, the cold reaction mixture was poured into ethyl acetate (50 mL) and washed twice with IN HCl then brine. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane / ethyl acetate 100: 0 to 40: 1) to give 3,5-dimethyl-4- (3 '-iso-propyl-4'-methoxyphenylsulphane) anisole (0.358 g, 49%); 1 H NMR (200 MHz, DMSO-d6): d 6.87-6.80 (m, 4 H), 6.56 (m, 1 H), 3.76 (s, 3 H), 3.71 (s, 3 H), 3.15 (m, 1 H), 2.34 ( s, 6 H), 1.06 (d, 6H, J = 7 Hz); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 25% ethyl acetate in hexane; Rf = 0.36. Step c: 3,5-Dimethyl-4- (4'-hydroxy-3'-iso-propyl-phenylsulphane) phenol was prepared from 2,5-dimethyl-4- (3'-iso-propyl-4) '-methoxy-phenylsulphane) anisole according to the procedure described in example 8, step d. X H NMR (300 MHz, DMSO-d 6): d 9.58 (bs, 1 H), 9.21 (bs, 1 H), 6.77 (m, 1 H), 6.63 (, 3 H), 6.46 (dd, 1H, J = 2.7 Hz and J = 8.1 Hz), 3.09 (m, 1 H), 2.28 (s, 6 H), 1.06 (d, 6 H, J = 7.2 Hz); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 25% ethyl acetate in hexane; Rf = 0.12. Step d [3, 5-Dimethyl-4- (4'-hydroxy-3'-iso-propyl-phenylsulfanyl) -phenoxylmethylphosphonate diethyl ester was prepared according to the procedure described in compound 8, step e: R NMR (300 MHz, DMSO-d6): d 9.26 (s, 1 H), 6.92 (s, 2 H), 6.81 (d, 1 H, J = 2.4 Hz), 6.65 (d, 1 H, J = 8.4 Hz), 6.47 (dd, 1 H, J = 2.1 Hz and J = 8 Hz), 4.42 (d, 2 H, J = 10 Hz), 4.11 (m, 4 H), 3.10 (m, 1 H), 2.35 (s) , 6 H), 1.25 (m, 6 H), 1.06 (d, 6 H, J = 2.9 Hz); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 50% ethyl acetate in hexane; Rf = 0.12. Step f: The title compound was prepared according to the procedure described in compound 8, step f: 1H NMR (300 MHz, DMSO-de): d 9.22 (s, 1 H), 6.88 (s, 2 H), 6.81 (d, J = 2.1 Hz, 1 H), 6.64 (d, J = 8.4 Hz, 1 H), 6.46 (dd, J = 2 Hz and J = 8.2 Hz, 1 H), 4.08 (d, J = 10.2 Hz, 2 H), 3.10 (m, 1 H), 2.34 (s, 6 H), 1.07 (d, J = 6.6 H, 6 Hz); LC-MS m / z = 381 [C? 8H23? 5PS-H] ~; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = IPA / NH4OH / H20 [7: 1: 2]; Rf = 0.53; CLAR, YMC Pack ODS-AQ, AQ 302.150mm x 4.6 mm, S 5 μm, 12nm, flow 2 mL / min, Solvent A: 0.05% aqueous TFA, Solvent B: acetonitrile / 0.05% TFA, Gradient 20% B up to 70 % B in 13 min-wait 1 min. to 70% B- Gradient to 100% B in 6 min. Rt = 10.23 min. Example 44: Compound 44: acid [3, 5-dimethyl-4- [4 '-hydroxy-3' - (iso-propylsulfonyl) benzyl] phenoxymethylphosphonic Step a: Triisopropyl- [3,5-dimethyl-4- (4'-methoxymethoxy-3'-iso- propylsulfanylbenzyl) -phenoxy] silane was synthesized according to the procedure described in Example 35, step d using di-iso-propyl disulfide as the electrophilic. The product of this reaction was carried out in the next step as a mixture of the desired product and the starting material triisopropyl- [3,5-dimethyl-4- (4'-methoxymethoxybenzyl) -phenoxy] silane: H NMR. { 200 MHz, DMS0-d6): d 1.15 (d, J = 6.4 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 5% ethyl acetate in hexane; Rf = 0.32. Step b: 3,5-Dimethyl 4- (4'-methoxymethoxy-3'-iso-propylsulfanylbenzyl) phenol was prepared according to the procedure described in Example 35, step e. The product of this reaction was carried out as a mixture of the desired product and 3,5-dimethyl 4- (4'-methoxymethoxybenzyl) phenol: 2 H NMR (200 MHz, DMSO-de): d 1.16 (d, J = 9.9 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 5% ethyl acetate in hexane; Rf = 0.25. Step c: Diethyl [3, 5-dimethyl-4- (4'-methoxymethoxy-3'-iso-propylsulfanylbenzyl) phenoxymethylphosphonate was prepared according to the procedure described in Example 8, step e, and was carried out as a mixture of desired product and [3,5-dimethyl-4- (4'-methoxymethoxybenzyl) phenoxy] methylphosphonate diethyl ester: 1 H NMR (200 MHz, DMSO-d 6): d 4.36 (d, 2H, J = 15Hz), 4.11 (, 4H ), 1.26 (t, 6H, J = 10.8 Hz), 1.16 (d, 6H, J = 9.9 Hz); LC-MS m / z = 465 [C23H360ePS + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 50% ethyl acetate in hexane; Rf = 0.12. Step d: A mixture of diethyl [3, 5-dimethyl-4- (4'-methoxymethoxy-3'-iso-propylsulfanylbenzyl) phenoxymethylphosphonate (0.200g, 0.402mmol), saturated sodium bicarbonate (1 MI) and mCPBA 50% -60% (0.173 g, 1.01 mmol) in dichloromethane (5 L) was stirred overnight at room temperature. The layers were separated and the organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative CCD (2000 μm, 5% hexanes in ethyl acetate) to give [3,5-dimethyl-4- [4 '-methoxymethoxy-3' - (iso-propylsulfonyl) benzyl] phenoxy] methylphosphonate from diethyl (0.090 g, 42%); X H NMR (200 MHz, DMSO-d 6): d 7.42 (s, 1 H), 7.24 (s, 2 H), 6.77 (s, 2 H), 5.32 (s, 2 H), 4.36 (d, J = 10 Hz, 2 H), 4.11 (m, 4 H), 3.96 (s, 2 H), 3.69 (m, 1 H), 3.39 (s, 3 H), 2.16 (s, 6 H), 1.26 (t , J = 7 Hz, 6 H), 1.12 (d, J = 7 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate; Rf = 0.28. Step e: The title compound was prepared according to that described by example 8, step f (0.057 g, 82); X H NMR (200 MHz, DMSO-de): d 10.89 (bs, 1 H), 7.31 (s, 1 H), 7.12 (dd, J = 5.8, 2.2 Hz, 1 Hz), 6.93 (d, J = 8 H, 1 Hz), 6.72 (s, 2 H), 4.04 (d, J = 10.2 H, 2 Hz), 3.89 (s, 2 H), 3.64 (m, 1 H), 2.15 (s, 6 H) , 1.11 (d, J = 7 Hz, 6 H); LC-MS m / z = 427 [C19H25? 7PS-H] "; CCD Conditions: Silica gel uniplaca, 250 microns; Mobile phase = iso-propyl alcohol / NH4OH / H20 [7: 1: 2]; Rf = 0.53; Analysis calculated for (C? 8H2305PS + 1 M H20 + 0.1M EtOAc) C, 51.18; H, 6.15 Found: C, 51.01; H, 5.94 Example 45 Compound 45: [4,6-dimethyl- 5- (4'-Hydroxy-3'-iso-propyl) benzylbenzofuran-2-phosphonic Step a: To a mixture of 3,5-dimethyl-4- (4 '-methoxymethoxy-3'-iso-propylbenzyl) phenol ( 1.0 g, 3.18 mmol, G. Chiellini et al., Bioorg Med. Chem. Lett., 2000, 10, 2607) in C2H50H (30.0 mL) and 40% aqueous methylamine (6.20 mL) at 0 ° C was added a solution of iodide. of potassium (2.5 g, 15.0 mmol) and iodide (0.98 g, 3.82 mmol) in H20 (6.20 mL) The reaction mixture was stirred at 0 ° C for 1 h, quenched with water and extracted with ethyl acetate (2x30 mL) The organic layers were dried over MgSO4, filtered and concentrated under reduced pressure.The crude product was purified by Columum chromatography. Na gel was eluted with 20% ethyl acetate in hexanes to provide 3,5-dimethyl-2-iodo-4- (4 '-methoxymethoxy-3'-iso-propylbenzyl) phenol as white solid: XH NMR (300 MHz, CD30D): d 6.93 (m, 2 H), 6. 65 (, 2 H), 5.18 (s, 2 H), 4.05 (s, 2 H), 3.48 (s, 3 H), 3.30 (m, 1 H), 2.41 (s, 3 H), 2.19 (s, 3 H), 1.18 (d, J = 6.6 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 5); Rf = 0.60. Step b: A solution of diethyl ethynylphosphonate was added to a mixture of Cu20 (0.08 g, 0.57 mmol) in DMF (2.0 mL).

(O.llg, 0.68 mmol) in DMF (0.5 mL) followed by a solution of 3,5-dimethyl-2-iodo-4- (4 '-methoxymethoxy-3'-iso-propylbenzyl) phenol in diisopropylethylamine (0.40 mL). ) and DMF (1.0 mL). The reaction mixture was heated at 90 ° C for 48 h, it was cooled to room temperature and filtered through a plug of celite. The solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL). The organic layer was separated, dried over MgSO4. Solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel, eluted with 50% ethyl acetate in hexanes to provide [4,6-dimethyl-5- (4'-hydroxy-3 '-iso-propyl) benzyl] benzofuran-2-diethyl phosphonate (0.07 g, 26%) as a colorless oil: XH NMR (300 MHz, CD3OD): d 7.66 (dd, J = 8.1, 2.4 Hz, 1 H ), 7.35 (s, 1 H), 6.97 (d, J = 2.1 Hz, 1 H), 6.92 (d, J = 8.1 Hz, 1 H), 6.64 (dd, J = 8.1, 2.1 Hz, 1 H) , 5.18 (s, 2 H), 4.24 (, 4 H), 4.14 (s, 2 H), 3.47 (s, 3 H), 3.30 (m, 1 H), 2.49 (s, 3 H), 2.39 ( s, 3 H), 1.40 (t,, J = 6.0 Hz, 6 H), 1.14 (d, J = 6.6 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 1); Rf = 0.50. Step c: [4,6-Dimethyl-5- (4'-hydroxy-3'-iso-propyl) benzyl] benzofuran-2-phosphonic acid was prepared from [4,6-dimethyl-5- (4 Diethyl-2-hydroxy-3'-iso-propyl) benzyl] benzofuran-2-phosphonate according to the procedure described in example 7, step b: mp: 180-182 ° C; XE NMR (300 MHz, CD30D): d 7.44 (dd, J = 8.1, 2.4 Hz, 1 H), 7.30 (s, 1 H), 6.85 (d, J = 2.1 Hz, 1 H), 6.61 (d, J = 8.1 Hz, 1 H), 6.55 (d, J = 8.1 Hz, 1 H), 4.08 (s, 2 H), 3.24 (m, 1 H), 2.46 (s, 3 H), 2.37 (s, 3 H), 1.14 (d, J = 6.6 Hz, 6 H); LC-MS m / z = 375 [C 20 H 23 O 5 P + H] +; Analysis calculated for (C 20 H 23 O 5 P + 0.7 H 20 + 0.1 CH 3 OH): C, 61.87; H, 6.41. Found: C, 61.80; H, 6.60. Example 46 Compound 46: [3,5-Dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) -2-iodophenoxy] methylphosphonic acid The title compound was prepared from 3,5-dimethyl-4 - (3 '-iso-propyl-4' -methoxymethoxy) benzyl-2-iodophenol (compound 45, stagea) according to the procedure described in example 7: aH NMR (300 MHz, DMSO-d6): d 9.00 (s) , 1 H), 6.87 (d, J = 3.9 Hz, 1 H), 6.61 (d, J = 12.0 Hz, 1 H), 6.40 (d, J = 12.6 Hz, 1 H), 4.32 (d, J = 10.2 Hz, 2 H), 3.94 (s, 2 H), 3.12 (m, 1 H), 2.36 (s, 3 H), 2.21 (s, 3 H); LC-MS m / z = 491 [C? 9H24I05P + H] +; Analysis calculated for C? 9H24I05P: C, 46.55; H, 4.93. Found: C, 46.93; H, 4.99. Example 47 Compound 47: [3,5-Dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) -phenylamino] methylphosphonic acid Step a: A solution of 3,5-dimethyl-4- (4'-methoxymethoxy) -3 '-iso-propylbenzyl) -trifluoromethanesulfonyloxyphenyl (2.04 g, 4.57 mmol, intermediate for the synthesis of compound 24-1), triethylamine (1.27 mL, 9.14 mmol), 1,3-bis (diphenylphosphino) propane (0.19 mL, 0.45 mmol), MeOH (3.71 L, 91.40 mmol), and Pd (OAc) 2 (0.102 g, 0.46 mmol) in DMF (25 mL) was heated at 90 ° C under 60 psi (4.218 kg / cm2) of CO in a Parr reactor for 16 h. The reaction mixture was cooled to 0 ° C, diluted with ethyl acetate (25 mL) and washed with H20 (25 mLx2). The organic solution was dried over Na 2 SO 4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (1: 4) to provide 3,5-dimethyl-4- (4'-methoxymethoxy-3'-iso-propylbenzyl) methyl benzoate as an oil (1.52 g, 93%): X H NMR (300 MHz, DMSO-d 6): d 7.68 (s, 2 H), 6.97 (m, 1 H), 6.91 (m, 2 H), 6.20 (m, 1 H), 5.16 (s, 2 H), 4.01 (s, 3 H), 3.85 (s, 3 H), 3.21 (m, 1 H), 2.28 (s, 6 H), 1.14 ( d, J = 6.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 4); Rf = 0.42. Step b: To a stirred solution of methyl 3,5-dimethyl-4- (4'-methoxymethoxy-3'-iso-propylbenzyl) benzoate (0.750 g, 2.11 mmol) in MeOH (20.0 mL) at 0 ° C was added. added 1M NaOH (12.64 mL, 12.64 mmol). The reaction mixture was heated at 50 ° C for 16 h, cooled to 0 ° C and acidified with 2 N HCl. The mixture was extracted with ethyl acetate (20 mL) and washed with H20 (10 mL x 2.). Solvent was removed under reduced pressure to provide 3,5-dimethyl-4- (4'-methoxymethoxy-3'-iso-propylbenzyl) benzoic acid as white solid (0.71 g, 98%): X H NMR (300 MHz, DMSO-d 6): d 12.76 (s, 1 H), 7.65 (s, 2 H), 6.98 (m, 1 H), 6.91 (m, 1 H), 6.60 (m, 1 H ), 5.17 (s, 2 H), 4.00 (s, 2 H), 3.37 (s, 3 H), 3.23 (m, 1 H), 2.27 (s, 6 H), 1.14 (d, J = 6.0 Hz , 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (4: 1); Rf = 0.00 Step c: To a suspension of 3,5-dimethyl-4- (4'-methoxymethoxy-3'-iso-propylbenzyl) benzoic acid (0.70 g, 2.04 mmol), tert-butanol (0.756 mg, 10.22 mmol) and triethylamine (0.71 g, 5.11 mmol) in toluene (30 mL) was added diphenylphosphoryl azide (0.44 mL, 2.04 mmol). The reaction mixture was heated under reflux for 16 h, cooled to room temperature and drained into a cold solution of 0.25 M HCl (30 mL). The mixture was diluted with ethyl acetate and washed with H20 (30 mL). The organic layer was separated and concentrated under redupressure. The crude product was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (1: 9) to give N-3,5-dimethyl-4- (4'-methoxymethoxy-3'-iso- propylbenzyl) t-butyl carbamate as a yellow oil (0.63 g, 75%): 1 H NMR (300 MHz, DMS0-d6): d 9.16 (s, 1 H), 7.16 (s, 2 H), 6.96 (, 1 H), 6.90 (m, 1 H), 6.62 (m, 1 H), 5.16 (s, 2 H), 3.86 (s, 2 H), 3.37 (s, 3 H), 3.22 (m, 1 H), 2.15 (s, 6 H), 1.48 (m, 9 H), 1.23 (d, J = 6.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (3: 7); Rf = 0.72. Step d: To a mixture of t-butyl N-3, 5-dimethyl-4- (4'-methoxymethoxy-3'-iso-propylbenzyl) carbamate (0.315 g, 0.76 mmol) in THF (8.0 mL) at - 78 ° C was added lithium diisopropylamide (0.46 g, 0.91 mmol, 2.0 M solution in THF / heptane / ethylbenzene). The reaction mixture was stirred at -78 ° C for 20 minutes and trifluoromethanesulfonic acid diethoxyphosphoryl methyl ester (0.16 g, 0.76 mmol) was added. The reaction mixture was stirred at -78 ° C for 1 h, allowed to warm to room temperature and stirred for 4 h. The reaction mixture was quenched with 2.5 M aqueous ammonium chloride and diluted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride (8.0 mL), H20 (8.0 mL) and brine (8.0 mL). The organic solution was dried over MgSO4, filtered and concentrated under redupressure. The crude product was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (1: 1) to give Nt-butoxycarbonyl- [3,5-dimethyl-4- (4 '-methoxymethoxy-3' diethyl-isopropylbenzyl) phenylamino] methylphosphonate as an oil (0.21 g, 49%): 2 H NMR (300 MHz, DMSO-de): d 7.00 (s, 2 H), 6.94 (m, 1 H), 6 90 (, 1 H), 6.64 (, 1 H), 5.16 (s, 2 H), 4.09 (d, J = 6.0 Hz, 2 H), 4.00 (m, 4 H), 3.8 (m, 2 H) ), 3.37 (s, 3 H), 3.22 (, 1 H), 2.20 (s, 6 H), 1.40 (s, 9 H), 1.27 (m, 6 H), 1.13 (m, 6 H);; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (3: 2); Rf = 0.20. Step e: To a stirred solution of diethyl Nt-butoxycarbonyl- [3,5-dimethyl-4- (4'-methoxymethoxy-3'-iso-propylbenzyl) phenylamino] methylphosphonate (0.19 g, 0.34 mmol) in MeOH (4.0 mL) at 0 ° C was added 2 M HCl (1.68 mL, 3.37 mmol). The reaction mixture was allowed to warm to room temperature and was stirred for 48 h. The reaction mixture was cooled to 0 ° C, neutralized with NaHCO 3, diluted with ethyl acetate (20 mL) and washed with H 2 O (10 mL x 2). The organic solution was dried over MgSO, filtered and concentrated under redupressure. The residue was purified by Column chromatography on silica gel, eluted with ethyl acetate-hexanes (3: 2) to provide [3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenylamino] diethyl methylphosphonate as a white solid (0.07 g, 51%): X H NMR (300 MHz, DMSO-d 6): d 8.95 (s, 1 H), 6.84 (m, 1 H), 6.63 (m, 1 H), 6.50 (m, 1 H), 6.45 (s, 2 H), 5.39 (m, 1 H), 4.06 (s, 6 H), 3.74 (s, 2 H), 3.51 (m, 2 H), 3.13 (m, 1 H), 2.09 (s, 6 H), 1.20 (m, 6 H), 1.11 (d, J = 6.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (4: 1); Rf = 0.29. Step f: To a solution of diethyl [3, 5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenylamino] methylphosphonate (0.070 g, 0.17 mmol) in CH2C12 (3.0 mL) at -30 ° C was added bromotrimethylsilane (0.28 mL, 2.08 mmol). The reaction mixture was stirred at room temperature for 16 h and the solvent was removed under reduced pressure. The residue was treated with acetonitrile-water (4: 1, 5.0 mL) and stirred at 38 ° C for 30 min. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with H20. The organic solution was dried over MgSO4, filtered and concentrated under reduced pressure to provide the title compound as an opaque white powder (0.050 g, 79%); mp: 147-150 ° C; NMR (300 MHz, DMSO-ds): d 8.97 (s, 1 H), 6.86 (m, 1 H), 6.59 (m, 1 H), 6.49 (m, 1 H), 6.45 (s, 2 H), 3.74 (s, 2 H), 3.20 (d, J = 12.0 Hz, 2 H), 3.13 (m, 1 H), 2.10 (s, 6 H), 1.12 (d, J = 6.0 Hz, 6 H); LC-MS m / z = 364 [C19H26N04P-H] +; Analysis calculated for (C? 9H26N0P + 1.0 H20 + 0.2 HBr + 0.2 CH3C02CH2CH3): C, 57.28; H, 7.23; N, 3.37; Br, 3.85. Found: C, 57.60; H, 7.33; N, 3.12; Br, 3.48.

Example 48 Compound 48: [4- (3'-cyclopropyl-4'-hydroxybenzyl) -3,5-dimethylphenoxyphenylmethylphosphonic acid Step a: To a suspension of methyltriphosphonium bromide (4.81 g, 13.46 mmol) in THF (10.0 mL) a 0 ° C n-butyllithium (4.30 g, 10.76 mmol, 2.5 M solution in hexane) was added. The reaction mixture was stirred at 0 ° C for 1 h and a solution of 5- (2,6-dimethyl-4-triisopropylsilanyloxybenzyl) -2-methoxymethoxy-benzaldehyde (1.23 g, 2.69 mmol, intermediate by the synthesis of Example 35, step d) in THF (5.0 mL). The reaction mixture was stirred at room temperature for 2.5 h, cooled to 0 ° C and quenched with saturated ammonium chloride (15.0 mL). The mixture was extracted with ethyl acetate (20 mL), washed with H20 (25 mLx2) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (1:50) to give triisopropyl- [3,5-dimethyl-4- (4'-methoxymethoxy-3'-vinylbenzyl) ) phenoxy] silane as oil (1.19 g, 97%): "" "H NMR (300 MHz, DMSO-de): d 7.12 (m, 1 H), 7.00-6.93 (m, 2 H), 6.80 (m, 1 H), 6.59 (s, 2 H), 5.62 (d, J = 18.0 Hz, 1 H), 5.24 (d, J = 12.0 Hz, 1 H), 5.19 (s, 2 H), 3.88 (s, 2 H), 3.37 (s, 3 H), 2.15 (s, 6 H), 1.37 (s, 1 H), 1.21 (m, 3 H), 1.08 (d, J = 4.5 Hz, 18 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 5); Rf = 0.74. Step b: A mixture of copper powder (0.094 g, 1.48 mmol) and iodide (0.005 g, 0.016 mmol) in benzene (2.3 mL) was stirred at room temperature for 10 min. To this was added a solution of triisopropyl- [3,5-dimethyl-4- (4 '-methoxymethoxy-3'-vinylbenzyl) phenoxy] silane (0.15 g, 0.33 mmol) in benzene (1.0 mL) followed by diiodomethane (0.053). mL, 0.66 mmol). The reaction mixture was heated at 70 ° C for 144 h, cooled to room temperature and filtered through a plug of celite. Solvent was removed under reduced pressure to provide triisopropy- [4- (3'-cyclopropyl-4'-methoxymethoxybenzyl) -3,5-dimethylphenoxy] silane as an oil (0.14 g, 91%): XHRMN (300 MHz, DMSO- of): d 6.92 (m, 1 H), 6.67 (m, 1 H), 6.58 (s, 2 H), 6.43 (s, 1 H), 5.18 (s, 2 H), 3.82 (s, 2 H) ), 3.39 (s, 3 H), 2.14 (s, 6 H), 1.26 (m, 3 H), 1.08 (d, J = 4.5 Hz, 18 H), 0.87 (m, 2 H), 0.46 (, 2 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 5); Rf = 0.74. Step c: To a mixture of triisopropyl- [3,5-dimethyl-4- (3'-cyclopropyl-4'-methoxymethoxybenzyl) phenoxy] silane (0.38 g, 0.81 mmol) in THF (10.0 mL) at 0 ° C added TBAF (1.22 mL, 0.81 mmol, 1.0 M in THF). The reaction mixture was stirred at room temperature for 1 h, diluted with diethyl ether (20 mL) and washed with H20 (20 mL x 2). The organic solution was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (1: 9) to give 4- (3'-cyclopropyl-4'-methoxymethoxybenzyl) -3,5-dimethylphenol as a oil (0.18 g, 71%): a H NMR (300 MHz, DMSO-de): d 9.01 (s, 1 H), 6.90 (m, 1 H), 6.61 (m, 1 H), 6. 58 (s) , 1 H), 6.46 (s, 2 H), 5.17 (s, 2 H), 3.77 (s, 2 H), 3.39 (s, 3 H), 2.11 (s, 6 H), 0.87 (m, 2 H), 0.51 (m, 2 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 9); Rf = 0.47. Step d: To a mixture of 4- (3'-cyclopropyl-4'-methoxymethoxybenzyl) -3,5-dimethylphenol (0.16 g, 0.53 mmol) and Cs 2 CO 3 (0.859 g, 2.64 mmol) in DMF (6.0 mL) at 0 ° C diethylphosphoryl methyl ester of trifluoromethanesulfonic acid (0.11 g, 0.53 mmol) was added. The reaction mixture was stirred at 0 ° C for 5 h, allowed to warm to room temperature and stirred for 16 h. The reaction mixture was cooled to 0 ° C, quenched with cold 1N HCl and extracted with ethyl acetate (8.0 mL). The organic solution was dried over MgSO, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gelwas eluted with ethyl acetate-hexanes (1: 1) to provide [diethyl 4- (3'-cyclopropyl-4'-methoxymethoxybenzyl) -3,5-dimethylphenoxy] ethylphosphonate as oil (0.10 g, 28%): 1 H NMR (300 MHz, DMSO-d 6): d 6.90 (m, 1 H), 6.75 (s, 2 H), 6.59 (m, 2 H), 5.17 (s, 2 H), 4.39 (d, J = 9.0 Hz, 2 H), 4.15 (m, 4 H), 3.83 (s, 2 H), 3.39 (s, 3 H), 2.19 (s, 6 H), 2.09 (m, 1 H), 1.24 (m , 6 H), 0.87 (m, 2 H), 0.52 (m, 2 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (4: 1); Rf = 0.25. Step e: To a solution of diethyl [4- (3'-cyclopropyl-4'-methoxymethoxybenzyl) -3,5-dimethylphenoxy] methylphosphonate (0.090 g, 0.19 mmol) in CH2C12 (3.0 mL) at -30 [deg.] C. added bromotrimethylsilane (0.26 mL, 1.94 mmol). The reaction mixture was stirred at room temperature for 16 h and the solvent was removed under reduced pressure. The residue was treated with acetonitrile-water (4: 1, 5.0 mL), stirred at 38 ° C for 30 minutes and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with H20. The organic solution was dried over MgSO4, filtered and concentrated under reduced pressure to provide the title compound as an opaque white powder (0.040 g, 57%); mp: 153-156 ° C; 1 HOUR NMR (300 MHz, DMSO-d6): d 9.02 (s, 1 H), 6.67 (s, 2 H), 6.58 (m, 1 H), 6.41 (m, 2 H), 4.00 (d, J = 10.5 Hz, 2 H), 3.75 (s, 2 H), 2.13 (s, 6 H), 1.98 (, 1 H), 0.81 (m, 2 H), 0.47 (m, 2 H); LC-MS m / z = 362 [C19H2305P-H] +; Analysis calculated for (C? 9H2305P + 0.9 H20): C, 60.28; H, 6.60. Found: C, 60.40; H, 6.92.

Example 49 Compound 49: [4- (3 '-Dimethylamino-4' -hydroxybenzyl) -3,5-dimethylphenoxy] methylphosphonic acid Step a: To a stirred solution of 4-bromo-2-nitro-phenol (6 g, 27.52 mmol) in MeOH (150 mL) at room temperature was added a suspension of Na2S20 (29 g, 165.13 mmol). The mixture was stirred at room temperature for 3 hrs, filtered and concentrated. The residue was partitioned between EtOAc and water. The organic layer was collected and dried over Na 2 SO, filtered and concentrated under reduced pressure to give crude 2-amino-4-bromo-phenol as a yellow solid (3.9 g, 75%): 1 H NMR (200 MHz, DMSO -d6): d 9.27 (s, 1 H), 6.70 (d, J = 2.2 Hz, 1 H), 6.50 (m, 2 H), 4.79 (s, 2 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 20% ethyl acetate in hexanes; Rf = 0.35. Step b: The 2-Amino-4-bromo-phenol (3.9 g, 20.74 mmol) was dissolved in AcOH (120 L) and heated to 40 ° C. To this stirred solution at 40 ° C was added (HCHO) n (1.9 g, 62.23 mmol), followed by NaBH 3 CN (3.9 g, 62.23 mmol). The reaction mixture was stirred for 1 hr at 40 ° C, then another (HCHO) n (1.9 g, 62.23 mmol) and NaBH 3 CN (3.9 g, 62.23 mmol) were added. The mixture was stirred for 16 hrs at 40 ° C. Solvent was removed under reduced pressure. The residues were partitioned between EtOAc and water. The organic layer was collected and dried over Na 2 SO, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (30:70) to give 4-bromo-2-dimethylamino-phenol as a light yellow solid (3.7 g, 83%). : X H NMR (300 MHz, DMSO-d 6): d 9.44 (s, 1 H), 6.92 (m, 2 H), 6.71 (d, J = 8.4 Hz, 1 H), 2.69 (s, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 20% ethyl acetate in hexanes; Rf = 0.57. Step c: To a stirred solution of 4-bromo-2-dimethylamino-phenol (3.7 g, 17.13 mmol) in CH2C12 (100 mL) at room temperature was added ethyl-diisopropylamine (4.47 mL, 25.7 mmol) and chlorine. methoxy-methane (1.69 mL, 22.27 mmol). The mixture was refluxed for 16 hrs, water was added. The organic layer was collected and dried over Na 2 SO 4, filtered and concentrated under reduced pressure to give crude N- (5-bromo-2-methoxymethoxyphenyl) dimethylamine as a red oil (4.4 g, 99%): aH NMR (200 MHz, DMSO-d6): 6.96 (m, 3 H), 5.17 (s, 2 H), 3.40 (s, 3 H), 2.72 (s, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 15% ethyl acetate in hexanes; Rf = 0.59.

Step d: To a stirred solution of N- (5-bromo-2-methoxymethoxyphenyl) dimethylamine (3.4 g, 13.07 mmol) in THF (80 mL) at -78 ° C was added n-BuLi (5.22 mL, 2.5 M in hexanes). The mixture was stirred at -78 ° C for 1 hr and a solution of 2,6-dimethyl-4-triisopropylsilanyloxy-benzaldehyde (3.6 g, 11.77 mmol) was added. The reaction mixture was stirred at -78 ° C for 1 hr, allowed to warm to room temperature and stirred for 1 hr. The reaction mixture was quenched with saturated NH C1 and was diluted with diethyl ether. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by Column chromatography on silica gel, eluted with ethyl acetate-hexanes (30:70) to provide (3-dimethylamino-4-methoxymethoxy-phenyl) - (2,6-dimethyl-4-). triisopropylsilanyloxyphenyl) methanol as a yellow oil (4 g, 63%): a H NMR (300 MHz, DMS0-d 6): d 6.89 (d, J = 8.4 Hz, 1 H), 6.79 (s, 1 H), 6.61 ( m, 1 H), 6.51 (s, 2 H), 6.01 (d, J = 4.0 Hz, 1 H), 5.65 (d, J = 4.0 Hz, 1 H), 5.14 (s, 2 H), 3.41 ( s, 3 H), 2.64 (s, 6 H), 2.17 (s, 6 H), 1.24 (m, 3 H), 1.08 (d, J = 7.2 Hz, 18 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 25% ethyl acetate in hexanes; Rf = 0.27.

Step e: To a stirred solution of (3-dimethylamino-4-methoxymethoxy-phenyl) - (2,6-dimethyl-4-triisopropylsilanyloxy-phenyl) -methanol (3.4 g, 6.97 mmol) in CH2C12 (150 mL) at room temperature. At room temperature, Et3SiH (5.6 mL, 34.85 mmol) and TFA (2.6 mL, 34.85 mmol) were added. The reaction mixture was stirred at room temperature for 6 hrs. Solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated NaHCO 3. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by Column chromatography on silica gel, eluted with ethyl acetate-hexanes (3: 7) to give N- [5- (2 ', 6'-dimethyl-4'-trisopropylsilanyloxybenzyl) -2 -methoxymethoxyphenyl] dimethylamine as a yellow oil (3 g, 91%): a H NMR (300 MHz, DMSO-d 6): d 6.86 (d, J = 8.1 Hz, 1 H), 6.59 (s, 2 H), 6.54 (d, J = 2.1 Hz, 1 H), 6.41 (m, 1 H), 5.12 (s, 2 H), 3.85 (s, 2 H), 3.40 (s, 3 H), 2.64 (s, 6 H) ), 2.15 (s, 6 H), 1.26 (m, 3 H), 1.08 (d, J = 7.2 Hz, 18 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (25:75); Rf = 0.54. Step f: To a stirred solution of N- [5- (2 ', 6'-dimethyl-4'-trisopropylsilanyloxybenzyl) -2-methoxymethoxyphenyl] dimethylamine (3 g, 6.36 mmol) in THF (60 mL) at room temperature was added tetrabutylammonium fluoride (9.54 L, 1.0 M in THF). The reaction mixture was stirred at room temperature for 2 hr, diluted with diethyl ether and washed with water (30 mL x 2). The solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (1: 1) to provide 4- (3'-dimethylamino-4'-methoxymethoxybenzyl) -3,5-dimethylphenol as a light yellow oil (1.8 g, 90%): 2 H NMR (300 MHz, DMSO-de): d 9.01 (s, 1 H), d 6.85 (d, J = 8.1 Hz, 1 H), 6.63 (d, J = 2.1 Hz, 1 H), 6.47 (s, 2 H), 6.35 (m, 1 H), 5.12 (s, 2 H), 3.80 (s, 2 H), 3.40 (s, 3 H), 2.67 (s, 6 H), 2.17 (s, 6) H), CCD Conditions: Silica gel uniplaca, 250 microns; Mobile phase = 30% ethyl acetate in hexanes; Rf = 0.28. Step g: To a stirred solution of 4- (3'-dimethylamino-4 '-methoxymethoxybenzyl) -3,5-dimethylphenol (0.525 g, 1.66 mmol) in DMF (18 mL) at 0 ° C was added NaH (80 mg , 1.99 mmol, 60%) and stirred for 1 hr at room temperature. Diethyl tosyloxymethylphosphonate (0.7 g, 2.16 mmol) was added and the mixture was stirred for 16 hrs at room temperature. Solvent was removed under reduced pressure, and the residue was partitioned between EtOAc and saturated NaHCO 3. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by Column chromatography on silica gel, eluted with ethyl acetate-hexanes (8: 2) to provide [4- (3'-dimethylamino-4 '-methoxymethoxybenzyl) -3,5-dimethylphenoxy] diethyl ethylphosphonate as a light yellow oil (0.5 g, 65%): X H NMR (300 MHz, DMSO-d 6): d 6.85 (d, J = 8.1 Hz, 1 H), 6.76 (s, 2 H), 6.64 (d, J = 2.1 Hz, 1 H), 6.34 (m, 1 H), 5.12 (s, 2 H), 4.38 (d, J = 9.8 Hz, 2 H), 4.14 (m, 4 H), 3.86 (s, 2 H), 3.40 (s, 3 H), 2.67 (s, 6 H), 2.19 (s, 6 H), 1.25 (t, J = 7.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (6: 4); Rf = 0.43. Step h: To a stirred solution of diethyl [4- (3'-dimethylamino-4'-methoxymethoxybenzyl) -3,5-dimethylphenoxy] methylphosphonate (0.48 g, 1.03 mmol) in MeOH (6 mL) and water (1 mL) ) at room temperature HCl (1.03 mL, 10 N) was added, and it was heated at 100 ° C for 5 minutes by microwaves. The solvent was removed under reduced pressure, and the residue was partitioned between EtOAc and saturated NaHCO 3. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluted with ethyl acetate-CH2Cl2 (3: 1) to provide [4- (3'-dimethylamino-4'-hydroxybenzyl) -3,5-dimethyl- diethyl phenoxy] methylphosphonate as a light yellow oil (0.29 g, 67%): X H NMR (200 MHz, DMSO-d 6): d 8.77 (s, 1 H), 8. 6.72 (s, 2 H), 6.57 (m , 2 H), 6.26 (m, 1 H), 4.35 (d, J - 9.8 Hz, 2 H), 4.13 (m, 4 H), 3.79 (s, 2 H), 2.60 (s, 6 H), 2.17 (s, 6 H), 1.25 (t, J = 7.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-CH2Cl2 (1: 3); Rf = 0.49. Step i: The title compound was prepared according to the procedure described by the synthesis of compound 8, step f. XR NMR (300 MHz, DMS0-d6): d 7.34 (s, 1 H), 6.92 (d, J = 8.7 Hz, 1 H), 6.79 (m, 1 H), 6.73 (s, 2 H), 4.03 (d, J = 10.2 Hz, 2 H), 3.88 (s, 2 H), 3.13 (s, 6 H), 2.17 (s, 6 H); pf: degassed at 90 ° C; LC-MS m / z = 366 [C18H24N05P + H] +; Analysis calculated for (C18H24N05P + 1.4HBr + 0.4 H20 + 0.1 MeOH): C, 44.45; H, 5.48; N, 2.86; Br, 22.87. Found: C, 44.64; H, 5.67; N, 2.65; Br, 22.74.

Example 50 Compound 50: [4- (3 '-Benzyloxycarbonylamino-4' -hydroxybenzyl) -3,5-dimethyl-phenoxy] methylphosphonic acid Step a: To a stirred solution of [3,5-dimethyl-4- (3 ' diethylcarboxyl-4'-methoxymethoxybenzyl) phenoxy] methylphosphonate (0.36 g, 0.77 mmol) in toluene (20 mL) at room temperature was added diphenylphosphoryl azide (0.17 mL, 0.77 mmol), triethylamine (0.2 mL, 1.4 mmol) and Benzyl alcohol (0.4 mL, 3.85 mmol). The mixture was refluxed for 16 hrs. The solvent was removed under reduced pressure, and the residue was partitioned between EtOAc and saturated NH 4 Cl. The organic layer was dried over Na 2 SO, filtered and concentrated under reduced pressure. The crude product was purified by Column chromatography on silica gel, eluted with ethyl acetate to provide [diethyl 4- (3'-benzyloxycarbonylamino-4'-methoxymethoxybenzyl) -3,5-dimethylphenoxy] methylphosphonate as a yellow oil. light (0.4 g, 91%): ""? NMR (300 MHz, DMSO-de): d 8.60 (s, 1 H), 7.38 (m, 6 H), 6.99 (d, J = 8.4 Hz, 1 H), 6.76 (s, 2 H), 6.65 ( m, 1 H), 5.13 (s, 2 H), 5.12 (s, 2 H), 4.37 (d, J = 9.6 Hz, 2 H), 4.13 (m, 4 H), 3.87 (s, 2 H) , 3.37 (s, 3 H), 2.19 (s, 6 H), 1.27 (t, J = 6.9 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 75% ethyl acetate in hexanes; Rf = 0.45. Step b: To a stirred solution of diethyl [4- (3'-benzyloxycarbonylamino-4'-methoxymethoxy-benzyl) -3,5-dimethylphenoxy] ethylphosphonic acid (0.1 g, 0.175 mmol) in MeOH (2 mL) at room temperature HCl (0.18 mL, 10 N) was added, and the reaction mixture was heated at 100 ° C for 5 minutes by microwaves. The solvent was removed under reduced pressure, and the residue was partitioned between EtOAc and saturated NaHCO 3. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by Column chromatography on silica gel, eluted with ethyl acetate to give [diethyl 4- (3'-benzyloxycarbonylamino-4'-hydroxybenzyl) -3,5-dimethylphenoxy] methylphosphonate as a yellow oil light (0.076 g, 82%): X H NMR (300 MHz, DMSO-d 6): d 9.48 (s, 1 H), 8.34 (s, 1 H), 7.38 (m, 6 H), 6.71 (m, 3 H), 6.53 (m, 1 H), 5.11 (s, 2 H), 4.37 (d, J = 9.6 Hz, 2 H), 4.13 (m, 4 H), 3.82 (s, 2 H), 2.19 ( s, 6 H), 1.27 (t, J = 6.9 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 75% ethyl acetate in hexanes; Rf = 0.40. Step c: To a stirred solution of diethyl [4- (3'-benzyloxycarbonylamino-4'-hydroxybenzyl) -3,5-dimethylphenoxy] methylphosphonic acid (0.076 g, 0.144 mmol) in CH2C12 (8 mL) at room temperature was added hexamethyldisilazane (0.28 mL, 1.27 mmol) and bromotrimethylsilane (0.15 mL, 1.15 mmol). The reaction mixture was stirred at room temperature for 16 hrs. The solvent was removed under reduced pressure, and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was washed by CH2C12 to give the title compound as a white amorphous solid (0.03 g, 44%): 1 H NMR (300 MHz, DMS0-d6): d 9.41 (s, 1 H), 8.30 (s, 1 H), 7.33 (m, 6 H), 6.66 (m, 3 H), 6.48 (m, 1 H), 5.08 (s, 2 H), 3.97 (d, J = 10.2 Hz, 2 H), 3.77 (s, 2 H), 2.13 (s, 6 H). pf: contracted at 180 ° C. CL-MS m / z = 472 [C2H26N07P + H] +; Analysis calculated for (C24H26N07P + 1.1H20): C, 58.68; H, 5.79; N, 2.85. Found: C, 58. 44; H, 5.89; N, 2.77.

Example 51: Compound 51-1: [3,5-dimethyl-4- (4'-Hydroxy-3'-methanesulfonylamino-benzyl) phenoxy] methylphosphonic acid Step a: To a solution of [4- (3'-benzyloxycarbonylamino- 4 '-methoxymethoxybenzyl) -3,5-dimethylphenoxy] methylphosphonic diethyl ester (0.33 g, 0.58 mmol) in EtOH (20 mL) at room temperature was added Pd / C (50 mg). The reaction mixture was stirred at room temperature under 50 psi (3.515 kg / cm2) H2 for 16 hrs then filtered through Celite®. The solvent was removed under reduced pressure to provide [diethyl 4- (3'-amino-4'-methoxymethoxybenzyl) -3,5-dimethylphenoxy] methylphosphonate as a colorless oil (0.25 g, 99%): XH NMR (300 MHz , DMSO-de): d 6.76 (m, 3 H), 6.29 (d, J = 2.4 Hz, 1 H), 6.12 (m, 1 H), 5.07 (s, 2 H), 4.69 (s, 2 H) , 4.35 (d, J = 10.2 Hz, 2 H), 4.12 (m, 4 H), 3.76 (s, 2 H), 3.39 (s, 3 H), 2.19 (s, 6 H), 1.27 (t, 3 = 1 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 75% ethyl acetate in hexanes; Rf = 0.51. Step b: To a stirred solution of diethyl [4- (3'-amino-4'-methoxymethoxybenzyl) -3,5-dimethyl-phenoxy] ethylphosphonic acid (0.13 g, 0.3 mmol) in CH2C12 (10 mL) at room temperature pyridine (0.037 mL, 0.45 mmol) and methanesulfonyl chloride (0.026 mL, 0.33 mmol) were added. The reaction mixture was stirred at room temperature for 16 hrs then divided between CH2C12 and water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by Column chromatography on silica gel, eluted with ethyl acetate to provide [3,5-dimethyl-4- (3'-methanesulfonylamino-4'-methoxymethoxybenzyl) phenoxy] methylphosphonate diethyl as an oil light yellow (0.12 g, 77%): XR NMR (300 MHz, DMSO-de): d 8.91 (s, 1 H), 7.02 (d, J = 8.4 Hz, 1 H), 6.96 (d, J = 2.1 Hz, 1 H), 6.76 (m, 3 H), 5.18 (s, 2 H), 4.37 (d, J = 9.9 Hz, 2 H), 4.16 (m, 4 H), 3.87 (s, 2 H) , 3.41 (s, 3 H), 2.93 (s, 3 H), 2.19 (s, 6 H), 1.27 '(t, J = 6.9 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 75% ethyl acetate in hexanes; Rf = 0.42. Step c: To a stirred solution of diethyl [3, 5-dimethyl-4- (3'-methanesulfonylamino-4'-methoxymethoxybenzyl) phenoxy] methylphosphonate (0.12 g, 0.23 mmol) in MeOH (2 mL) at room temperature HCl (1.2 mL, 2 N) was added, and the reaction mixture was heated at 100 ° C for 5 minutes by microwaves. Solvent was removed under reduced pressure, and the residue was partitioned between EtOAc and saturated NaHCO 3. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluted with ethyl acetate to give [3,5-dimethyl-4- (4'-hydroxy-3'-methanesulfonylaminobenzyl) phenoxy] methylphosphonate diethyl as a solid. white (0.08g, 74%): XR NMR (300 MHz, DMS0-d6): d 6.85 (d, J = 1.8Hz, 1H), 6.76 (m, 3 H), 6.63 (m, 1 H), 4.37 (d, J = 9.9Hz, 2 H), 4.14 (m, 4 H), 3.82 (s, 2 H), 2.89 (s, 3 H), 2.18 (s, 6 H), 1.27 (t, J = 6.9 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate; Rf = 0.42. Step d: The title compound was prepared according to the procedure described in Example 8, step f, (60 mg, 85%): X H NMR (200 MHz, DMSO-d 6): d 9.61 (s, 1 H), 8.61 (s, 1 H), 6.74 (m, 5 H), 4.02 (d, J = 10.2 Hz, 2 H), 3.80 (s, 2 H), 2.88 (s, 3 H), 2.16 (s, 6 H); pf: contracted at 200 ° C; LC-MS m / z = 416 [C17H22N07PS + H] +; Analysis calculated for (C17H22N07PS + 0.1 MeOH + 0.8 H20): C, 47.43; H, 5.59; N, 3.23. Found: C, 47.57; H, 5.68; N, 3.10. Using the appropriate starting materials, compounds 51-2 were prepared in a manner analogous to those described by the synthesis of compound 51-1. Compound 51-2: [3,5-Dimethyl-4- (4'-hydroxy-3'-trifluoroacetylaminobenzyl) phenoxy) methylphosphonic acid XR NMR (200 MHz, DMSO-d6): d 10.41 (s, 1 H), 9.71 (s, 1 H), 6.95 (s, 1 H), 6.74 (m, 4 H), 4.03 (d, J = 10.2 Hz, 2 H), 3.83 (s, 2 H), 2.16 (s, 6 H) ); mp: 170-172 ° C; LC-MS m / z = 434 [C18H19F3N06P + H] +; Analysis calculated for (C18H19F3N06P + 0.4H20): C, 49.08; H, 4.53; N, 3.18. Found: C, 49.26; H, 4.75; N, 2.83.

Compound 51-3: [3,5-dimethyl-4- (4'-Hydroxy-3'-isobutyrylaminobenzyl) phenoxy] methylphosphonic acid Step a: The (3'-amino-4'-hydroxybenzyl) -3,5-dimethylphenoxy ] diethyl methylphosphonate was prepared according to the procedure described by the synthesis of example 51-1, step c: XR NMR (200 MHz, DMSO-d6): d 8.70 (s, 1 H), 6.71 (s, 2 H) , 6.48 (d, J = 7.6 Hz, 1 H), 6.19 (s, 1 H), 6.01 (m, 1 H), 4.38 (s, 2 H), 4.33 (d, J = 9.6 Hz, 2 H) , 4.12 (m, 4 H), 3.70 (s, 2 H), 2.16 (s, 6 H), 1.23 (t, J = 7.4 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 75% ethyl acetate in hexanes; Rf = 0.46. Step b: To a stirred solution of diethyl (3 '-amino-4'-hydroxybenzyl) -3,5-dimethylphenoxy] methylphosphonate (0.046 g, 0.12 mmol) in THF (5 mL) at 0 ° C was added pyridine ( 0. 015 mL, 0.18 mmol) and isobutyric anhydride (0.021 mL, 0.13 mmol). The reaction mixture was stirred at 50 ° C for 16 hrs. This was added EtOAc and water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by Column chromatography on silica gel, eluted with ethyl acetate to give [diethyl 3,5-dimethyl-4- (4'-hydroxy-3'-isobutyrylaminobenzyl) phenoxy] methylphosphonate as an oil. yellow (0.046 g, 83%): X H NMR (300 MHz, DMSO-d 6): d 9.55 (s, 1 H), 9.22 (s, 1 H), 7.36 (s, 1 H), 6.73 (m, 3 H), 6.58 (, 1 H), 4.36 (d, J = 9.6 Hz, 2 H), 4.13 (m, 4 H), 3.82 (s, 2 H), 2.73 (m, 1 H), 2.19 (s) , 6 H), 1.27 (t, J = 6.9 Hz, 6 H), 1.07 (d, J = 6.9 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 80% ethyl acetate in hexanes; Rf = 0.37. Step c: The title compound was prepared according to the procedure described by the synthesis of example 8, step f:? R NMR (200 MHz, DMSO-d6): d 9.51 (s, 1 H), 9.22 (s, 1 H), 7.33 (s, 1 H), 6.72 (m, 3 H), 6.58 (m, 1 H), 4.03 (d, J = 10.2 Hz, 2 H), 3.80 (s, 2 H), 2.71 ( m, 1 H), 2.17 (s, 6 H), 1.06 (d, J = 7.0 Hz, 6 H); LC-MS m / z = 408 [C 20 H 26 NO 6 P + H] +; Analysis calculated for (C20H26NO6P + 0.9 H20 + 0.45 HBr): C, 52.22; H, 6.19; N, 3.04; Br, 7.82. Found: C, 52.31; H, 6.42; N, 2.66; Br, 7.60.

Example 52: Compound 52: [3,5-dimethyl-4- (4'-Hydroxy-3'-iso-propylbenzyl) benzenesulfonyl] methylphosphonic acid Step a: To a stirred solution of 3,5-dimethyl-4- (4) '-methoxymethoxy-3' -isopropylbenzyl) phenylamine (0.5 g, 1.6 mmol) at 80 ° C in dimethyldisulfide (5 mL) was added isoamylnitrite (0.86 mL, 6.4 mmol). The reaction mixture was stirred at 80 ° C for 1 h. The solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (1: 3) to provide 3,5-dimethyl-4- (4'-methoxymethoxy-3'-iso-propylbenzyl) Methylsulfanylbenzene as a light yellow oil (0.24 g, 44%): X H NMR (300 MHz, CDCl 3 -d?): d 6.90-6.94 (m, 4 H), 6.62 (, 1 H), 5.19 (s, 2 H), 3.97 (s, 2 H), 3.50 (s, 3 H), 3.31 (m, 1 H), 2.52 (s, 3 H), 2.25 (s, 6H) 1.20 (d, J = 6.9 Hz, 6 H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 2); Rf = 0.73.

Step b: To a stirred solution of 3,5-dimethyl-4- (4'-methoxymethoxy-3'-iso-propylbenzyl) methyl sulfyl anilbenzene (0.24 g, 0.7 mmol) at room temperature in CH2C12 (10 mL) was added in-CPBA (0.42 g, 2.45 mmol). The reaction mixture was stirred at room temperature for 16 hrs. This was quenched by saturated Na 2 SO 3. The organic layer was washed with saturated NaHCO 3 and dried over Na 2 SO 4, filtered and concentrated under reduced pressure to provide 3,5-dimethyl-4- (4'-methoxymethoxy-3'-iso-propylbenzyl) methylsulfonylbenzene as an oil. light yellow (0.23 g, 87%): XR NMR (200 MHz, CDC13-di): d 7. 62 (s, 2 H), 6.88 (m, 2 H), 6.55 (m, 1 H), 5.16 ( s, 2 H), 4.10 (s, 2 H), 3.46 (s, 3 H), 3.28 (m, 1 H), 3.06 (s, 3 H), 2.33 (s, 6 H) 1.17 (d, J = 6.9 Hz, 6 H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 2); Rf = 0.46. Step c: To a stirred solution of 3,5-dimethyl-4- (4'-methoxymethoxy-3'-iso-propylbenzyl) methylsulfonylbenzene (0.23 mL, 0.61 mmol) in THF (10 mL) at -78 ° C was added. added n-BuLi (2.5 M in hexanes, 0.29 mL), the reaction mixture was stirred at -78 ° C for 1 hr and at 0 ° C for 40 min, then diethyl phosphorocloridate (0.11 mL, 0.73 mmol) was added to 0 ° C. The reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was quenched with saturated NH4C1 and diluted with diethyl ether. The organic layer was dried over Na 2 SO, filtered and concentrated under reduced pressure. The residue was purified by Column chromatography on silica gel, eluted with ethyl acetate to provide [3,5-dimethyl-4- (4'-methoxymethoxy-3'-iso-propylbenzyl) phenylsulfonyl] methylphosphonate diethyl ester as a light yellow oil (130 mg, 42%): ""? NMR (200 MHz, DMS0-d6): d 7.63 (s, 2 H), 7.00 (d, J = 3.0 Hz, 1 H), 6.88 (d, J = 8.4 Hz, 1 H), 6.60 (dd, J = 3.0, 8.4 Hz, 1 H), 5.15 (s, 2 H), 4.36 (d, J = 17.2 Hz, 2 H), 3.97 (m, 6 H), 3.36 (s, 3 H), 3.22 (m, 1 H), 2.31 (s, 6 H), 1.19 (m, 12 H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (3: 1); Rf = 0.43. Step d: The title compound was prepared by the procedure described by the synthesis of example 8, step f: X H NMR (200 MHz, DMSO-de): d 9.08 (s, 1 H), 7.61 (s, 2 H) , 6.89 (d, J = 3.0 Hz, 1 H), 6.62 (d, J = 8.0 Hz, 1 H), 6.43 (d, J = 3.0, 8.0 Hz, 1 H), 3.96 (s, 2 H), 3.85 (d, J = 16.6 Hz, 2 H), 3.13 (m, 1 H), 2.28 (s, 6 H), 1.10 (d, J = 6.8 Hz, 6 H); LC-MS m / z = 413 [C19H2506PS + H] +; Analysis calculated for (C19H2506PS + 1.0 H20 + 0.15HBr + 0.2 Et20): C, 51.99; H, 6.42; Br, 2.62. Found: C, 51.67; H, 6.50; Br, 2.62.

Example 53 Compound 53: [3,5-dimethyl-4- (4'-Hydroxy-3'-iso-propylphenoxy) benzenesulfonyl] methylphosphonic acid Step a: To a stirred solution of 4-bromo-2,6-dimethylphenol (6) g, 29.85 mmol) in CH2C12 (80 mL) at 0 ° C was added imidazole (4.1 g, 59.70 mmol) and triisopropylsilyl chloride (7.1 mL, 32.84 mmol). The reaction mixture was stirred at room temperature for 16 hrs. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by Column chromatography on silica gel, eluted with ethyl acetate-hexanes (1: 9) to give (4-bromo-2,6-dimethylphenoxy) triisopropylsilane as a colorless oil (1.6 g, 15 g). %): 1 H NMR (300 MHz, DMS0-d 6): d 7.19 (s, 2 H), 2.20 (s, 6 H), 1.29 (m, 3 H), 1.10 (d, J = 7.2 Hz, 18 H ). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (5:95); Rf = 0.70. Step b: To a stirred solution of (4-bromo-2,6-dimethylphenoxy) triisopropylsilane (0.5 g, 1.4 mmol) in THF (15 mL) at -78 ° C was added n-BuLi (2.5 M in hexanes, 0.56. mL), the reaction mixture was stirred at -78 ° C for 1 hr, then di-ethyl disulfide (0.16 mL, 1.82 mmol) was added at -78 ° C. The reaction mixture was stirred at room temperature for 1 h and quenched with saturated NH4C1 and diluted with diethyl ether.

The organic layer was dried over Na 2 SO, filtered and concentrated under reduced pressure to provide crude (2,6- (dimethyl-4-methylsulfanylphenoxy) triisopropyl-silane as an oil (0.46 g, 100%): XH NMR (300 MHz , DMSO-d6): d 6.92 (s, 2 H), 2.41 (s, 3 H), 2.20 (s, 6 H), 1.29 (m, 3 H), 1.10 (d, J = 7.2 Hz, 18 H ). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (2:98); Rf = 0.57. Step c: To a stirred solution of (2,6-dimethyl-4-methylsulfanylphenoxy) triisopropyl-silane (0.46 g, 1.4 mmol) in CH2C12 (15 mL) at room temperature was added m-CPBA (0.85 g, 4.9 mmol). The reaction mixture was stirred at room temperature for 16 hrs. This was quenched by saturated Na2S03. The organic layer was washed by saturated NaHCO 3 and dried over Na 2 SO 4, filtered and concentrated under reduced pressure to give crude (2,6-dimethyl-4-methanesulfonylphenoxy) triisopropylsilane as an oil (0.47 g, 94%): 1 H NMR (200 MHz, DMSO-d 6): d 7.57 ( s, 2 H), 3. 14 (s, 3 H), 2.28 (s, 6 H), 1.19 (m, 3 H), 1.10 (d, J = 7.2 Hz, 18 H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (5:95); Rf = 0. 49. Step d: To a stirred solution of (2,6-dimethyl-4-methanesulfonylphenoxy) triisopropylsilane (0.47 g, 1.32 mmol) in THF (15 mL) at -78 ° C was added n-BuLi (2.5 M in hexanes, 0.58 mL), the reaction mixture was stirred at -78 ° C for 1 hr, then diethylphosphorochloridate (0.25 mL, 1.72 mmol) at -78 ° C. The reaction mixture was stirred at room temperature for 16 hrs. The reaction mixture was quenched with saturated NH4C1 and diluted with diethyl ether. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (1: 1) to give (3,5-dimethyl-4-triisopropylsilanyloxy-benzenesulfonyl) methylphosphonate diethyl ester as a colorless oil (0.1 g, 15%): 1 H NMR (200 MHz, CDCl 3 -d 6): d 7.57 (s, 2 H), 4.17 (m, 4 H), 3.71 (d, J = 17.2 Hz, 2 H), 2.29 (s) , 6 H), 1.33 (m, 9 H), 1.10 (d, J = 7.2 Hz, 18 H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 1); Rf = 0.45. Step e: To a stirred solution of diethyl (3, 5-dimethyl-4-triisopropylsilanyloxy-benzenesulfonyl) methylphosphonate in THF (3 mL) at room temperature was added TBAF (0.3 mL, 1 M in THF). This was stirred at room temperature for 2 hrs. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (5: 1) to give diethyl (3,5-dimethyl-4-hydroxybenzenesulfonyl) methylphosphonate as a light yellow oil (70 mg, 100%): 1 H NMR (300 MHz, CDCl 3 -d 6): d 7.54 (s, 2 H), 4.12 (m, 4 H), 3.65 (d, J = 16.8 Hz, 2 H), 2.22 (s) , 6 H), 1.22 (d, J = 7.2 Hz, 6 H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (5: 1); Rf = 0.44. Step f: To a stirred mixture of bis (4-methoxy-3-iso-propylphenyl) iodide tetrafluoroborate (0.15 g, 0.3 mmol) and copper powder (16 mg, 0.26 mmol) in CH2C12 (5 L) at 0 ° C was added a solution of triethylamine (0.031 mL, 0.22 mmol) and diethyl (3,5-dimethyl-4-hydroxybenzenesulfonyl) ethylphosphonate. (70 mg, 0.2 mmol) in CH2C12 (2 mL). The reaction mixture was stirred at room temperature for 16 hrs and filtered through a plug of celite. Solvent was removed under reduced pressure and the crude product was purified by Column chromatography on silica gel, eluted with ethyl acetate-hexanes (5: 1) to provide [3,5-dimethyl-4- ('-methoxy Diethyl-3'-iso-propylphenoxy) benzenesulfonyl] methylphosphonate as a light yellow oil (40 mg, 41%): 2 H NMR (200 MHz, DMS0-d6): d 7.76 (s, 2 H), 6.79 (m, 2 H), 6.35 (m, 1 H), 4.44 (d, J = 16.8 Hz, 2 H), 4.02 (m, 4 H), 3.73 (s, 3 H), 3.18 (m, 1H), 2.14 (s, 6 H), 1.15 (m, 12 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (3: 2); Rf = 0.49.

Step g: The title compound was prepared according to the procedure described by the synthesis of example 22, step d, (40 mg, 0.083 mmol): XR NMR (200 MHz, DMS0-d6): d 9.02 (s, 1 H ), 7.70 (s, 2 H), 6.67 (m, 2 H), 6.19 (dd, J = 3.0, 8.4 Hz, 1 H), 3.72 (d, J = 15.8 Hz, 2 H), 3.14 (m, 1 H), 2.09 (s, 6 H), 1.11 (d, J = 6.6 Hz, 6 H); LC-MS m / z = 415 [C18H2307PS + H] +; Analysis calculated for (C18H2307PS + 1.3 H20 + 0.1 EtOAc): C, 49.48; H, 5.96. Found: C, 49.18; H, 5.67. Example 54: Compound 54: [3,5-Dimethyl-4- (4'-hydroxy-3'-iso-propylphenoxyphosphonic acid) Step a: To a stirred solution of (2,6-dimethyl-4-methylsulfanylphenoxy) triisopropylsilane (2.18 g, 6.72 mmol) in CC14 (25 mL) at room temperature was added N-chlorosuccinimide (0.99 g, 7.39 mmol.) The reaction mixture was stirred at room temperature for 16 hrs and filtered through a stopper. The solvent was removed under reduced pressure to give crude (4-chloromethylsulfanyl-2,6-dimethylphenoxy) triisopropylsilane as an oil (2.4 g, 100%) .This crude oil was dissolved in phosphorus acid triethyl ester (1.5 mL) This was heated at 180 ° C for 30 minutes by microwaves The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (1: 1) to provide diethyl (3, 5-dimethyl-4-triisopropylsilanyloxy-phenylsulfanyl) methylphosphonate omo yellow oil (1.6 g, 52%): X H NMR (200 MHz, DMSO-de): d 7.09 (s, 2 H), 4.98 (, 4 H), 3.31 (d, J = 13.8 Hz, 2 H ), 2.17 (s, 6 H), 1.25 (m, 9 H), 1.09 (d, J = 7.0 Hz, 18 H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate / Hexanes (2: 3); Rf = 0.45. Step b: The title compound was prepared according to the procedure described by the synthesis of example 53, steps e, f and g: 1 H NMR (300 MHz, DMSO-d 6): d 8.91 (s, 1 H), 7.16 (s, 2 H), 6.64 (m, 2 H), 6.21 (dd, J = 3.3, 8.7 Hz, 1 H), 4.13 (m, 3 H), 2.02 (s, 6 H), 1.11 (d, J = 6.9 Hz, 6 H); LC-MS only = 383 [C18H2305PS + H] +; Analysis calculated for (C18H2305PS + 0.15 TFA + 0.2 Et20): C, 55.00; H, 5.98.

Found: C, 54.88; H, 5.76.

Example 55 Compound 55: [3,5-Dimethyl-4- (4'-hydroxy-3'-methylsulfanyl-benzyl) -phenoxy] methylphosphonic acid Step a: To a stirred solution of [3,5-dimethyl-4- ( 3'-amino-4'-methoxymethoxybenzyl) phenoxy] methylphosphonate diethyl ester (Example 51, step a, 0.29g, 0.66 mmol) at 80 ° C in dimethyldisulfide (3 mL) was added isoamyl nitrite (0.4 mL, 2.64 mmol) . The reaction mixture was stirred at 80 ° C for 1 h. The solvent was removed under reduced pressure. The crude product was purified by Column chromatography on silica gel, eluted with ethyl acetate-hexanes (1: 1) to provide [3,5-dimethyl-4- (3'-methylsulfanyl-4'-methoxymethoxybenzyl) phenoxy] ] diethyl methylphosphonate as a red oil (0.12 g, 39%): XR NMR (200 MHz, DMSO-d6): d 6.91 (d, J = 8.4 Hz, 1 H), 6.86 (d, J = 2.1 Hz, 1 H), 6.75 (s, 2 H), 6.58 (dd, J = 2.2, 8.4 Hz, 1 H), 5.16 (s, 2 H), 4.36 (d, J = 10.0 Hz, 2 H), 4.11 (m, 4 H), 3.89 (s, 2 H), 3.37 (s, 3 H), 2.30 (s, 3 H), 2.17 (s, 6 H), 1.25 (t, J = 7.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 50% ethyl acetate in hexanes; Rf = 0.61. Step b: The title compound was prepared according to the procedure described by the synthesis of example 8, step f as a yellow foam (40 mg, 42%). X H NMR (300 MHz, DMSO-de): d 9.58 (s, 1 H), 6.80 (d, J = 2.1 Hz, 1 H), 6.72 (s, 2 H), 6. 66 (d, J = 8.4 Hz, 1 H), 6.50 (dd, J = 2.1, 8.4 Hz, 1 H), 4.06 (d, J = 10.2 Hz, 2 H), 3.84 (s, 2 H), 2.28 (s, 3 H), 2.18 (s, 6 H); LCMS m / z = 369 [C17H2105PS + H] +; Analysis calculated for (C17H2105PS + 0.1 EtOAc + 0.1 TFA): C, 54.40; H, 5.68. Found: C, 54.65; H, 5.33.

Example 56: Compound 56: 3, 5-Dithiane-4- (4 '-hydroxy-3' -iso-propylphenoxy) phenoxy] methylphosphonate Step a: To a solution of 4-benzoyloxyphenol (0.2 g, 0.93 mmol) in dichloromethane (9.3 mL) at 0 ° C was added bis (pyridine) iodide tetrafluoroborate (0.76 g, 2.06 mmol). The reaction mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and the residue was purified by Column chromatography on silica gel, eluted with acetone-hexanes (1: 9) to give 4-benzoyloxy-3,5-diiodophenol as an opaque white solid (0.22). g, 50%): 1 H NMR (300 MHz, DMSO-de): d 9.60 (s, 1 H), 8.06 (m, 2 H), 7.72 (s, 2 H), 7.59 (m, 3 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-acetone (4: 1); Rf = 0.45. Step b: To a mixture of bis (4-methoxy-3-iso-propylphenyl) iodide tetrafluoroborate (0.77 g, 1.51 mmol) and copper powder (0.13 g, 2.01 mmol) in CH2C12 (4.4 mL) at 0 ° C was added a solution of TEA (0.15 mL, 1.10 mmol) and 4-benzoyloxy-3, 5-diiodophenol (0.47 g, 1.00 mmol) in dichloromethane ( 4.0 mL). The reaction mixture was stirred at room temperature for 24 h and filtered through a plug of celite. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluted with acetone-hexanes (1: 9) to give 3,5-diiodo-4- (4'-methoxy) benzoate. 3'-iso-propylphenoxy) phenyl as a white opaque solid (0.61 g, 98%): 2 H NMR (300 MHz, DMSO-d 6): d 8.10 (m, 2 H), 7.96 (s, 2 H), 7.73. (m, 1 H), 7.60 (, 2 H), 6.85 (d, J = 9.0 Hz, 1 H), 6.73 (d, J = 3.0 Hz, 1 H), 6.35 (m, 1 H), 3.74 ( s, 3 H), 3.21 (, 1 H), 1.13 (d, J = 6.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-acetone (1: 9); Rf = 0.42. Step c: To a stirred solution of 3,5-diiodo-4- (4 '-methoxy-3'-iso-propylphenoxy) phenyl benzoate (0.4 g, 0.76 mmol) in DMF (5.0 mL) at room temperature CuCN (0.27 g, 3.0 mmol) was added. The reaction mixture was heated at 160 ° C for 5 minutes under microwave irradiation, the reaction mixture was cooled to room temperature and was emptied into 1N HCl (50 mL) and extracted with ethyl acetate (100 mL × 2). The organic layers were dried over Na 2 SO, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (3: 7) to provide 3,5-dicyano-4- (4'-methoxy-3 '-isopropylphenoxy) phenol. as a viscous (105 mg, 35%): 1 H NMR (300 MHz, CDC13): d 7.35 (s, 2 H), 6.99 (d, J = 3.0 Hz, 1 H), 6.78 (d, J = 8.7 Hz, 1 H), 6.99 (dd, J = 3.0, 8.7 Hz, 1 H), 3.84 (s, 3 H), 3.38-3.30 (m, 1 H), 1.21 (d, J = 6.9 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (7: 3); Rf = 0.38. Step d: 3, 5-dicyano-4- (4 '-hydroxy-3'-iso-propylphenoxy) phenol was prepared according to the procedure described by the synthesis of compound 54, step d (132 mg, 32%): 1 H NMR (300 MHz, CD3OD) d 7.38 (s, 2H), 6.81 (d, J = 3.0 Hz, 1 H), 6.70 (d, J = 9.0 Hz, 1H), 6.52 (dd, J = 9.0, 3.0 Hz, 1 H), 3.26 (heptuplet, J = 7.0 Hz, 1H), 1.18 (d, J = 7.0 Hz, 6H); CCD conditions: Merck silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (1: 1), Rf = 0.35. Stage e: Diethyl trifluoromethanesulfonyloxymethylphosphonate (148 mg, 0.5 mmol) was added to a heterogeneous mixture of 3,5-dicyano-4- (4'-hydroxy-3'-iso-propylphenoxy) phenol (132 mg, 0.45 mmol) and cesium carbonate (440 mg). , 1.35 mmol) in DMF at room temperature. After being stirred at room temperature for 1 week, the reaction mixture was diluted with ethyl acetate and the pH was less than 1 with IN hydrochloric acid. The organics were washed with water then brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexanes / ethyl acetate 50/50 to 0/100) to give 3, 5-dicyano-4- (4'-hydroxy-3'-iso-propylphenoxy) phenoxy ] diethyl methylphosphonate (44 mg, 22%): XE NMR (300 MHz, CDC13) d 7.42 (s, 2 H), 6.73 (d, J = 3.0 Hz, 1 H), 6.68 (d, J = 9.0 Hz , 1 H), 6.57 (dd, J = 9.0, 3.0 Hz, 1 H), 4.35-4.20 (m, 6 H), 3.23 (heptuplet, J = 7.0 Hz, 1 H), 1.38 (t, J = 7.0 Hz, 6 H), 1.18 (d, J = 7.0 Hz, 6 H); CCD conditions: Merck silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (1: 1), Rf = 0.2. Step f: The title compound was prepared by the procedure described by the synthesis of compound 8, step f (18 mg, 47%): 1 H NMR (300 MHz, CD 3 OD) d 7.74 (s, 2 H), 6.85 (d, J = 3.0 Hz, 1 H), 6.72 (d, J = 9.0 Hz, 1 H), 6.56 (dd, J = 9.0, 3.0 Hz, 1 H), 4.35 (d, J = 6.8 Hz 2 H), 3.27 (heptuplet, J = 7.0 Hz, 1 H), 1.18 (d, J = 7.0 Hz, 6 H); Analysis calculated for (C18H? 7N206P + 1.4 H20): C, 52.28; H, 4.83; N, 6.77. Found: C, 52.55; H, 4.90; N, 6.12.

Example 57 Compound 57: [4,6-dichloro-3-fluoro-5- (4'-hydroxy-3'-iso-propylphenoxy) -pyrid-2-yloxyjmethyl phosphonic acid Step a: To a stirred solution of 3, 5 -dichloro-2,6-difluoro-4- (4 '-methoxymethoxy-3'-iso-propyl-phenoxy) -pyridine (0.11 g, 0.29 mmol) and diethyl hydroxymethyl phosphonate (0.045 L, 0.31 mmol) in THF (3 mL) at 0 ° C was added NaH (13 mg, 0.31 mmol). The reaction mixture was stirred at room temperature for 16 hrs, diluted with EtOAc and washed with water (30 mL x 2). The solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (2: 1) to provide [4,6-dichloro-3-fluoro-5- (4'-hydroxy-3 ' diethyl-bis-propylphenoxy) -pyrid-2-yloxy] methylphosphonate as a yellow oil (43 mg, 28%): 1 H NMR (300 MHz, DMSO-d 6): d 7.00 (d, J = 9.0 Hz, 1 H ), 6.96 (d, J = 3.3 Hz, 1 H), 6.67 (dd, J = 3.3, 9.0 Hz, 1 H), 5.19 (s, 2 H), 4.77 (d, J = 8.1 Hz, 2 H) , 4.15 (m, 4 H), 3.40 (s, 3 H), 3. 28 (m, 1 H), 1.27 (t, J = 7.2 Hz, 6 H), 1.17 (d, J = 6.6 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 66% ethyl acetate in hexanes; Rf = 0.31. Step b: The title compound was prepared according to the procedure described by the synthesis of example 8, step f as a white solid (30 mg, 71%): mp: 139-141 ° C; XH NMR (200 MHz, DMSO-de): d 9.22 (s, 1 H), 6.84 (d, J = 2.8 Hz, 1 H), 6.68 (d, J = 8.8 Hz, 1 H), 6.47 (dd, J = 2.8, 8.8 Hz, 1 H), 4.46 (d, J = 8.8 Hz, 2 H), 3.17 (m, 1 H), 1.13 (d, J = 6.6 Hz, 6 H); LC-MS m / z = 427 [C15H15Ca2FN? 6P + H] +; Analysis calculated for (C? 5H? 5C12FN06P + 0.5 H20): C, 41.40; H, 3.71; N, 3.22. Found: C, 41.09; H, 3.87; N, 2.89.

Example 58: Compound 58: [4- (4'-Acetoxy-3'-iso-propylbenzyl) -3,5-di-ethylphenoxy] methylphosphonic acid A mixture of [3, 5-Dimethyl-4- (4'-hydroxy] acid -3 '-iso-propylbenzyl)] phenoxymethylphosphonic (5.0 g, 13.7 mmol) and acetic anhydride (5.0 g, 48.9 mmol) in toluene (70 mL) was stirred at 20 ° C for 3 hrs. Water (5 mL) was added and the mixture was stirred 1 hr. The solvent was removed under reduced pressure. Toluene (50 mL) was added to the residue then removed under reduced pressure. The addition of toluene and evaporation was repeated twice more. The resulting solid was dried under vacuum at 45 ° C to give the title compound (5.6 g, 100%). A purified sample (420 mg) was obtained by stirring the crude product in boiling isopropyl ether, cooled to 20 ° C, collecting the solid by filtration, and drying under vacuum, mp: 169-172 ° C; a H NMR (300 MHz, DMSO-d 6): d 7.06 (d, J = 2.1 Hz, 1 H), 6.85 (d, J = 8.4 Hz, 1 H), 6.70 (s, 2 H), 6.65 (dd, J = 9.0 and 2.4 Hz, 1 H), 4.02 (d, J = 10.2 Hz, 2 H), 3.90 (s, 2 H), 2.94-2.84 (, 1 H), 2.25 (s, 3 H), 2.15 (s, 6 H), 1.07 (d, J = 6.9 Hz, 6 H). Analysis calculated for (C21H2706P): C, 62.06; H, 6.70. Found: C, 62.22; H, 6.82.

Example 59 (S) -2- [(4- (4'-Acetoxy-3'-iso-propylbenzyl) -3,5-dimethylphenoxy) methyl] -4- (3-chlorophenyl) -2-oxo-2? 5 - [1,3,2] -dioxaphosphonane Cis and Trans: A solution of oxalyl chloride (3.0 g, 23.6 mmol) in dichloromethane (14 mL) was added over 20 minutes to a stirred suspension of acid [4- (4 ' 3-acetoxy-3 '-isopropylbenzyl) -3,5-dimethylphenoxy] methylphosphonic acid (3.2 g, 7.88 mmol) in dichloromethane (50 mL). The resulting solution was stirred at 20 ° C for 1 hr, then the solvent was removed under reduced pressure. Dichloromethane (30 mL) was added to the residue then evaporated under reduced pressure. The resulting oil was dissolved in THF (32 mL) and the solution was added over 40 minutes to a stirred solution of (S) -1- (3-chlorophenyl) -1,3-propanediol (1.5 g, 7.88 mmol) and triethylamine. (2.4 g, 23.6 mmol) in THF (32 mL) while maintaining the low temperature of -70 ° C. The reaction mixture was stirred at -70 ° C for 2 hrs, then heated to 15 ° C. To the reaction mixture was added 0.5 M aqueous HCl (32 mL) and ethyl acetate (32 mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (32 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, and filtered. The solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel, eluted with ethyl acetate-hexanes (50% -100%) to provide: Compound 59-trans: (610 mg, 14%): XR NMR (300 MHz, DMSO-d6): d 7.48-7.36 (m, 4 H), 7.07 (d, J = 2.1 Hz, 1 H), 6.85 ( d, J = 8.4 Hz, 1 H), 6.83 (s, 2 H), 6.64 (dd, J = 9.0 and 2.0 Hz, 1 H), 5.85-5.82, (m, 1 H), 4.74-4.68 (m , 1 H), 4.61 (d, J = 9.3 Hz, 2 H), 4.52-4.42 (m, 1 H), 3.92 (s, 2 H), 2.94-2.85 (m, 1 H), 2.25 (s, 3 H), 2.24-2.20 (m, 2 H), 2.17 (s, 6 H), 1.07 (d, J = 6.9 Hz, 6 H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = dichloromethane-acetone (9: 1); Rf = 0.5 59-cis Compound: (2.5g, 57%): 1 H NMR (300 MHz, DMSO-d 6): d 7.47 (m, 1 H), 7.38-7.26 (m, 3 H), 7.06 (d, J = 2.1 Hz, 1 H), 6.85 (d, J = 8.7 Hz, 1 H), 6.76 (s, 2 H), 6.67 (dd, J = 8.1 y 2. 1 Hz, 1 H), 5.76-5.72 (m, 1 H), 4.61-4.36 (m, 4 H), 3.92 (s, 2 H), 2.94-2.85 (m, 1 H), 2.25 (s, 3 H), 2.20-2.19 (m, 2) H), 2.16 (s, 6 H), 1.07 (d, J = 6.9 Hz, 6 H). Terms CCD: Uniplaca of silica gel, 250 microns; Mobile phase = dichloromethane-acetone (9: 1); Rf = 0.35; Analysis calculated for (C30H34CIO6P + 0.13H20): C, 64.42; H, 6.17. Found: C, 64.12; H, 6.07.

Example 60 Compound 60: [4- (4'-Hydroxy-3'-iso-propyl-2'-methylbenzyl) -3-methylphenoxyl) -3-methylphosphonic acid Step a: To a stirred solution of 1-bromo-3-iso -propyl-4-methoxy-2-methyl-benzene (compound 7-16, step c; 0.7 g, 2.88 mmol) in THF (20 mL) at -78 ° C was added n-BuLi (1.6 mL, 2.5 M in hexanes). The mixture was stirred at -78 ° C for 1 hr and 4-methoxy-2-methyl-benzaldehyde (0.37 mL, 2.74 mmol) was added. The reaction mixture was stirred at -78 ° C for 1 hr, allowed to warm to room temperature and stirred for 1 hr. The reaction mixture was quenched with saturated NH4C1 and diluted with diethyl ether. The organic layer was dried over Na 2 SO 4, filtered and concentrated under reduced pressure to give crude (4 '-methoxy-3' -iso-propyl-2 '-methylphenyl) - (4-methoxy-2-methylphenyl) -methanol as a light yellow oil (1.0 g, 100%). This crude oil was dissolved in EtOAc (25 mL) and AcOH (5 mL) and Pd / C (0.1 g) was added. After being stirred at room temperature for 6 hours, the reaction mixture was filtered through Celite and concentrated under reduced pressure to provide 4- (4 '-methoxy-2'-methyl-3' -iso-propylbenzyl) -3 crude methyl-anisole as a yellow oil (0.8 g, 93%):? E NMR (300 MHz, DMSO-d6): d 6.88-6.80 (m, 5 H), 3.77 (s, 2 H), 3.74 ( s, 3 H), 3.71 (s, 3 H), 3.34 (m, 1 H), 2.22 (s, 3 H), 2.14 (s, 3 H), 1.28 (d, J = 6.9 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 8% ethyl acetate in hexanes; Rf = 0.56. Step b: To a stirred solution of 4- (4 '-methoxy-2'-methyl-3' -iso-propylbenzyl) -3-methyl-anisole (0.8 g, 2.68 mmol) in CH2C12 (10 mL) at -20 ° C was added BBr3 (10.7 mL, 1M in CH2C12). The reaction mixture was stirred at room temperature for 16 hrs. To this ice was added and diluted with CH2C12. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluted with ethyl acetate / hexanes (1: 1) to give 4- (4'-hydroxy-2'-methyl-3'-iso-propylbenzyl) - 3-methylphenol as a yellow solid (0.54 g, 75%): XR NMR (200 MHz, DMSO-de): d 9.03 (s, 1 H), 8.84 (s, 1 H), 6.41-6.60 (m, 5 H), 3.65 (s, 2 H), 3.33 (m, 1 H), 2.12 (s, 3 H), 2.08 (s, 3 H), 1.27 (d, J = 6.9 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 20% ethyl acetate in hexanes; Rf = 0.31. Stage c: To a solution of 44- (4'-hydroxy-2'-methyl-3 '-isopropylbenzyl) -3-methylphenol (0.54 g, 2 mmol) in DMF (15 mL) at room temperature was added Cs2CO3 (2.6 g). , 8 mmol) and diethyl trifluoromethanesulfonyloxymethylphosphonate (0.66 g, 2.2 mmol). The reaction mixture was stirred at room temperature for 1 hr. Solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated NaHCO 3. The organic layer was dried over Na 2 SO, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (4: 1) to provide [4- (4'-hydroxy-3'-iso-propyl-2'-methylbenzyl) -3-methylphenoxy] diethyl methylphosphonate as a colorless oil (0.14 g, 17%): X H NMR (300 MHz, DMSO-d 6): d 8.89 (s, 1 H), 6.86 (d, J = 2.7 Hz, 1 H), 6.76 (dd, J = 2.7, 9. 0 Hz, 1 H), 6.67 (d, J = 9.0 Hz, 1 H), 6.51 (m, 2 H), 4. 36 (d, J = 9.6 Hz, 2 H), 4.11 (m, 4 H), 3.73 (s, 2 H), 3. 34 (, 1 H), 2.22 (s, 3 H), 2.09 (s, 3 H), 1.27 (m, 12 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 66% ethyl acetate in hexanes; Rf = 0.45. Step d: The title compound was prepared according to the procedure described by the synthesis of example 8, step f as a white solid (80 mg, 67%): 1 H NMR (300 MHz, DMSO-d 6): 8.88 (s, 1 H), 6.85 (d, J = 2.1 Hz, 1 H), 6.73 (dd, J = 2.1, 8.7 Hz, 1 H), 6.66 (d, J = 8.7 Hz, 1 H), 6.51 (m, 2 H), 4.02 (d, J = 10.2 Hz, 2 H), 3.73 (s, 2 H), 3.34 (m, 1 H), 2.22 (s, 3 H), 2.10 (s, 3 H), 1.30 ( d, J = 6.9 Hz, 6 H); mp: 166-168 ° C; LC-MS m / z = 363 [C19H2505P-H] ~; Analysis calculated for (C19H2505P + 0.13 HBr): C, 60.87; H, 6.76; Br, 2.77. Found: C, 61.19; H, 6.84; Br, 3.10.

Example 61: Compound 61-1: [4- (4'-Hydroxy-3'-iso-propylbenzyl) -2,3,5-trimethylphenoxy] methylphosphonic acid Step a: A mixture of 3,5-dimethyl-2-iodo-4- (4 '-methoxymethoxy-3'-iso-propylbenzyl) phenol (compound 47, step a, 1.0 g, 2.27 mmol) and PdCl 2 (PPh 3) 2 (0.10 g, 0.14 mmol) in TEA (1.6 mL) and methanol (8.0 L) was heated under a CO atmosphere (60 psi (4.218 kg / cm2)) at 80 ° C for 72 h. The reaction mixture was cooled to room temperature and filtered through a plug of celite. The solvent was removed under reduced pressure and the crude product was purified by Column chromatography on silica gel, eluted with 10% ethyl acetate in hexanes to provide 2,4-dimethyl-6-hydroxy-3- (4 '- methyl methoxymethoxy-3'-iso-propylbenzyl) benzoate (0.32 g, 38%): 2 H NMR (300 MHz, CD 3 OD): d 6.93 (m, 2 H), 6.67 (s, 2 H), 5.18 (s, 1 H), 3.98 (s, 2 H), 3.92 (s, 3 H), 3.48 (s, 3 H), 3.30 (m, 1 H), 2.22 (m, 6 H), 1.18 (d, J = 6.9 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 5); Rf = 0.60. Step b: To a solution of methyl 2,4-dimethyl-6-hydroxy-3- (4'-methoxymethoxy-3'-iso-propylbenzyl) benzoate in ethanol-water (3.0 mL, 95: 5) at room temperature NaBH4 was added. The reaction mixture was heated at 80 ° C for 4 h and cooled to room temperature. The reaction mixture was quenched with aqueous NH 4 Cl and extracted with ether. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by Column chromatography on silica gel, eluted with 30% acetone in hexanes to provide 2, -dimethyl-6-hydroxy-3- (4'-methoxymethoxy-3'-iso-propylbenzyl) benzyl alcohol. 1 H NMR (300 MHz, CD3OD): d 6.97 (d, J = 2.4 Hz, 1 H), 6.92 (d, J = 13.2 Hz, 1 H), 6.68 (dd, J = 13.2, 2.4 Hz, 1 H ), 6.59 (s, 1 H), 5.17 (s, 2 H), 4.78 (s, 2 H), 3.96 (s, 2 H), 3.47 (s, 3 H), 3.30 (m, 1 H), 2.24 (s, 3 H), 2.19 (s, 3 H), 1.18 (d, J = 10.8 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (3: 7); Rf = 0.40. Stage c: A mixture of 2,4-dimethyl-6-hydroxy-3- (4'-methoxymethoxy-3'-iso-propylbenzyl) benzyl alcohol ((0.20 g, 0.58 mmol) and Pd-C (0.08 g, 10%) in Ethyl acetate-acetic acid (3.5 mL, 95: 5) was stirred at room temperature under an H2 atmosphere for 6 h.The reaction mixture was filtered through a plug of celite and the solvent was removed under reduced pressure to provide 4- (4'-methoxymethoxy-3'-iso-propylbenzyl) -2,3,5-trimethylphenol (0.19 g, 100%) as a colorless oil: XR NMR (300 MHz, CD3OD): d 6.94 (m, 1 H), 6.91 (d, J = 13.2 Hz, 1 H), 6.68 (dd, J = 13.2, 2.4 Hz, 1 H), 6.55 (s, 1 H), 5.17 (s, 2 H), 3.95 (s) , 2 H), 3.47 (s, 3 H), 3. 30 (m, 1 H), 2.19 (s, 3 H), 2.16 (s, 3 H), 2.11 (s, 3 H), 1.17 (d , J = 10.8Hz, 6H); CCD Conditions: Silica gel uniplaca, 250 microns; Mobile phase = acetone-hexanes (3: 7); Rf = 0.60 The title compound was prepared according to the procedure described by the synthesis of compound 7: mp: 56.0-58.0 C; XH NMR (300 MHz, CD3OD): d 6.85 (d, J = 2.4 Hz, 1 H), 6.76 (s, 1 H), 6.60 (d, J = 12.0 Hz, 1 H), 6.52 (dd, J = 12.6, 2.4 Hz, 1 H), 4.22 (d, J = 10.2 Hz, 2 H), 3.94 (s, 2 H), 3.23 (m, 1 H), 2.25 (s, 3 H), 2.24 ( s, 3 H), 2.15 (s, 3 H), 1.17 (d, J = 10.8 Hz, 6 H); LC-MS m / z = 379 [C 20 H 27 O 5 P + H] +; Analysis calculated for [C20H27O5P + 1.1H20]: C, 60.32; H, 7.39. Found: C, 60.05; H, 7.14.

EXAMPLE 62 Compound 62: [6-iodo-4- (4'-hydroxy-3'-iso-propylbenzyl) -2,3,5-trimethylphenoxy] methylphosphonic acid [6-Iodo-4- (4'-hydroxy-3'-iso-propylbenzyl) -2,5,5-trimethylphenoxy] methylphosphonic acid was prepared from 4- (4'-methoxymethoxy-3'-iso- propylbenzyl) -2, 3, 5-trimethylphenol (compound 61-1, step c) was prepared according to the procedure described by the synthesis of compound 45, step a and is transformed into the title compound according to the procedure described by the synthesis of compound 7-1: mp: 185-187 ° C; R NMR (300 MHz, CD3OD): d 6.88 (d, J = 2.4 Hz, 1 H), 6.61 (d, J = 12.3 Hz, 1 H), 6.50 (d, J = 2.4 Hz, 1 H), 4.14 (d, J = 10.5 Hz, 1 H), 4.09 (s, 2 H), 3.24 (, 1 H), 2.46 (s, 3 H), 2.39 (s, 3 H), 2.19 (s, 3 H) , 1.18 (d, J = 6.9 Hz, 6 H); LC-MS m / z = 504 [C20H27O P] +; Analysis calculated for (C20H2eIO5P + 0.8 H20): C, 46.26; H, 5.41. Found: C, 46.48; H, 5.78.

Example 63 Compound 63: [3-Bromo-4- (4'-hydroxy-3'-iso-propylphenoxy) -5-trifluoromethyl-phenylamino] methylphosphonic acid Step a: The intermediate 1,5-dibromo-2- (3 ') -iso-propyl-4'-methoxy-phenoxy) -3-trifluoromethyl-benzene was prepared from 2,4-dibromo-6-trifluoromethyl-phenol (J. Amer. Chem. Soc., 1947, 2346) according to the procedure described by the synthesis of compound 4, step a: XR NMR (200 MHz, DMSO-d6): d 8.39 (m, 1 H), 8.07 (m, 1 H), 6.85 (m, 2 H), 6.45 (m, 1 H), 3.73 (s, 3 H), 3.15 (m, 1 H), 1.08 (d, J = 10.5 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes; Rf = 0.54. Step b: To a mixture of Pd (OAc) 2 (0.031 g, 0.14 mmol) in toluene (40 mL) at room temperature was added (+/-) 2,2'-bis (diphenylphosphino) -1, 1 '- binaphthyl (0.13 mL, 0.21 mmol). The reaction mixture was stirred at room temperature for several minutes and Cs2CO3 (3.62 g, 11.10 mmol), 1, 5-dibromo-2- (3 '-iso-propyl-4' -methoxyphenoxy) -3-trifluoromethyl-benzene ( 1.30 g, 2.77 mmol, was dissolved in 10 mL of toluene), and diethyl aminomethylphosphonate oxalate (0.76 g, 2.97 mmol) were added. The reaction mixture was stirred at 100 ° C for 16 h. The solution was cooled to room temperature, diluted with diethyl ether (25 mL), filtered and concentrated. The crude product was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (1: 1) to provide [3-bromo-4- (4'-methoxy-3'-iso-propyl-phenoxy). ) -5-trifluoromethylphenylamino] methylphosphonate diethyl ester as an oil (0.28 g, 18%): X H NMR (300 MHz, DMSO-d 6): d 7.33 (m, 1 H), 7.16 (m, 1 H), 6.85 ( , 1 H), 6.65 (m, 1 H), 6.55 (m, 1 H), 6.39 (m, 1 H), 4.08 (m, 4 H), 3.74 (s, 3 H), 3.68 (m, 2 H), 3.21 (m, 1 H), 1.19 (m, 6 H), 1.11 (d, J = 6.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (4: 1); Rf = 0.25. Step c: The title compound was prepared according to the procedure described by the synthesis of example 19, step e: mp: 98-102 ° C; 1 H NMR (300MHz, CD3OD): d 7.11 (m, 1 H), 6.95 (m, 2 H), 6.48 (m, 1 H), 6.45 (m, 1 H), 6.20 (m, 1 H), 3.41 (d, J = 12.0 Hz, 2 H), 3.12 (m, 1 H), 1.17 (m, 18 H), 1.04 (d, J = 6.0 Hz, 6 H); LC-MS m / z = 484 [C17H? 8BrF3N05P-H] +; CLAR conditions: Column = Shimadzu LC-A8, SPD-10A; YMC Pack RP-18 filter, 150x4.6; Mobile phase = Solvent Acetonitrile / 0.05% TFA; Solvent B = H2O / 0.05% TFA.

Gradient: 0 min .: 20% B; 13 min .: 70% B; 16 min .: 100% B; 18 min .: 20% B. Flow ratio = 2.0 mL / min .; UV @ 254 nm. tr = 9.16 min.

Example 64 Compound 64: [3,5-Dimethyl-4- [4 '-hydroxy-3' - (3-trifluoromethylphenoxy) benzyl] phenoxy] methylphosphonic acid Step a: Al 5- (2,6-dimethyl-4-triisopropylsilanyloxybenzyl) -2-methoxymethoxy-benzaldehyde (compound 15, step e; 0.460 g, 1.01 mmol) in dichloromethane 30 mL was added mCPBA (0.870 g, 2.52 mmol) and saturated sodium bicarbonate solution (2 mL). After being stirred at room temperature overnight, the reaction mixture was poured into dichloromethane 50 mL and washed 3 x with 10 mL saturated aqueous sodium bicarbonate. The dichloromethane was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was combined with methanol (10 mL) and 2 mL of 1 N NaOH and stirred for 1.5 hours at room temperature. The reaction was acidified with 12 N HCl (pH <3) and it was emptied into 50 mL ethyl acetate. The layers were separated and organics were dried over sodium sulfate, filtered and concentrated. Flash column chromatography using silica and a step gradient of hexane / ethyl acetate [20: 1], hexane / ethyl acetate [9: 1] afforded 5- (2,6-dimethyl-4-triisopropylsilanyloxybenzyl) -2 -methoxymethoxy-phenol (0.189 g, 42%): XR NMR (300 MHz, DMSO-d6): d 8.95 (s, 1 H), 6.86 (d, 1 H, J = 8.1 Hz), 6.56 (s, 2 H), 6.41 (d, 1 H, J = 2.1 Hz), 6.34 (dd, 1 H, J = 2.1 Hz and J = 8.7 Hz), 5.05 (s, 2 H), 3.78 (s, 2 H), 3.38 (s, 3 H), 2.13 (s, 6 H), 1.11 (m, 3 H), 1.00 (m, 18 H); Uniplaca of silica gel, 250 microns; Mobile phase = 10% ethyl acetate in hexane: Rf = 0.15. Step b: (2,6-Dimethyl-4-triisopropylsilanyloxybenzyl) -4-methoxymethoxy-3- (3-trifluoromethylphenoxy) benzene was prepared from 5- (2,6-dimethyl-4-triisopropylsilanyloxybenzyl) -2-methoxymethoxy -phenol according to the procedure described in Dominic MT Chan et al. Tetrahedron Lett. 1998, 39, 2933-2936, (0.070 g, 37%) X H NMR (300 MHz, DMSO-d 6): d 7.53 (t, 1 H, J = 7.8 Hz), 7.35 (d, 1 H, J = 7.8 Hz), 7.21-7.10 (m, 2 H), 6.98 (s, 1 H), 6.89 (m, 1 H), 6.59 (m, 1 H), 6.64 (s, 2 H), 5.09 (s, 2 H), 3.89 (s, 2 H), 3.18 (s, 3 H), 2.11 (s, 6 H), 1.16 (m, 3 H), 1.01 (m, 18 H); Uniplaca of silica gel, 250 microns; Mobile phase = 10% ethyl acetate in hexane: Rf = 0.47.

Step c: 3, 5-Dimethyl-4- [4'-methoxymethoxy-3 '- (3-trifluoromethylphenoxy) benzyl] phenol was synthesized according to the procedure described by the synthesis of compound 35, step e, (0.059 g, 100%); X H NMR (300 MHz, DMSO-d 6): d 9.02 (s, 1 H), 7.55 (t, 1 H, J = 7.8 Hz), 7.38 (1 H, d, J = 8.4 Hz), 7.14 (m, 2 H), 7.02 (s, 1 H), 6.88 (dd, 1 H, J = 1.5 Hz and J = 6.6 Hz), 6.72 (d, 1 H, 2.1 Hz), 6.44 (s, 2 H), 5.08 (s, 2 H), 3.85 (s, 2 H), 3.18 (s, 3 H), 2.08 (s, 6 H); (Silica gel uniplaca, 250 microns; Mobile phase = 25% ethyl acetate in hexane: f = 0.28) Step d: [3,5-dimethyl-4- [4 '-methoxymethoxy-3' - (3- diethyl trifluoromethylphenoxy) benzyl] phenoxy] methylphosphonate was prepared according to the procedure described by the synthesis of compound 8, steps e (0.015 g, 15%); 1 H NMR (300 MHz, DMSO-d6): d 7.55 (t, 1 H, J = 8.4 Hz), 7.37 (d, 1 H, J = 7.5 Hz), 7.14 (m, 2 H), 7.02 (s, 1 H), 6.86 (dd, 1 H, J = 1.7 Hz and J = 7 Hz), 6.73 (s, 2 H), 5.08 (s, 2 H), 4.34 (d, 2 H, J = 9.9 Hz), 4.09 (m, 4 H), 3.91 ( s, 2 H), 3.18 (s, 3 H), 2.18 (s, 6 H), 1.24 (t, 6 H, J = 7 Hz); Uniplaca of silica gel, 250 microns; Mobile phase = 25% hexane in ethyl acetate: Rf = 0.2. Step e: The title compound was prepared according to the procedure described by the synthesis of compound 8, steps f, (0.022g, 90%); a H NMR (300 MHz, DMSO-d 6): d 9.48 (s, 1 H), 7.53 (t, 1 H, J = 7.8 Hz), 7.34 (d, 1 H, J = 7.2 Hz), 7.07 (d, 1 H, J = 9 Hz), 7.01 (s, 1 H), 6.90 (d, 1 H, J = 8.4 Hz), 6.71 (m, 4 H), 4.00 (d, 2 H, J = 10.2 Hz) 3.84 (s, 2 H), 2.15 (s, 6 H); LC-MS m / z = 481 [C23H22F306P-H] -; Uniplaca of silica gel, 250 microns; Mobile phase = isopropyl alcohol / water / ammonium hydroxide [7: 2: 1]: Rf = 0.47; CLAR, zorbax, XDB-C8,150mm x 4.6 mm, 5 μm, flow 1 mL / min, Solvent A: 0.05 M aqueous KH2P04 pH 6.2, Solvent B: acetonitrile, Gradient 40% B at 60% B for 1 min. then 60% B. total time running 12 min. tr 1.87 min; Analysis calculated for (C23H22F30eP + 0.3M H20 + 0.1M EtOAc) C, 56.60; H, 4.70. Found: C, 56.68; H, 3.97.

Example 65 Compound 65-1: 2,6-diiodo-3,5-dimethyl- [4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy] methylphosphonic acid Step a: To a stirred solution of 3,5-dimethyl-4- (4'-methoxymethoxy-3'-iso-propylbenzyl) phenol (0.22 g, 0.70 mmol), (G. Chiellini et al., Bioorg, Med. Chem. Lett. 2000, 10, 2607) in EtOH (6.2 mL) and CH3NH2 40% in water (2.5 mL) were added iodide (0.39 g, 1.54 mmol) and Kl (0.25 g 1.54 mmol) in H20 (3 mL) at 0 ° C. The reaction mixture was stirred at room temperature for 16 h, quenched with brine (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (1: 4) to provide 2,6-diiodo-3,5-dimethyl-4- (4 '-methoxymethoxy-3). '-iso-propylbenzyl) phenol as a colorless oil (198 mg, 50%): "" "H NMR (300 MHz, CDC13): d 6.97 (d, J = 2.1 Hz, 1 H), 6.92 (d, J = 5.6 Hz, 1 H), 6.59 (dd, J = 2.4, 8.4 Hz, 1 H), 6.0 (s, 1 H), 5.19 (s, 2 H), 4.16 (s, 2 H), 3.50 (s, 3 H), 3.35-3.30 (m, 1 H), 2.48 (s, 6 H), 1.21 (d, J = 6.9 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (4: 1); Rf = 0.62. Step b: To a stirred solution of 2,6-diiodo-3,5-dimethyl-4- (3'-iso-propyl-4'-methoxymethoxybenzyl) phenol (0.2 g, 0.35 mmol) in DMF (3.0 mL) at 0 ° C was added Cs2C03 (0.34 g, 1.05 mmol).

After 10 minutes, diethyl trifluoromethanesulfonyloxymethyl phosphonate (0.1 g, 0.35 mmol) was added. The reaction mixture was stirred at 0 ° C for 1 h, allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with 1N HCl, diluted with ethyl acetate, and washed with water (10 mLx4) and brine. The organic layer was concentrated under reduced pressure and the crude product was purified by column chromatography, on silica gel, eluted with ethyl acetate-hexanes (2: 3) as mobile phase to provide [2,6-diiodo-3, Diethyl 5-dimethyl-4- (3'-iso-propyl-4'-methoxymethoxybenzyl) phenoxy] methylphosphonate as an oil (0.21 g, 85%): XR NMR (300 MHz, CDC13): d 6.96 (d, J = 2.4 Hz, 1 H), 6.92 (d, J = 8.4 Hz, 1 H), 6.56 (dd, J = 2.1, 8.4 Hz, 1 H), 5.18 (s, 2 H), 4.45-4.35 (m, 6 H), 4.18 (s, 2 H), 3.50 (s, 3 H), 3.39-3.25 (m, 1 H), 2.49 (s, 6 H), 1. 47 (t, J = 6.9 Hz, 6 H), 1.20 (d, J = 6.9 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase hexanes-ethyl acetate (1: 1); Rf = 0.35. Step c: To a solution of diethyl [2,6-diiodo-3,5-dimethyl-4- (3'-iso-propyl-4'-methoxymethoxybenzyl) phenoxy] methylphosphonate (0.14 g, 0.19 mmol) in CH2C12 ( 4.0 mL) at 0 ° C was added bromotrimethylsilane (0.31 mL, 1.9 mmol). The reaction mixture was stirred at room temperature for 16 h and the solvent was removed under reduced pressure. The residue was treated with methanol and water (4: 1, 5.0 mL) and the solvents were removed under reduced pressure. The residue was treated with acetonitrile and filtered to give 2,6-diiodo-3,5-dimethyl- [4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy] methylphosphonic acid as a white solid (97 mg, 80%): mp 236 ° C; XH NMR (300 MHz, CD3OD): d 6.87 (s, 1 H), 6.62 (d, J = 7.8 Hz, 1 H), 6.46 (d, J = 8.7 Hz, 1 H), 4.31 (d, J = 10.8 Hz, 2 H), 4.19 (s, 2 H), 3.35-3.18 (m, 1 H), 2.50 (s, 6 H), 1.17 (d, J = 6.9 Hz, 6 H); LC-MS M = 616 [C? 9H23I205P] +; CLAR conditions: ODSAQ AQ-303-5 Column; Mobile phase = CH3OH: 0.05% TFA (7: 3) flow ratio = 1.0 mL / min; detection = UVT280 nm retention time in minutes: 13.82; Analysis calculated for (C20H25OeP + 0.9 H20): C, 36.09; H, 3.95. Found: C, 35.80; H, 4.22. Using the appropriate starting material, the compounds 65-2 were prepared in a manner analogous to that described by the synthesis of compound 65-1.

Compound 65-2: 2,6-dibromo-3,5-dimethyl- [4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy] methyl-1-methyl acid Stage a: To a stirred solution of 3,5-dimethyl-4- (4'-methoxymethoxy-3'-iso-propylbenzyl) phenol (0.2 g, 0.63 mmol), (G. Chiellini et al., Bioorg, Med. Chem. Lett. 2000, 10, 2607) in EtOH (6.0 mL) and CH3NH2 40% in water (2.5 mL) was added bromide (0.25 g, 1.59 mmol) and KBr (0.11 g 1.59 mmol) in H20 (2 mL) at 0 ° C. . The reaction mixture was stirred at room temperature for 16 h, quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude product was purified by Column chromatography on silica gel, eluted with ethyl acetate-hexanes (1: 9) to provide 2,6-dibromo-3,5-dimethyl-4- (4 '-methoxymethoxy-3). '-iso-propylbenzyl) phenol as a white solid (0.18 g, 60%): XH NMR (300 MHz, CDC13): d 6.97 (d, J = 2.1 Hz, 1 H), 6.92 (d, J = 8.4 Hz , 1 H), 6.60 (dd, J = 2.4, 8.7 Hz, 1 H), 6.0 (s, 1 H), 5.19 (s, 2 H), 4.08 (s, 2 H), 3.50 (s, 3 H) ), 3.35-3.30 (m, 1 H), 2.38 (s, 6 H), 1.21 (d, J = 6.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (4: 1); Rf = 0.62. Step b: The title compound was prepared according to the procedure described by the synthesis of example 45, step b and c: as a white solid (0.15 g, 80%) mp 190 ° C; aH NMR (300 MHz, CD30D): d 6.88 (d, J = 2.1 Hz, 1 H), 6.62 (d, J = 8.4 Hz, 1 H), 6.46 (dd, J = 2.4, 8.7 Hz, 1 H) , 4.27 (d, J = 10.5 Hz, 2 H), 4.12 (s, 2 H), 3.35-3.18 (m, 1 H), 2.40 (s, 6 H), 1.17 (d, J = 6.9 Hz, 6 H); LC-MS m / z = 523 [C19H23I205P + H] +; CLAR conditions: ODSAQ AQ-12S05146W Column; Mobile phase = 0.05% TFA / CH3CN: 0.05% TFA / H20 (1: 1) flow ratio = 1.0 mL / min; detection = UV @ 254 nm retention time in minutes: 10.45; Analysis calculated for (C2oH23Br2OsP): C, 43:70; H, 4.44. Found: C, 43.78; H, 4.46.

Example 66 Compound 66: 4,6-Dimethyl-4- (4'-hydroxy-3'-iso-propylphenoxy) indolfosphonic acid Step a: A solution of sodium nitrite (155 mg, 2.24 mmol) in water (1 mL) was added to a suspension of 3,5-dimethyl-4- (4'-methoxy-3'-iso-propylphenoxy) -aniline (J. Med. Chem. 1995, 38, 695.640 mg, 2.24 mmol) in ethanol (3 mL) and hydrochloric acid (12 M, 1.12 mL, 13.44 mmol) was concentrated at 0 ° C. The yellow heterogeneous solution slowly became a clear, free-flowing solution. After being stirred at 0 ° C for 30 minutes, a solution of tin dichloride (1.53 g, 8.06 mmol) in hydrochloric acid (12 M, 1.3 mL, 15.68 mmol) was added. The annealed solution turned green and a white precipitate formed. Ethanol (3 mL) was added to dissolve more of the precipitate and the heterogeneous reaction mixture was stirred at 0 ° C. After 2 hours, water was added and the precipitate was collected by filtration. The thick solid was dissolved in ethyl acetate and washed with water, IN sodium hydroxide then brine. The organics were dried over sodium sulfate, concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, dichloromethane / methanol 95/5 to 90/10) to give 3,5-dimethyl-4 hydrazine. - (4'-methoxy-3'-iso-propylphenoxy) -phenyl (305 mg, 45%): XH NMR (300 MHz, CDC13) d 6.77 (d, J = 3.0 Hz, 1 H), 6.67 (d, J = 9.0 Hz, 1 H) 6.58 (s, 2 H), 6.37 (dd, J = 9.0, 3.0 Hz, 1 H), 3. 77 (s, 3 H), 3.27 (heptuplet, J = 6.9 Hz, 1 H), 2.09 (s, 3 H), 1.18 (d, J = 6.9 Hz, 6 H); CCD conditions: Merck silica gel, 250 microns; Mobile phase = dichloromethane-methanol (9: 1), Rf = 0.6. Step b: Diethyl acetylphosphonate (183 mg, 1.02 mmol) was added to a yellow solution of hydrazine in toluene at room temperature. After stirring 10 minutes at room temperature, polyphosphoric acid (PPA, 0.4 g) was added and the turbid reaction mixture was placed in an oil bath at 115 ° C. After refluxing for 5 minutes, the cold brown biphasic solution was partitioned between ethyl acetate and water and the organic layer was washed with water then brine, dried over sodium sulfate, concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, hexanes / ethyl acetate 70/30 to 20/80) to give diethyl 5,6-dimethyl-4- (4'-methoxy-3'-iso-propylphenoxy) indolephosphonate (276) mg, 61%): XH NMR (300 MHz, CDC13) d (s, 1H, interchangeable with D20), 7.17 (s, 1 H), 7.07 (m, 1 H), 6.83 (d, J = 3.0 Hz, 1 H), 6.65 (d, J = 9.0 Hz, 1 H), 6.34 (dd, J = 9.0, 3.0 Hz, 1 H), 4.30-4.08 (m, 4 H), 3.77 (s, 3 H), 3.28 (heptuplet, J = 6.9 Hz, 1 H), 2.35 (s, 3 H), 2.24 (s, 3 H), 1.37 (t, J = 7.1 Hz, 6 H), 1.18 (d, J = 6.9 Hz , 6 H); CCD conditions: Merck silica gel, 250 microns; Mobile phase = dichloromethane-methanol (9: 1); Rf = 0.55. Step c: 5,6-Dimethyl-4- (4'-hydroxy-3'-iso-propylphenoxy) indolephosphonic acid was prepared according to the procedure described by the synthesis of example 8, step f (100 mg, 51%): 2 H NMR (300 MHz, CD30D) d 7.14 (s, 1 H), 6.97 (s, 1 H), 6.75 (d, J = 9.0 Hz, 1 H), 6.68 (d, J = 3.0 Hz, 1 H), 6.35 (dd, J = 9.0, 3.0 Hz, 1 H), 3.75 (s, 3 H), 3.25 (heptuplet, J = 6.9 Hz, 1 H), 2.27 (s, 3 H), 2.16 (s) , 3 H), 1.11 (d, J = 6.9 Hz, 6 H); LC-MS m / z = 390.4 [C2oH24N05P + H] +. Step d: A solution of boron tribromide (1 M in dichloromethane, 1.3 mL, 1.3 mmol) was added to a solution of 5,6-dimethyl-4- (4'-methoxy-3'-iso-propylphenoxy) indolfosphonic (100 mg, 0.26 mmol) in dichloromethane (10 mL) at -78 ° C. The ice bath was stirred and the reaction mixture was warmed to room temperature. After being stirred at room temperature overnight, the reaction mixture was quenched with ice, diluted with ethyl acetate and washed with water then brine, dried over sodium sulfate and concentrated under reduced pressure to give the title compound. title (86.3 mg, 80%): - "? NMR (300 MHz, CD3OD) d 7.18 (s, 1 H), 6.97 (d, J = 3.0 Hz, 1 H), 6.60 (s, 1 H), 6.57 (d, J = 9.0 Hz, 1 H), 6.26 (dd, J = 9.0, 3.0 Hz, 1 H), 3.22 (heptuplet, J = 6.9 Hz, 1 H), 2.28 (s, 3 H), 2.18 ( s, 3 H), 1.12 (d, J = 6.9 Hz, 6 H); Analysis calculated for (C? 9H22N05P + 1.5 H20 + 0.1 C3H60): C, 56.79; H, 6.32; N, 3.43. Found: C, 56.61; H, 5.92; N, 3.22.

Abbreviations: CH2C12: dichloromethane DMF: dimethy1formamide TEA: triethylamine THF: tetrahydrofuran TFA: trifluoroacetic acid MgS0: magnesium sulphate TBSCI: t-butyldimethylsilyl chloride H20: water DMSO: dimethyl sulfoxide CH3CN: acetonitrile For the purposes of clarity and brevity of the compounds referenced by the compound numbers (from the table below) in the biological examples below. c-. . Composite Structure Number Number of Composite Structure Number of Composite Structure 25 Number of Composite Structure Number of Composite Structure Compound Structure Number 25 Compound Structure Number 25 Compound Structure Number 25 Compound Structure Number 25 Compound Structure Number 25 Compound Structure Number 25 Compound Structure Number 25 Compound Structure Number 25 Compound Structure Number 25 Compound Structure Number Composite Structure Number Compound Structure Number 25 Compound Structure Number 25 Compound Structure Number 25 Compound Structure Number BIOLOGICAL EXAMPLES Examples of use of the method of the invention include the following. It will be understood that these examples are exemplary and that the method of the invention is not limited to these examples only. For purposes of clarity and brevity, the chemical compounds are referred to as numbers of synthetic examples in the biological examples below.

Example A: Receptor Link The purpose of these studies was to determine the affinity of T3 and various thyromimetics for the human thyroid hormone receptors TRal and TRßl. Methods: Baculoviruses expressing TRal, TRßl and RXRa were generated using cDNA and other Invitrogen reagents (Carlsbad, CA). To produce the TR / RXR heterodimer proteins, the sf9 insect cells were first grown at a density of -5xl05 cells / mL. Reserves of baculovirus TRal or TRßl and RXRa were added to the cell culture at a ratio of 1 to 1 (multiplicity of infection = 10). Cells were harvested three days after infection. Cells were used in a buffer assay (50 mM NaCl, 10% Glyceron, 20 mM Tris, pH 7.62 mM EDTA, 5 mM β-mercaptoethanol and 1.25% CHAPS) and the used ones were tested by binding to T3 as follows: 125 I -T3 was incubated with the Used of the recombinant baculoviruses TR and RXR as coinfected cells (50μl) in a test buffer for one hour and then the complex of - ^ I-TR / RXR was separated from the free 125-I-T3 by a mini-gel filtration column (Sephadex G50). The bound 125-I-T3 was counted with a scintillation counter. The binding of the compounds to either TRal or TRßl was also carried out by means of scintillation proximity assays (SPA). The SPA assay, a common method used for the quantification of receptor binding equilibrium, makes use of special beads coated with a capture molecule and a scintillation agent, copper, which binds to the receptor labeled with histidine a or β. When the tagged T3 is mixed with the receptor and the SPA beads, the radioactive beads are observed only when the protein complex is captured and binding radiolabeling on the surface of the bead. Displacement curves were also generated with the labeled T3 and increasing unlabeled, tynomimetic concentrations of interest. Results: Examples of representative T3 bond results using the gel filtration method are shown in Figure 1 (a). The SPA test results for T3 are shown in Figures 1 (b) and 1 (c). Table 3 below shows the SPA data generated with various thyromimetics of interest. The link results for T3 showed a Kd = 0.29nM for TRa and a Kd = 0.67nM by TRβ.

TABLE 3 Compound Kl TR «(nia) Kl THp (nM) 17 121 0.29 1 285 36.1 12-1 1666 662 3 45 S.42 6 16 26 9 350 204 11 121 30.3 13-1-trans 1744 1322 13- 6-cfe 4710 35B? 13-2-c / s 488 419 13-3-e / s 2837 3431 Compound ITR < nM) Kl TRß. { nM} 13-3-f / MS 2006 245B 3-6-fra / ies 1526 1574 13-5-S s 354 281 13-5-Cís 4432 1008 íZ-7 ra 1554 3798 13-4-íra / Js 2129 181S 13- 4-C & 6531 1521 13-7-c / s 49632 45135 7 58 3.3 2 1416 271 4 14.1 0.99 5 1.84 0.84 8 3.74 0.97 10 > 2000 > 2GQ0 8-1 Í8.6 2,51 1S-3 > 2000 > 2000 19 304 52 B-2 114 20 24-1 378 31 7-5 67 9.5 25 > 2000 363 22 186 31 21 > 1400 > 180 7-6 98 7.6 24-2 > 2000 24 26 634 87 19-2 343 20 7-4 > 2000 > 200d 30 > 2000 > 20D0 23 > 2000 > 2000 19-3 1760 128 28 375 14.0 26 > 2000 > 2000 7-3 31 d.6 7-2 > 2G0G 146 29 661 47 7-1 1166 106 32 284 98 24 > 200O > 2000 27 > 2000 > 2000 31 540 73 24-3 113 2.87 33 267? E.7 34 118 6.5 41-2 > 20QO > 2000 38 254 S, 4 42-2 > 20GO > 2000 39 > 2000 58 7-7 898 90 41-3 > 2000 280 mp Kl TRa (nM) Kí TRß (nlWI) 24-4 > 2000 82 7-8 62 9.7 42 794 16.2 40 30 1.1 7-14 429 52 7-9 110 5.4 35 > 2000 > 2000 37 294 23 36 > 2000 106 7-12 > 2000 61 12-3 738 156 41 5 * 2000 181 7-10 112 48 47 24.3 2.5 48 128.6 9 45 216 14 46 20 2 52 > 2000 4 44 832 44 54 143 42 43 363 108 Conclusion: The tested thyminimetic precursors had a good to excellent affinity for the TRal and / or TRßl receptors. The pro-drugs had a poor affinity for the receptors and therefore are unlikely to exert a thyromimetic effect until they are activated in the liver.

Example B: Sub-acute Studies in Mice / Normal Rats that They demonstrate the Selectivity of the Liver against the heart of the T3 Mimetics of Carboxylic Acid and of Phosphonic Acid.

The purpose of these studies was to compare the difference in efficacy, cardiac effects and endocrine effects between the T3 and T3 mimetics that are carboxylic acids and T3 mimetics that are phosphonic acids. In one example, T3 and compounds 7 and 17, which differ only in that for compound 7 X is -P (0) OH2 and for compound 17 X is C (0) OH, they were compared. Efficacy endpoints include serum cholesterol, glycerol phosphate dehydrogenase activity in the liver mitochondria (GPDHm), and expression of relevant liver genes (eg LDL receptor, apoB, cpt-1, spotl4, and apoAI) . Safety parameters include heart weight, cardiac pulse, cardiac activity of GPDHm, expression of key genes involved in cardiac structure and function (eg, Serca2, HCN2, Kvl.5, MHCa, MHCß, Alpha le) , and standard plasma chemistry analysis (liver enzymes, electrolytes, creatinine). Endocrine effects are observed by analysis of serum thyroid stimulating hormone (TDH). [Taylor et al., Mol Pharmacacol 52 (3): 542-7 (1997); Weitzel et al., Eur J Biochem 268 (14): 4095-4103 (2001)]. Methods: The activity of GPDHm in the isolated mitochondria was analyzed using 2- (4-idiphenyl) -3- (4-nitriphenyl) -5-phenyl tetrazolium chloride as the terminal electron acceptor (Gardner RS, Analytical Biochemistry 59: 272 (1974)). GPDH commercially available in each assay was used as a standard (Sigma, St. Louis, MO). Changes in ÜNAM levels for liver and heart genes are analyzed using reverse transcriptase followed by real-time PCR analysis. The analysis was carried out using an iCycler instrument (Biorad) and suitable primers by means of standard methodology [for example, Schwab DA et al. (2000) Life Sciences 66: 1683-94]. The amounts of ANRm are normalized to an internal control typically cyclophilin. Serum TSH is measured using an enzyme inhibitor assay (EIA) kit designed for rat TSH (Amersham Pharmacia Biotech, Arlington Heights, IL). Serum cholesterol is analyzed using a commercially available enzyme kit (Sigma Diagnostics, St. Louis, MO). Normal rats (Sprague-Dawley) were kept on a standard diet. Compounds 7 and 17 or T3 were administered by continuous infusion using an osmotic pump (Alzet, subcutaneous implant) at a dose of 1 mg / kg / day. The compounds were dissolved in a 0. IN NaOH solution and the pH was adjusted to 7.4-8.0. The compounds were brought to an adequate volume using PBS and BSA to maintain solubility inside the pump. The compounds were chemically stable in the excipient at 37 ° C for 7 days.

Results: compound 7, a T3 mimetic of phosphonic acid, produced a significant thyromimetic effect in the liver equivalent to that of T3 or of compound 17, a T3 mimetic of carboxylic acid, without producing any significant effect on the heart. Compound 17 produced a significant thyromimetic effect comparable to that of T3 in both organs. The values are expressed as a percentage of control. (Table 4).

TABLE 4 Conclusion: Based on the activity of the enzyme GPDHm, compound 7 had significant thyromimetic activity in the liver and none in the heart. In addition, compound 7 did not cause cardiac hypertrophy. T3 and compound 17 in contrast did not show selective thyromimetic effects in the liver. Thus, the results demonstrate that the T3 mimetics of phosphonic acid have a greater selectivity for the heart in terms of drug activity and distribution than the T3 mimetics of the carboxylic acid.

Example C: Sub-acute Studies in ZDF Rats Demonstrating an Improved Therapeutic Index for T3 Mimetics Containing Phosphonic Acid. ZDF rats were treated either with compound 18 (a T3 mimetic of carboxylic acid) or the compound cis-13-1 (a HepDirect prodrug of a T3 mimetic of phosphonic acid) for 28 days dosed orally once a day. Compound 18 was administered at doses of up to 5 mg / kg / d. The cis-13-1 compound was administered at doses of up to 50 mg / kg / d. It is reasoned that ZDF rats as an animal model with metabolic immunogenic test would be more sensitive to the potential adverse cardiac effects of the thyromimetics than a normal rat fed with cholesterol. When sacrificed, the cardiac pulse and the first derivative of the left ventricular pressure (LV dP / dt) were measured with a Millar catheter inserted in the left ventricle. The therapeutic index (TI) for compound 18 in the rat fed cholesterol was 40 with respect to increases in heart rate (Grover et al., PNAS 2003). The TI measurement was a dose that ED15 for the heart rate, that is, a dose that increased the heart rate greater than or equal to 15% compared to the ED50 for the cholesterol decrease. The therapeutic index for compound 18 ZDF rats with respect to the cardiac pulse was 0.4, which indicates that the model is much more sensitive to cardiac effects in an animal that was not metabolically applied an immunogenic test. Additionally, the TI for LV dP / dt was 0.15. An increase in LV dP / dt of 25% was the value used in the IT calculation. The most sensitive measurement of cardiac effects in this animal was LV dP / dt. The ZDF rats treated with the cis-13-1 compound showed no changes in any of the parameters measured. Since only 50 mg / kg / d were dosed, the exact therapeutic index for some of these parameters is not known. However, the IT improvement over compound 18 is listed in the table below: Parameter Improvement of IT ED15 HR > 39 ED25 LV dP / dt > 102 The reason that TI is listed as greater than, for example, ">" is that the cis-13-1 compound doses were not high enough to reach the 15% or 25% threshold at 50 mg / kg / d. By extrapolation with the rat fed cholesterol for the data of compound 18, the ZDF rat was 100 times more sensitive to the cardiac effects of the compound (a TI of cholesterol ED 15 HR / ED50 from 40 in the normal rat to 0.4 in the rat ZDF). Therefore, it is calculated that the IT in an animal not metabolically applied with an immunogenic test would be > 3900 with respect to the cardiac pulse and > 10,000 with respect to LV dP / dt. Dosing at such high levels was not chosen this time as the results of the ZDF animals demonstrated a significantly improved safety window. Thus, the compounds of the present invention demonstrate an IT that is unexpected and vastly superior than the T3 mimetics of the carboxylic acid.

Example D: Sub-Acute Studies in Rats Fed with Cholesterol. The rat fed cholesterol is an animal model of hypercholesterolemia generated by feeding the animals with a diet high in cholesterol. The purpose of these studies was to evaluate the effects of compounds 7 and 17 on serum cholesterol (a parameter of efficacy) and on cardiac weight and cardiac activity GPDHm (parameters of potential toxicity).

Methods: Rats were kept on a diet containing 1.5% cholesterol and 0.5% cholic acid for 2 weeks prior to the start of treatment. Serum cholesterol values were evaluated and the animals were randomized into groups for treatment. Serum cholesterol was analyzed using a commercially available enzyme kit (Sigma Diagnostics, St. Louis, MO). Compound 17 and compound 7 in various concentrations were administered IP once a day for seven days.

Result: Doses of 0.1-1 mg / kg / day of compound 17 significantly decreased serum cholesterol. Doses of compound 7 from 1-100 mg / kd / day significantly decreased serum cholesterol. The decreases in serum cholesterol at 1 mg / kg / day were identical for compound 17 and compound 7 (see figure 2). Undesirable cardiac hypertrophy was observed with compound 17 at all doses which significantly lowered serum cholesterol 0.1-lmg / kg / day. Cardiac hypertrophy was not observed with compound 7 (see Figure 3). The cardiac activity of GPDH was also increased by compound 17 to 1 mg / kg / day while a tendency towards increased cardiac GPDH activity was observed with compound 7 at only 100 mg / kg (see figure 4). No adverse cardiac effects were observed with compound 7 in any dose. These studies also indicate that cardiac weight is more sensitive to thyromimetic effects than GPDH activity.

Conclusion: there is no separation between the efficacy (decrease in cholesterol) and toxicity (cardiac hypertrophy, induction of GPDH) for compound 17. Compound 7, in contrast, showed a therapeutic window of 10 to 100 times. Thus, the results show that the T3 mimetics of phosphonic acid had a greater therapeutic window than the T3 mimetics of the carboxylic acid. Example E: Stability Studies with Primary Hepatocytes / Microsomes. i. Activation of Prodrug in Rat Liver Microsomes The purpose of these studies was to determine the kinetics of the activation of the prodrugs of the thyromimetics in microsomal preparations. Microsomes contain the P450 enzyme that is required for the activation of many of the prepared prodrugs. The Km, and the determined intrinsic clearance values are measures of the affinity of the prodrug for the microsomal enzymes, the rate at which the prodrug is activated and the catalytic efficiency with which the prodrug is activated respectively. Methods: Activation of prodrugs by rat hepatocyte microsomes treated with dexamethasone. Microsomes were isolated by standard differential centrifugation methods from rats treated with dexamethasone. The treatment to increase the activity of cytochrome P450-3A (CYP3A4). The induction of CYP3A4 was confirmed by an increase in the hydroxylation of testosterone.

Various concentrations of compound 7 HepDirect ™ were incubated with microsomes of rat hepatocytes. The formation of compound 7 was analyzed by CHLP UV-Vis as detection. The kinetic parameters (V MAX and Km) were calculated from transformed data and the intrinsic depuration calculated from the kinetic parameters. RESULTS AND CONCLUSION: Table 5 shows that prodrugs of compound 7 are well activated in rat liver microsomes and have a good affinity for microsomal enzymes that catalyze their activation: TABLE 5 ii. Activation of the Prodrug by the Human Liver S9 Prodrugs are tested for conversion to their respective precursor compounds by the human liver S9. Fraction S9 is a fraction that contains both the cytosolic and microsomal proteins. Method: Reaction mixtures (0.5 mL at 37 ° C) consist of 0.2 M potassium phosphate pH 7.4, 13 mM glucose-6-phosphate, 2.2 mM NADP +, 1 unit of glucose-6-phosphate dehydrogenase, 0-2.5 mg / mL fraction S9 of human liver (In Vitro Technologies, Inc.), and up to 250 μM of the prodrug. The activation of the prodrugs to the respective precursor compounds is observed by reverse class CLAR or LC-MS / MS (Example F). Resulted: The rate of formation of the parent compound is measured. The genetic parameters of the enzyme Vmax, Km and the intrinsic K CLint depuration are calculated. Conclusion: The prodrugs of the T3 mimetics are easily activated to their respective precursor compound by the human liver S9. iii. Activation of Pordrug in Isolated Rat Hepatocytes The purpose of these studies was to observe the uptake and activation of the prodrugs of T3 mimetics with their respective active species in isolated fresh rat hepatocytes. Method: Hepatocytes are prepared from rats Sprague-Dawley fed (250-300 g) according to the procedure of Berry and Friend (Berry, MN, Friend, DSJ Cell Biol. 43, 506-520 (1969)) when modified by Arpen (Groen, AK et al. ., Eur J. Biochem 122, 87-93 (1982)). The hepatocytes (60 mg wet weight / mL) are incubated in 1 mL of Krebs bicarbonate buffer containing 10 mM glucose and 1 mg / mL BSA. The incubations are carried out with a 95% oxygen, 5% carbon dioxide atmosphere in closed 50-mL Falcon tubes submerged in a rapidly stirring water bath (37 ° C). The pordrugs are dissolved in DMSO to produce 10 mM stock solutions, and then diluted in the cell suspension to produce a final concentration of 100 μM. At appropriate time points during the course of 1 hour, aliquots of the cell suspension are removed and rotated through a layer of mineral oil / silicon in 10% perchloric acid. The cell extracts in the acid layers are neutralized and the intracellular prodrug metabolite content is analyzed by reverse phase HPLC or LC-MS / MS (Example F). The AUC of the active species in the hepatocytes is calculated from the concentration and time profile of the precursor compound.

Results: The results are shown in table 6 below: TABLE 6 Conclusion: Prodrugs of T3 mimetics are easily taken and activated with their active species in fresh rat hepatocytes.

Example F: Oral Bioavailability / Efficacy Studies in Normal Rats. i. Oral Bioavailability The oral bioavailability (OBAV) of compound 12-1, a bisPOM prodrug of compound 7, was estimated by comparison of the normalized area with the dose under the curve (AUC) of time profile and plasma concentration of compound 7 that follows to IV and PO administration of compound 7 and compound 12-1, respectively with normal rats.

Method: Groups of male SD rats without fasting were administered either with 5 mg / kg of compound 7 by an IV bolus or 20 mg / kg of compound 12-1 by oral priming. Prior to the administration of the drug, the rats were catheterized in the tail artery to facilitate blood collection. Plasma samples were obtained at pre-specified time points after dosing, extracted with 1.5 volumes of methanol and then assayed by a LC-UV method using a C18 column diluted with a gradient from 20% to 45% v / v of acetonitrile in a potassium phosphate buffer solution, pH 6.2 for 15 minutes with a UV absorbance observed at 280 nm. The AUC values were determined without compartment from the plasma concentration and time graphs by a trapezoidal sum of the last measurable time point. In another experiment, the OBAV of compound 19-2, a T3 mimic of phosphonic acid was evaluated using catheterized rats. The plasma levels of the compound by HPLC and the AUCs were analyzed for the intravenous dose of 5 mg / kg and the p dose. or. of 20 mg / kg was compared. The maximum OBAV for compound 19-2 was 0.003%. Typically, compounds that are taken forward as an oral drug candidate have OBAV values of at least 15-20%, when tested in an animal model. This minimum requirement for OBAV in a genetically homogeneous model system ensures that the exposure can be accurately monitored when treating humans with the compound. Additionally, in a genetically variable backbone such as in humans, the variability for a compound with low OBAV in genetically homogeneous model systems can be widely variable which leads some subjects to have a much greater exposure than anticipated, while others subjects have no exposure. OBAV of the compound cis-13-1 is calculated to be 25% when the AUC of the compound cis-13-1 is used, and to be 40-50% when comparing the AUC of the compound 7 using serial samples of plasma of a compound administered intravenously against a compound administered p. or .. The levels of the liver 1.5 hours after the dosage of compound 7 and the prodrugs thereof are listed in table 7, example F (ii). Results: Compound 12-1 was suitably absorbed in the rat with an estimated OBAV of 25%. After oral administration of the prodrug, the plasma concentrations of compound 7 generated (Cmax = 1.2 ± 0.2 μg / mL up to Tax = 3 + 1 hr) were sustained for a period of 8 hours t? / 2 = 6 ± 6 hr ). Compound 19-2 was not absorbed properly.

Conclusion: Adequate systemic exposure of compound 7 was maintained for 8 hours after oral administration of compound 12-1 to the rats. ii. Distribution in the Liver after Oral Administration. Levels in the liver of compound 7 were evaluated in normal rats after oral administration of HepDirec ™ or other prodrugs. The levels were used to estimate the potential efficacy. Levels in the liver were evaluated by LC-MS using the peak area 363.3 / 63.0 to estimate the levels of compound 7 generated by orally administered prodrugs.

Results: The results are shown in table 7. TABLE 7 Conclusion: All tested compounds produced adequate levels in the binding of compound 7. All are predicted to in fact induce thyromimetics in vivo after oral administration.

Example G: Study of Oxygen Consumption Thermogenesis is a measure of energy consumption. Compounds that increase thermogenesis are likely to increase caloric expenditure and thereby cause a loss of body weight and its benefits associated with the metabolic situation (eg, insulin sensitivity). Thermogenesis is evaluated in subcellular fractions of various tissues, isolated cells, whole tissues or in whole animals using changes in oxygen consumption as the end point. Oxygen is used up when calories are burned by various metabolic processes.

M all: The animals are dosed once or several times a day by means of a parenteral or oral route for a period of treatment in the interval from 1 day to several weeks. Oxygen consumption is measured by following single or multiple days of treatment. Thermogenesis in the mitochondria is measured graphically in polar form with a Clark type oxygen electrode using mitochondria isolated from various tissues including the liver. The mitochondria are isolated by differential centrifugation. As those skilled in the art are familiar, respiration in stage 3 or the activity of cytochrome C oxidase are measured in the mitochondria. The mitochondria are incubated at 30 ° C in a buffered medium containing 80 mM KCl, 50 mM HEPES, 5 mM KH2P04, 1 mM EGTA, 0.1% (w / v) of bovine serum albumin free of fatty acids (BSA) , pH 7.0 in the presence of 10 mM succinate, rotenone 3/75 μM and 0.3 mM ADP (Iossa, S, FEBS Lettens, 544: 133-7 (2003)).

Oxygen consumption rates are measured in isolated hepatocytes using a portable CLARP type oxygen electrode placed in the hepatocyte medium. Hepatocytes are isolated from the liver using a two-step collagenase perfusion (Berry, MN, Friend, DS J Cell Biol. 43: 506-520 (1969)) as modified by (Groen, AK et al., Eur J. Biochem 122: 87-93 (1982)). The non-parenchymal cells are removed using a Percoll gradient and the cells are resuspended in a tissue culture medium in a rotating flask. The oxygen consumption of the cells is measured over time once the system is sealed. Oxygen consumption is measured in an isolated perfused liver (Fernandez, V., Toxicol Lett, 69: 205-10 (1993)). The liver is perfused in situ and the oxygen consumption is calculated by measuring the difference between the oxygen saturation of the inlet buffer and the exit buffer maintained at a constant flow. In one trial, oxygen consumption in whole animals is measured using an indirect calorimeter (Oxymax, Columbus Instruments, Columbus, OH). The animals are removed from their cages and placed in the chambers. Resting oxygen consumption is measured in animals during periods of inactivity when measured by activity monitoring. Oxygen consumption is calculated based on the flow through the chamber and the difference in the partial pressures of oxygen at the inlet and outlet ports. The carbon dioxide outlet (C02) is also measured in parallel using a C02 electrode. Male Sprague Dawley rats were treated with 3, 10, or 30 mg / kg / d of the compound cis-13-1 orally for 14 days. The rats were placed in a FoxBox apparatus (Sable Systems, Las Vegas, NV), allowed to acclimatize and oxygen consumption at rest is measured. The rates of oxygen consumption are compared with the previous measurements at the doses taken in each individual animal. Oxygen consumption after treatment was 116, 125, 132% of the pre-dose ratio for 3, 10, and 30, respectively. Thus, the compounds of the present invention are useful in increasing oxygen consumption. Example H: Tissue Distribution Studies The tissue distribution and pharmacokinetics of Compound 7 and Compound 17 are evaluated after IP administration to normal rats.

Method: In separate studies, Compound 7 of T3 phosphonate mimetic and its carboxylate analog Compound 17 are administered at 10 mg / kg to groups of male SD rats via the tail vein under light isoflurane anesthesia. At time points previously selected after dosing, the rats were re-anesthetized and the peritoneal cavity is then opened and a blood sample is obtained from the vena cava of the abdominal vein. In addition, the liver, kidney, and heart are removed and immersed in 3 volumes of cold 60% acetonitrile. The blood samples are centrifuged briefly and the plasma fraction is then extracted with 1.5 volume of methanol, processed, and analyzed by LC-UV as described in Example G. Frozen liver, kidney, and heart tissues are homogenize in 60% v / v of acetonitrile, centrifuge, and then analyzed by LC-UV. The pharmacokinetic and AUC parameters of the time-concentration profiles of tissue and plasma are determined not in compartment by WinNonLin. Results: The following plasma pharmacokinetics are calculated for Compound 17 and Compound 7 and are shown in Table 8. TABLE 8 The AUC values of the time-concentration profiles of the plasma and tissue are calculated for Compound 17 and Compound 7 and are shown in Table 9. TABLE 9 Conclusion: In comparison with the T3 mimic of phosphonic acid (Compound 7), the T3 mimic of carboxylic acid (Compound 17) has a significantly higher plasma release and a volume of distribution in the rat. The substantially higher levels of Compound 7 measured in the liver indicate good penetration of the T3 mimetic phosphonate into the target organ. Compound 7 shows a greater liver exposure relative to Compound 17. Thus, the T3 phosphonic acid mimetics have a greater specificity to the liver, compared to cardiac tissue, than the T3 carboxylic acid mimetics.

Example I: Subacute Studies in the Reduction of Rats Fed with Cholesterol The purpose of this study was to evaluate the effects of the carboxylic acid T3 mimetic (Compound 18) a phosphonic acid T3 mimetic prodrug (Compound 13-lcis) on serum cholesterol and TSH levels, cardiac and hepatic gene expression and enzyme activities, cardiac weight, and clinical chemistry parameters.

Methods: Rats are maintained on a diet containing 1.5% cholesterol and 0.5% colic acid for 2 weeks before the start of treatment. The cholesterol values in the serum are evaluated and the animals are randomly placed in groups for treatment. Cholesterol in the serum is analyzed using a commercially available enzyme kit (Sigma Diagnostic, St. Louis, MO). Compound 13-lcis and Compound 18 are administered PO once a day for seven days. TSH in serum is measured using an enzyme immunoassay kit (EIA) designed for rat TSH (Amersham Pharmacia Biotech, Arlington Heights, IL). The expression levels of liver genes (eg, the LDL receptor, apoB, cot-1, spotl4 and supports) and cardiac genes (eg, Serca2, HCN2, Kvl.5, MHCa, MHCβ, Alphalc) are quantified by Northern spotting analysis or by RT-PCR. For Northern analysis, the RNA is isolated from the liver tissue by a guanidine thiocyanate method, and the total RNA is obtained using a Rneasy column (Quiagen). The mRNA is separated on a 1% agarose gel and transferred to a nylon membrane. Oligonucleotides specific for the complementary gene sequences are used to make probes labeled with 32 P (Multiprime DNA labeling systems, Amersham Pharmacia Biotech). After hybridization of the probes to the nylon membranes, the radioactivity is evaluated on a blue film (Eastman Kodak Co), and the resulting image is quantified using the appropriate software. The RT-PCR is performed using an iCycler instrument (Biorad) using the appropriate primers by means of standard methodology [e.g., Schwab DA et al. (2000) Life Sciences 66: 1683-94]. GPDH activity in the liver and heart are measured as described in Example B. The activities of PEPCK and glucose 6-phosphatase in the liver are measured by direct enzymatic assays of homogenized liver tissue as described by Andrikopoulos S et al. . (1993) Diabetes 42: 1731-1736. Alternatively, the expression levels of the corresponding genes are determined by Norther staining or RT-PCR analysis as described above. Results: Doses of 0.6-50 mg / kg / day of Compound 13-1-cis significantly reduce serum cholesterol (see Figure 5). The compound 18 to 1 mg / kg / day significantly reduces serum cholesterol. No significant undesirable cardiac hypertrophy is observed with the Compound 13-1-cis at some dose tested. Conclusion: Compound 13-1 shows a significant decrease in cholesterol even at the lowest dose evaluated (0.6 mg / kg). Additionally there is no evidence of undesirable effects on the weight of the heart over the entire tested dose range (up to 50 mg / kg). Example J: Decreases in Hepatic Fat Content following treatment with a thromomimetic phosphonic acid. The normal rats were chronically infused with compound 7 for 7 days. Triglycerides were analyzed after lipid extraction by the Bligh Dyer method (Bligh EG and Dyer WJ, A rapid meted of total lipid extraction and purification, Can J Med Sci. 1959 (August); 37 (8): 911-7 , which is incorporated herein by reference). The total triglycerides were analyzed in the liver extracts by an enzymatic assay (Thermo Electron Corporation). The total lipids were normalized to the initial weight of the liver and the triglyceride content was normalized to the liver weight. The administration of T3 would not be expected to decrease to decrease the content of triglycerides in the liver. Analysis of hepatic triglyceride content in rats with T3 infusion did not show a significant decrease in triglyceride content. There was a 4% reduction in triglycerides in the liver for this group and the results were not statistically significant. Animals infused with Compound 7 demonstrated a decrease in hepatic triglyceride content of 64%, a significantly different and unexpected result. In other experiments, compound 7 was orally administered to ZDF rats for 28 days. Triglycerides in the liver were analyzed as described above. Total triglycerides in the liver were reduced in the treated animals, 42% in the 2.5 mg / kg / d group. Histological analysis of sections of the liver following H & E staining demonstrates pronounced and diffuse microvesicular steatosis along the hepatic lobe in the group treated with the vehicle. Hepatic steatosis is a well-known and described phenomenon for the ZDF rat, and therefore is not attributed to vehicle treatment. There was a dose-dependent reduction in microvesicular steatosis and a remarkable appearance of the intact cytoplasm within the hepatocytes, consistent with a non-steatotic liver. Example K: Effects of the T3 Mimetic Prodrugs of In Vivo Phosphonic Acid on Cholesterol Another experimental trial was to evaluate the effects of prodrugs of the T3 mimetics of the phosphonic acid of the present invention on serum cholesterol. Rats were made hypercholesterolemic by maintenance on a diet containing 1.5% cholesterol and 0.5% cholic acid for at least 2 weeks prior to the start of treatment. The plasma cholesterol values were evaluated prior to, and after the treatment and the effects of the compound were expressed as a percentage change from the cholesterol levels prior to the dose. Total cholesterol was analyzed using a commercially available enzyme kit (Sigma Diagnostics, St. Louis, MO). The compounds were routinely tested for their oral efficacy at a dose of 0.5 mg / kg / d. The hypercholesterolemic rats were treated with vehicle, Compound 13-1-cis (a HepDirect version of Compound 7), Compound 19-1 (a diethyl ester of Compound 19-2), Compound 13-9 (a HepDirect version of Compound 19- 2), Compound 12-5 (a bisPo version of compound 19-2) or Compound 15-5 (a bisamidate version of Compound 19-2) at 0.5 mg / kg / d orally. Compound 13-1-cis has been extensively characterized and used as the positive control for the assay. Vehicle, Compound 13-9 and Compound 19-1 failed to demonstrate the cholesterol decrease in this assay while Compound 13-1-cis, Compound 12-5 and Compound 15-5 demonstrated a significant decrease in cholesterol. The HepDirect versions of the T3 mimetics of phosphonic acid normally show good results, however, the diethyl ester versions of the T3 mimetics of the phosphonic acid of the present invention were not found to be suitable as prodrugs. In another experiment, the efficacy of Compound 7 was compared with Compounds 12-9, cis-13-2 and 15-6, which are prodrugs of a compound that binds poorly to both TRa and TRβ (Ki from about 300 nM). Compound 7 was effective while compounds 12-9, cis-13-2 and 15-6 were not effective in lowering cholesterol. Table 10 (below) shows the results for the additional compound of the present invention tested in the current method.

TABLE 10 Compound supplied i.p. or. or decrease (0.2 mg / kg / d) of untreated cholesterol -3.6 Vehicle -5.3 40 -64.2 7-5 -63.3 7-9 -63.2 24-3 -48.6 8-2 -48 45 -46.3 7-3 -45.4 22 -. 22 -44 66 -42.9 7 -. 7 -41.5 eleven - . 11 -36.4 24-1 -35.4 7-14 -32.9 33 -. 33 -32.5 46 -. 46 -29.6 47 -. 47 -29.3 42 -. 42 -28.8 7-8 -28.6 7-10 -25.8 8 -. 8 -24.3 48 -23.4 29 -. 29 -21.9 38 -. 38 -21.7 31 -. 31 -21.1 27 -. 27 -20.8 24-2 -20.5 28 -. 28 -20.5 6 -. 6 -20.5 19 -. 19 -19 52 -18.8 7-6 -13.5 37 -. 37 -0. 4 Compound supplied p.o. % decrease (0.5 mg / kg / d) of untreated cholesterol -3.96093 Vehicle -5.07855 15-4 -39.5579 12-8 -33.7214 12-5 -32.5195 cis-13-1 -31.7885 12-4 -30.4743 15-5 -29.8974 15-7 -29.1462 13-8 -26.4936 13-11 -24.7878 13-9 -10.9392 19-1 -6.5639 '12-7 -39.1 13-10 -25.8 15-8 -31.1 Example L: Effects of the T3 mimetic prodrugs of phosphonic acid In vivo on circulating TSH Another concern with thyromimetics is the suppression of the endogenous thyroid axis. Thyroid homeostasis is maintained by the action of thyroid-releasing hormone (TRH) and thyroid stimulating hormone (TSH). HRT occurs in the paraventricular region of the hypothalamus (Dupre, SM et al, Endocrinology 145: 2337-2345 (2004). TRH acts on the TSH that releases the pituitary which then acts on the thyroid organ itself. The levels of TRH and TSH are controlled by a feedback sensor mechanism so that low levels of thyroid hormone (TH) (T3 or T4) will cause an increase in TRH and TSH and high levels of TH will cause a suppression of TRH and TSH. Because TSH can be measured more easily than HRT, TSH levels are tested as a measure of the systemic effects of TH or synthetic thyromimetics. Decreased levels of TSH are a concern because suppression of the thyroid axis can lead to systemic hypothyroidism. Although this particular side effect has been noted, it has typically been treated with less concern than cardiac safety issues. However, new evidence indicates that, in addition to possible systemic hypothyroidism, which concerns any long-term therapy, the suppression of THS will increase osteoclast function leading to reduction in bone mass and loss of bone structural integrity ( Abe, E et al., Cell 115: 151-62 (2003)). Therefore, previous investigators have measured TSH levels when they test synthetic thyromimetics and have used a 30% reduction in THS as the denominator in their therapeutic index calculations. The therapeutic index of TSH levels in rats fed cholesterol, treated with either Compound 17 or Compound 18 (both carboxylic acid mimetics T3) for 7 days, are 0.8 and 0.4, respectively. Therefore, both compounds suppress TSH at doses as low as required to reduce circulating cholesterol. In ZDF rats treated with 50 mg / kg / d of Compound 7 for 28 days, there is no statistically significant difference of the vehicle as measured by TSH. However, 0.2 mg / kg / d of Compound 18 in ZDF rats treated 28 days, reduces TSH levels by more than 90%. In mice treated with 10 mg / kg / d of Compound 7 for 77 days, no reduction in TSH is observed, indicating that Compound 7 can significantly reduce cholesterol levels without producing an adverse effect on the endogenous thyroid axis.

Example M: Effects of T3 Mimetic Prodrugs of In vivo Phosphonic Acid on Glucose The plasma glucose in ZDF rats treated with Compound 7 sacrificed is reduced from 618 mg / dL to 437 mg / dL after 4 weeks of treatment with Compound cis-13-1. The reduction was dose dependent. Blood glucose levels at those doses correspond to 442 mg / dL and 243 mg / dL, respectively. Similar changes are also evident two weeks after treatment. There is a dose-dependent reduction in water consumption of treated animals, which is consistent with an improvement in glycemic control.

Example N: Transcription of the T3 mediated myosin heavy chain gene and T3 mimic in the heart. An RT-PCR assay is described as described in: Sara Danzi, Kaie Oja aa, and Irwin Klein Am J Physiol Herat Circ Physiol 284: H2255-H2262, 2003 (incorporated herein by reference) is used to study both the time course and the mechanism for triiodothyronine-induced transcription (T3) of the ß-myosin heavy chain genes in vivo based on the amount of specific heterogeneous nuclear RNA (hnRNA). The temporal relationship of changes in transcriptional activity to the amount of a-MHC mRNA and the coordinated regulation of the transcription of more than one gene in response to T3 and T3 mimics is demonstrated. Analyzes of a time course of T3 and T3 mimetics that are not liver-specific show a mediated induction of α-MHC hnRNA and repression of ß-MHC hnRNA, while no significant effects are observed with the compounds of the present invention at doses that are therapeutically useful. Example O: Cardiovascular Activity of T3 Mimetics in the Rat The objective of these experiments was to evaluate the effect of phosphonic acid contained in T3 mimetics against the carboxylic acid contained in T3 mimetics, in cardiovascular function (cardiac rhythm, inotropic state, and aortic pressure). ) in the Sprague Dawley rat model (SD). Method: The cis-13-1 compound (a HepDirect prodrug of Compound 7) is dissolved in PEG400 and administered daily to SD male rats (n = 6 / group) by oral feeding (1, 5, 10, 30, 50 mg / kg / day) at 1 ml / kg of body weight. The control group (n = 6) is given only vahicle. Compound 18 (a T3 carboxylic acid mimetic) is administered at 1 mg / kg p.o. as a positive control (n = 6). On day 7 after the start of dosing, animals were anesthetized with Isoflurane and the left ventricle was cannulated with a high-fidelity catheter tip transducer via the right carotid artery. The left ventricular pressure, its first derivative (LVdP / dt), I EGG lead, and the heart rate (HR) triggered from the ECG waveform are recorded digitally. LV dP / dt is a well-accepted measurement of the inotropic state. Systolic and diastolic pressures are measured by retracting the catheter in the proximal aorta. RESULTS: Compared to animals treated with the vehicle, the administration of Compound 18 results in marked and statistically significant increases in HR, LV dP / dt, and systolic aortic pressure after 7 days of treatment. In contrast, HR, LV dP / dt, systolic and diastolic aortic pressures in all groups treated with Compound cis-13-1 are not significantly different compared to animals treated with vehicle. The weight of the heart and the weight of the heart normalized to body weight in animals treated with Compound 18 is significantly increased compared to control animals. There are no significant changes in heart weight or heart weight / cardiac weight ratios in groups treated with Compound cis-13-1.

Conclusions: It is concluded that Compound cis-13-1 when administered at doses of up to 50 mg / kg / day for 7 days avoids the important chronotropic and ionotropic effects in the normal SD rat. It is established in contrast that Compound 18 is associated with marked effects when given at 1 mg / kg / day. It is noted that with this date, the best method known to the applicant to carry out the practice of said invention, is that which is clear from the present description of the invention.

Claims (238)

1. Claims Having described the invention as above, the content of the following claims is claimed as property. 1. A compound of Formula I: characterized in that: G is selected from the group consisting of -0-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, ~ CF2-, -CHF-, -C (0) -, -CH (OH) -, -NH-, and -N (C? -C4 alkyl) -; T is selected from the group consisting of - (CR2) k ~, -CRb = CRb- (CRa2) n-, - (CRa2) n-CRb = CRb-, - (CRa2) -CRb = CRb- (CRa2) - , 0 (CRb2) (CRa2) n-, -S (CRb2) (CRa2) n-, -N (Rc) (CR2) (CRa2) n-, N (Rb) C (0) (CRa2) n-, - (CRa2) nCH (NRbRc) -, -C (O) (CRa2) m-, (CRa2) mC (0) -, - (CRa2) C (0) (CRa2) n-, - (CRa2) nC ( 0) (CRa2) -, and -C (0) NH (CRb2) (CRa2) p-; k is an integer from 0-4; m is an integer from 0-3; n is an integer from 0-2; p is an integer from 0-1; Each Ra is independently selected from the group consisting of hydrogen, optionally substituted C?-C4 alkyl, halogen, -OH, -O-C?-C 4 alkyl optionally substituted, -OCF 3, -S-C C-C optionally substituted alkyl, -NRbRc, optionally substituted C2-C alkenyl, and optionally substituted C2-C alkynyl; with the proviso that when a Ra is linked through an atom of O, S, or N, then the other Ra binds to the same C that is a hydrogen, or is bonded by means of a carbon atom. Each Rb is independently selected from the group consisting of hydrogen, optionally substituted C ?C alkyl; Each Rc is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 4 alkyl, -C (O) -alkyl C optionally substituted, and -C (0) H; R1 and R2 are each independently selected from the group consisting of halogen, optionally substituted C? -C alkyl, optionally substituted -S-C1-C3 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, -CF3, -OCF3, -O-C1-C3 alkyl optionally substituted, and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, C2-C? Alkynyl? optionally substituted, - (CRa2) optionally substituted maryl, (CRa2) optionally substituted cycloalkyl, (CRa2) optionally substituted metheterocycloalkyl, -0Rd, SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRfRg, -C (0) NRfRg, -C (0) 0Rh, -C (0) Re, -N (Rb) C (0) Re, -N (Rb) C (O) NRfRg, -N ( Rb) S (= 0) 2Re, N (Rb) S (= 0) 2NRfRg, and -NRfRg; Each Rd is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2-C1 alkenyl, optionally substituted C2-C2 alkynyl, - (CRb2) n optionally substituted aryl, - (CRb2) n optionally substituted cycloalkyl, ~ (CRb2) n optionally substituted heterocycloalkyl, and -C (0) NRfRg; Each Re is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2-C2 alkenyl, optionally substituted C2-C2 alkynyl, optionally substituted (CRa2), optionally substituted (CRa2) n-cycloalkyl, and - (CRa2) optionally substituted n-heterocycloalkyl; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C2-C2 alkenyl, optionally substituted C2-C2 alkynyl, optionally substituted (CRb2) naril, - ( CRb2) optionally substituted cycloalkyl, and optionally substituted - (CRb2) nheterocycloalkyl, or Rf and Rg together can form an optionally substituted heterocyclic ring, which may contain a second hetero group selected from the group of O, NRC, and S, wherein the ring optionally substituted heterocyclic may be substituted with 0-4 substituents selected from the group consisting of optionally substituted C 1 -C 4 alkyl, -OR b, oxo, cyano, -CF 3, optionally substituted phenyl, and -C (0) OR h; Each Rh is selected from the group consisting of optionally substituted C?-C? 2 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl, - (CRb 2) n optionally substituted aryl, (CRb 2) nCycloalkyl optionally substituted, and (CR2) optionally substituted n-heterocycloalkyl; R5 is selected from the group consisting of -OH, optionally substituted C6-C6alkyl, -OC (0) Re, -OC (0) ORh, -F, -NHC (0) Re, -NHS (= 0) Re , -NHS (= 0) 2Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); X is P (0) YR ^ Y'R11; Y and Y 'are each independently selected from the group consisting of -O-, and -NRV-; when Y and Y 'are -O-, R11 linked to -O- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 2OC (O) NRZ2, -NRZ-C (0) -Ry, -C (Rz) 2-OC (0) Ry, -C (Rz) 2-0- C (0) ORy, -C (Rz) 2OC (O) SRy, -alkyl-SC (O) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; when Y and Y 'are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-COORy, -C (Rx) 2COORy, - [C (Rz) 2] qC (O) SRy, and cycloalkylene-COORy; when Y is -O- and Y 'is NRV, then R11 linked to -O- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 2OC (O) NRZ, NRz-C (0) -Ry, -C (Rz) 2-OC (0) Ry, -C (Rz) 2- 0-C (O) ORy, C (Rz) 2OC (0) SRy, -alkyl-SC (O) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-COORy, -C (Rx) 2COORy, - [C (Rz) 2] qC (0) SRy , and -cycloalkylene-COORy; or when Y and Y 'are independently selected from -O- and -NRV-, then R11 and R11 together are -alkyl-S-S-alkyl to form a cyclic group, or together R11 and R11 are the group: wherein: V, W, and W are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and 1-alkynyl optionally replaced; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group to the beta and gamma bound position to the Y to the phosphorus; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and W are connected by means of 3-5 additional carbon atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHRzOH, -CHRzOC (0) Ry, -CHRzOC (S) Ry, -CHROC (S) 0Ry, -CHRz0C (O) SRy, CHRzOC02Ry, -ORz, -SRZ, -CHRZN3, -CH2aryl, -CH (aryl) OH, -CH (CH = CRz2) OH, -CH (C = CRz) 0H, -Rz, -NRZ2, -OCORy, -OC02Ry , -SCORy, -SC02Ry, -NHC0R2, -NHC02R ?, -CH2NHaril, - (CH2) q-0Rz, and - (CH2) q-SRz; q is an integer of 2 or 3; each Rz is selected from the group consisting of Ry and -H; each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; each Rx is independently selected from the group consisting of -H, and alkyl, or together Rx or Rx form a cyclic alkyl group; each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the proviso that: a) when G is -0-, T is -CH2-, R1 and R2 are each bromine, R3 is iso propyl, R4 is hydrogen, and R5 is -OH, then X is not -P (0) (0H) 2 or -P (O) (OCH 2 CH 3) 2; b) V, Z, W, W are not all -H; c) when Z is -R2, then at least one of V, W, and W are not -H, alkyl, aralkyl, or heterocycloalkyl; and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs.
2. 2. A compound of Formula I: characterized because: G is selected from the group consisting of -O-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF-, -C (O) -, -CH (OH) -, -NH-, and -N (C 1 -C 4 alkyl) -; T is selected from the group consisting of - (CRa2) k-, -CRb = CRb ~ (CRa2) n, - (CRa2) n-CRb = CRb-, - (CRa2) -CRb = CRb- (CRa2) -, 0 (CRb2) (CRa2) n-, '-S (CRb2) (CRa2) n-, -N (Rc) (CRb2) (CRa2) n-, N (Rb) C (0) (CRa2) n-, - (CRa2) nCH (NRbRc) -, -C (O) (CRa2) m-, (CRa2) mC (0) -, - (CRa2) C (0) (CRa2) n-, - (CRa2) nC ( 0) (CRa2) -, and -C (0) NH (CRb2) (CRa2) p-; k is an integer from 0-4; m is an integer from 0-3; n is an integer from 0-2; p is an integer from 0-1; each Ra is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl, halogen, -OH, -O-optionally substituted CL-C 4 alkyl, -OCF 3, -S-C optionally substituted C 1 -C 4 alkyl, NRbRc, optionally substituted C2-C alkenyl, and optionally substituted C2-C4alkynyl; with the proviso that when a Ra is linked through O, S, or N, then the other Ra binds to the same C as is a hydrogen, or is linked by means of a carbon atom; each Rb is independently selected from the group consisting of hydrogen, optionally substituted C? -C alkyl; each Rc is independently selected from the group consisting of hydrogen and optionally substituted C? ~C alkyl, -C (O) - optionally substituted C 1 -C 4 alkyl, and -C (0) H; R1 and R2 are each independently selected from the group consisting of halogen, optionally substituted C1-C4 alkyl, -S-optionally substituted C1-C3 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, -CF3, - OCF 3, -O-C 1 -C 3 alkyl optionally substituted, and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, C2-C? Alkynyl? optionally substituted, - (CRa2) optionally substituted maryl, (CRa) optionally substituted cycloalkyl, (CRa2) optionally substituted metheterocycloalkyl, -ORd, SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRfRg, -C (0) NRfRg, -C (0) ORh, -C (0) Re, -N (Rb) C (0) Re, -N (Rb) C (0) NRfRg, -N ( Rb) S (= 0) 2Re, N (Rb) S (= 0) 2NRfRg, and -NRfRg; Each Rd is selected from the group consisting of optionally substituted C?-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted (CRb2) naryl, optionally substituted (CRb2) n-cycloalkyl, (CRb2) nheterocycloalkyl optionally substituted, and C (0) NRfRg; Each Re is selected from the group consisting of optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, optionally substituted C2-C? 2 alkynyl, optionally substituted - (CRa2) naril, - (CRa2) n optionally substituted cycloalkyl, and (CRa 2) n-heterocycloalkyl optionally substituted; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C?-C? 2 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted - (CRb 2) naryl, - (CRb2) optionally substituted cycloalkyl, and - (CRb2) nheterocycloalkyl optionally substituted, or Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second hetero group selected from the group of O, NRC, and S, wherein the optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting of optionally substituted C 1 -C 4 alkyl, -0Rb, oxo, cyano, -CF 3, optionally substituted phenyl, and -C (0) ORh; Each Rh is selected from the group consisting of optionally substituted C? -C? 2 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C? 2 alkynyl, optionally substituted (CRb2) naryl, optionally substituted - (CRb2) n-cycloalkyl , and - (CRb2) optionally substituted n-heterocycloalkyl; R5 is selected from the group consisting of -OH, optionally substituted -Oalkyl C? -C6, -OC (0) Re, 0C (0) 0Rh, -F, -NHC (0) Re, -NHS (= 0) Re , -NHS (= 0) 2 Re, NHC (= S) NH (Rh), and -NHC (0) NH (Rh); X is P ^ YR ^ Y'R11; Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are -0-, R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRZ2, -NRZ-C (0) -Ry, -C (Rz) 2-0C (0) R ?, -C (Rz) 2-0 -C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; when Y and Y 'are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy, and cycloalkylene-C00Ry; when Y is -0- and Y 'is NRV, then R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRZ2, -NRZ- C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2 -0-C (0) 0Ry, -C (RZ) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy , and -cycloalkylene-C00Ry; or when Y and Y 'are independently selected from-0- and -NRV-, then together R11 and R11 are -alkyl-S-S-alkyl to form a cyclic group, or together R11 and R11 are the group: wherein: V, W, and W are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and 1-alkynyl optionally replaced; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group to the beta and gamma bound position to the Y to the phosphorus; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and W are connected by means of 3-5 additional atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHRzOH, -CHRzOC (0) Ry, -CHRzOC (S) Ry, -CHRzOC (S) ORy, -CHRz0C (O) SRy, CHRzOC02Ry, -ORz, -SRZ, -CHRZN3, -CH2aryl, -CH (aryl) OH, -CH (CH = CRz2) OH, -CH (C = CRz) OH, -Rz, -NRZ2, -OCORy, -OC02Ry, -SCORy, -SC02Ry, -NHC0RZ, - NHC02Ry, -CH2NHaril, - (CH2) q-ORz, and - (CH2) q-SRz; q is an integer of 2 or 3; each Rz is selected from the group consisting of Ry and -H; each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; each Rx is independently selected from the group consisting of -H, and alkyl, or together Rx or Rx form a cyclic alkyl group; each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the proviso that: a) when G is -O-, T is - (CH2) 0--, R1 and R2 are independently halogen, alkyl of 1 to 3 carbons and cycloalkyl of 3 to 5 carbons, R3 is alkyl of 1 to 4 carbons or cycloalkyl 3 to 7 carbons, R is hydrogen and R 5 is -OH, then X is not P (0) (OH) 2 or P (0) (O-lower alkyl) 2; b) when G is -0-, R5 is -NHC (0) Re, -NHS (= 0)? -2Re, -NHC (S) NH (Rh), or -NHC (0) NH (Rh), T is ~ (CH2) m, -CH = CH-, -0 (CH2)? -2-, or -NH (CH2)? _ 2-, then X is not -P (0) (0H) 2 or -P ( 0) (0H) NH2; c) V, Z, W, W are not all -H; and d) when Z is -Rz, then at least one of V, W, and W is not -H, alkyl, aralkyl, or heterocycloalkyl. and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs.
3. 3. The compound according to claim 1, characterized in that when G is -0-, T is -CH2-, R1 and R2 are each bromine, R3 is iso-propyl, and R5 is -OH, then R4 is not hydrogen.
4. 4. The compound according to claim 2, characterized in that G is -0-, T is - (CH2) 0--, - (CH) o- ~, R1 and R2 are independently selected from the group consisting of halogen, alkyl of 1 to 3 carbons, and cycloalkyl of 3 to 5 carbons, R3 is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 7 carbons, and R5 is -OH, then R4 is not hydrogen; and wherein when G is -0-, R5 is selected from the group consisting of NHC (0) Re, -NHS (= 0)? -2Re, -NHC (= S) NH (Rh), and -NHC (0) ) NH (Rh), T is selected from the group consisting of - (CH2) m-, -CH = CH-, -0 (CH2) 1-2-, and -NH (CH2)? _2-, then R4 does not It is hydrogen.
5. 5. The compound according to claim 1, characterized in that G is selected from the group consisting of -0- and -CH2-.
6. 6. The compound according to claim 2, characterized in that -0- and -CH2-.
7. 7. The compound according to claim 1, characterized in that T is selected from the group consisting of - (CRa2) n, -0 (CRb2) (CRa2) P-, -N (Rc) (CRb2) (CRa2) p -, S (CRb2) (CRa2) p-, -NRb (C0) -, and -CH2CH (NRcRb) -.
8. The compound according to claim 2, characterized in that T is selected from the group consisting of - (CRa2) n, -0 (CRb2) (CRa2) p-, -N (Rc) (CRb2) (CRa2) p-, S (CRb2) (CRa2) p-, -NRb (C0) -, and -CH2CH (NRcRb) -.
9. 9. The compound according to claim 1, characterized in that R1 and R2 are the same and are selected from the group consisting of halogen, C? -C alkyl, -CF3, and cyano.
10. 10. The compound according to claim 2, characterized in that R1 and R2 are the same and are selected from the group consisting of halogen, C? -C alkyl, -CF3, and cyano.
11. 11. The compound according to claim 1, characterized in that R1 and R2 are different and are selected from the group consisting of halogen, C1-C4 alkyl, -CF3, and cyano.
12. The compound according to claim 2, characterized in that R1 and R2 are different and are selected from the group consisting of halogen, C? -C4 alkyl, -CF and cyano.
13. The compound according to claim 1, characterized in that R 4 is selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, cyano and CF 3.
14. The compound according to claim 2, characterized in that R 4 is selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, cyano and CF 3.
15. 15. The compound according to claim 1, characterized in that R5 is selected from the group consisting of -OH, -0C (0) Re, -0C (0) 0Rh, -F and -NHC (0) Re.
16. 16. The compound according to claim 2, characterized in that R5 is selected from the group consisting of -OH, -0C (0) Re, -0C (0) 0Rh, -F and -NHC (0) Re.
17. 17. The compound according to claim 1, characterized in that R3 is selected from the group consisting of halogen, optionally substituted C6-C6 alkyl, -CF3, cyano, -C (0) NRfRg, - (CRa2), optionally substituted , -S02NRfRg, and -S02Re.
18. 18. The compound according to claim 2, characterized in that R3 is selected from the group consisting of halogen, optionally substituted C6-C6 alkyl, -CF3, cyano, -C (0) NRfRg, - (CRa2), optionally substituted , -S02NRfRg, and -S02Re.
19. 19. The compound according to claim 1, characterized in that X is selected from the group consisting of -P03H2, -P (0) [-OCRz2OC (0) Ry] 2, -P (0) [-0CRz20C (0) 0RY] 2, P (0) [-N (H) CRz2C (0) 0Ry] 2, -P (0) [-N (H) CRZ2C (0) 0Ry] [-0R11] and P (0) [- 0CH (V) CH2CH20-], wherein V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl.
20. The compound according to claim 2, characterized in that X is selected from the group consisting of -P03H2, -P (0) [-OCRz2OC (0) Ry] 2, -P (0) [-0CRz20C (0) 0Ry] 2, P (0) [-N (H) CRz2C (0) ORy] 2, -P (0) [-N (H) CRZ2C (0) 0Ry] [-0R11] and P (0) [- 0CH (V) CH2CH20-], wherein V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl.
21. 21. The compound according to claim 1, characterized in that G is selected from the group consisting of -0- and -CH2, T is selected from the group consisting of - (CRa2) n, -0 (CRb2) (CRa2) p-, -N (RC) (CRb2) (CRa2) p-, -S (CRb2) (CRa2) p-, -NRb (C0) -, and -CH2CH (NRcRb) -; R1 and R2 are each independently selected from the group consisting of halogen, C? -C4 alkyl, -CF3, and cyano; R4 is selected from the group consisting of hydrogen, halogen, C? -C alkyl, cyano and CF3; R5 is selected from the group consisting of -OH, -OC (0) Re, -OC (0) ORh, -F and -NHC (0) Re; R3 is selected from the group consisting of halogen, Ci-Ce alkyl optionally substituted, -CF3, cyano, -C (0) NR f R g, - (CR a 2) I narilo optionally substituted -S02NRfRg and -S02Re; and X is selected from the group consisting of -P03H2, -P (0) [-OCRz2OC (0) Ry] 2, -P (0) [-0CRz20C (0) 0Ry] 2, -P (0) [-Oalq -SC (0) Ry] 2, - P (0) [-N (H) CRz2C (0) 0Ry] 2, -P (0) [-N (H) CRZ2C (0) 0Ry] [-0R11] and P (0) [-0CH (V) CH2CH20-], wherein V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl.
22. 22. The compound according to claim 21, characterized in that when G is -0-, T is -CH2-, R1 and R2 are bromine, R3 is iso-propyl and R5 is -OH, then R4 is not hydrogen.
23. 23. The compound according to claim 2, characterized in that when G is selected from the group consisting of -0- and -CH2-; T is selected from the group consisting of - (CRa2) n, -0 (CRb2) (CRa2) p-, -N (Rc) (CRb2) (CRa2) p-, -S (CRb2) (CRa2) p-, -NRb (CO) -, and -CH2CH (NRcRb) -; R1 and R2 are each independently selected from the group consisting of halogen, C? -C4 alkyl, -CF3, and cyano; R4 is selected from the group consisting of hydrogen, halogen, C? -C alkyl, cyano and CF3; R5 is selected from the group consisting of -OH, -0C (0) Re, -0C (0) 0Rh, -F and -NHC (0) Re; R3 is selected from the group consisting of halogen, optionally substituted Cx-Ce, -CF3, cyano, -C (0) NR f R g, - (CR a 2) I narilo optionally substituted -S02NRfRg and -S02Re; and X is selected from the group consisting of -P03H2, -P (O) [-OCR2OC (O) Ry] 2, -P (O) [-0CRz20C (O) OR?] 2, -P (O) [- N (H) CRZ2C (O) ORy] 2, -P (O) [-N (H) CRz2C (0) ORy] [-OR11] and -P (O) [-OCH (V) CH2CH20-], in where V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl.
24. 24. The compound according to claim 23, characterized in that G is -O-, T is - (CH2) or -2 / 'R1 and R2 are independently selected from the group consisting of hydrogen, halogen, alkyl of 1 to 3 carbons, and cycloalkyl of 3 to 5 carbons, R3 is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 7 carbons, and R5 is -OH, then R4 is not hydrogen; and wherein when G is -O-, R5 is -NHC (0) Re, T is selected from the group consisting of - (CH2) m-, -0 (CH2)? _ 2-, -NH (CH2)? _2 -, then R4 is not hydrogen.
25. 25. The compound according to claim 21, characterized in that T is -CH 2 CH (NH 2) -; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl, and cyano; R4 is selected from the group consisting of hydrogen and halogen; R5 is selected from the group consisting of -OH and -OC (0) Re; and R3 is selected from the group consisting of halogen, optionally substituted Ci-Ce alkyl, optionally substituted -CH2aryl, optionally substituted -CH (OH) aryl, -C (0) -amino, -S (= 0) 2-amido, wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -S02Re wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, 4- fluorophenyl, and 4-pyridyl.
26. 26. The compound in accordance with the claim 25, characterized in that G is -0-; T is -CH2CH (NH2) -; R1 and R2 are each iodo; R4 is selected from the group consisting of hydrogen and iodine; R5 is -OH; and R3 is iodine.
27. 27. The compound in accordance with the claim 26, characterized in that X is selected from the group consisting of -P03H2, -P (0) [-0CH20C (0) -t-butyl] 2, -P (0) [-0CH20C (0) 0-i-propyl] 2, -P (0) [-N (H) CH (CH3) C (0) 0CH2CH3] 2, -P (0) [- N (H) C (CH3) 2C (0) OCH2CH3] 2, -P (0) [-N (H) CH (CH3) C (0) 0CH2CH3] [3,4-methylenedioxyphenyl], -P (0) [-N (H) C (CH3) 2C (0) 0CH2CH3] [3 , 4-methylenedioxyphenyl], and -P (0) [-0CH (3-chlorophenyl) CH2CH20-].
28. 28. The compound according to claim 21, characterized in that T is -N (H) C (0) -; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl, and cyano; R4 is selected from the group consisting of hydrogen and iodine; R5 is selected from the group consisting of -OH and -0C (0) Re; R3 is selected from the group consisting of hydrogen, iodine, bromine, optionally substituted C?-C6 alkyl, optionally substituted -CH2aryl, optionally substituted -CH (OH) aryl, -C (O) -amido wherein the amido group is selected of the group consisting of phenethylamino, piperidinyl, 4-methylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -S02Re wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, and 4-pyridyl.
29. 29. The compound in accordance with the claim 28, characterized in that G is -0-; R1 and R2 are each methyl; R4 is hydrogen; R5 is -OH; and R3 is -CH (OH) (4-fluorophenyl).
30. 30. The compound in accordance with the claim 29, characterized in that X is selected from the group consisting of -P03H2, -P (0) [-OCH2OC (O) -t-butyl] 2, -P (0) [-OCH2OC (0) 0-i-propyl] 2, -P (O) [-N (H) CH (CH3) C (O) OCH2CH3] 2, -P (0) [- N (H) C (CH3) 2C (0) OCH2CH3] 2, -P (O) [-N (H) CH (CH3) C (O) OCH2CH3] [3,4-methylenedioxyphenyl], -P (O) [-N (H) C (CH3) 2C (O) 0CH2CH3] [3 , 4-methylenedioxyphenyl], and -P (0) [-0CH (3-chlorophenyl) CH2CH20-].
31. 31. The compound according to claim 21, characterized in that T is -OCH2-; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl, and cyano; R4 is selected from the group consisting of hydrogen and iodine; R5 is selected from the group consisting of -OH and -0C (0) Re; and R3 is selected from the group consisting of iodine, bromine, optionally substituted Ci-Cß alkyl, optionally substituted -CH 2 aryl, optionally substituted -CH (OH) aryl, -C (0) -amido, -S (= 0) 2- amido wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -S02R wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, -fluorophenyl, and 4-pyridyl.
32. 32. The compound according to claim 31, characterized in that G is -CH2-; R1 and R2 are each methyl; R4 is hydrogen; R5 is -OH; and R3 is iso-propyl.
33. 33. The compound according to claim 32, characterized in that X is selected from the group consisting of -P03H2, -P (0) [-0CH20C (0) -t-butyl] 2, -P (0) [-0CH20C (0) 0-i-propyl] 2 , -P (0) [-N (H) CH (CH3) C (0) 0CH2CH3] 2, -P (0) [-N (H) C (CH3) 2C (0) 0CH2CH3] 2, -P ( 0) [-N (H) CH (CH3) C (0) OCH2CH3] [3,4-methylenedioxyphenyl], -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] [3, 4-methylenedioxyphenyl], and -P (0) [-0CH (3-chlorophenyl) CH2CH20-].
34. 34. The compound according to claim 21, characterized in that T is -CH-; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl, and cyano; R4 is selected from the group consisting of hydrogen and iodine; R5 is selected from the group consisting of -OH and -0C (0) Re; and R3 is selected from the group consisting of iodine, bromine, optionally substituted Ci-Cß alkyl, optionally substituted -CH 2 aryl, optionally substituted aryl -CH (OH), -C (0) -amido, -S (= 0) 2- amido wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -S02Re wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, -fluorophenyl, and 4-pyridyl.
35. 35. The compound according to claim 34, characterized in that when G is -0-, R1 and R2 are each bromine, R3 is iso-propyl, and R5 is -OH, then R4 is not hydrogen.
36. 36. The compound according to claim 34, characterized in that when G is -0-; R1 and R2 are each chlorine; R4 is hydrogen; R5 is -OH; and R3 is i-propyl.
37. 37. The compound according to claim 36, characterized in that X is selected from the group consisting of -P03H2, -P (0) [-0CH20C (0) -t-butyl] 2, -P (0) [-0CH20C (0) 0-i-propyl] 2, -P (0) [-N (H) CH (CH3) C (0) OCH2CH3] 2, -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] 2, -P (0) [-N (H) CH (CH3) C (0) OCH2CH3] [3, 4-methylenedioxyphenyl], -P (0) [-N (H) C (CH3 ) 2C (0) OCH2CH3] [3, 4-ethylenedioxyphenyl], and -P (0) [-0CH (3-chlorophenyl) CH2CH20-].
38. 38. The compound according to claim 21, characterized in that G is selected from the group consisting of -0- and -CH2-; T is -CH2CH2-; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl, and cyano; R4 is selected from the group consisting of hydrogen and iodine; R5 is selected from the group consisting of -OH and -OC (0) Re; and R3 is selected from the group consisting of iodo, bromo, optionally substituted C6-C6 alkyl, optionally substituted -CH2aryl, -CH (OH) optionally substituted aryl, -C (0) -amido, -S (= 0) 2 amido wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -S02Re wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, and 4-pyridyl.
39. 39. The compound according to claim 38, characterized in that G is -0-; R1 and R2 are each chlorine; R4 is hydrogen; R5 is -OH; R3 is iso-propyl.
40. 40. The compound according to claim 39, characterized in that X is selected from the group consisting of -P03H2, -P (0) [-0CH20C (0) -t-butyl] 2, -P (0) [- OCH2OC (0) 0-i-propyl] 2, -P (0) [-N (H) CH (CH3) C (0) 0CH2CH3] 2, -P (0) [- N (H) C (CH3) 2C (0) 0CH2CH3] 2, -P (0) [-N (H) CH (CH3) C (0) OCH2CH3] [3,4-methylenedioxyphenyl], -P (0) [-N (H) C (CH3 ) 2C (0) OCH2CH3] [3,4-methylenedioxyphenyl], and -P (0) [-0CH (3-chlorophenyl) CH2CH0-].
41. 41. The compound according to claim 23, characterized in that T is -CH2CH (NH) -; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl, and cyano; R4 is selected from the group consisting of hydrogen and halogen; R5 is selected from the group consisting of -OH, and -OC (0) Re; and R 3 is selected from the group consisting of halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted -CH 2 aryl, optionally substituted -CH (OH) aryl, -C (0) -amido, -S (= 0) 2-amido wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-ethylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -S02Re wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, 4- fluorophenyl, and 4-pyridyl.
42. 42. The compound according to claim 41, characterized in that when G is -O-, R1 and R2 are each iodo; R4 is selected from the group consisting of hydrogen and iodine; R5 is -OH; and R3 is iodine.
43. 43. The compound according to claim 42, characterized in that when X is selected from the group consisting of -P03H2, -P (O) [-OCH2OC (O) -t-butyl] 2, -P (O) [- OCH2OC (0) 0-i-propyl] 2, -P (0) [-N (H) CH (CH3) C (O) OCH2CH3] 2, -P (0) [- N (H) C (CH3) 2C (0) OCH2CH3] 2, -P (0) [-N (H) CH (CH3) C (0) OCH2CH3] [3,4-methylenedioxyphenyl], -P (0) [-N (H) C ( CH3) 2C (0) OCH2CH3] [3,4-methylenedioxyphenyl], and -P (0) [-0CH (3-chlorophenyl) CH2CH20-].
44. 44. The compound according to claim 23, characterized in that T is -N (H) C (0) -; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl, and cyano; R4 is selected from the group consisting of hydrogen and iodine; R5 is selected from the group consisting of -OH and -OC (0) Re; R3 is selected from the group consisting of iodine, bromine, optionally substituted Ci-Cß alkyl, optionally substituted -CH 2 aryl, optionally substituted aryl -CH (OH), -C (0) -amido, -S (= 0) 2-amido , wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl and -S02Re wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, 4- fluorophenyl, and 4-pyridyl.
45. 45. The compound according to claim 44, characterized in that G is -0-; R1 and R2 are each methyl; R4 is hydrogen; R5 is -OH; and R3 is -CH (OH) (4-fluorophenyl).
46. 46. The compound according to claim 44, characterized in that X is selected from the group consisting of -P03H2, -P (0) [-0CH20C (0) -t-butyl] 2, -P (0) [-OCH2OC (0) 0-i-propyl] 2, -P (0) [-N (H) CH (CH3) C (0) OCH2CH3] 2, -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] 2, -P (0) [-N (H) CH (CH3) C (0) OCH2CH3] [3,4-methylenedioxyphenyl], -P (0) [-N (H) C (CH3 ) 2C (0) OCH2CH3] [3,4-methylenedioxyphenyl], and -P (0) [-0CH (3-chlorophenyl) CH2CH20-].
47. 47. The compound according to claim 23, characterized in that T is -OCH2-; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl, and cyano; R4 is selected from the group consisting of hydrogen and iodine; R5 is selected from the group consisting of -OH and -OC (0) Re; and R 3 is selected from the group consisting of iodine, bromine, optionally substituted C 1 -C 6 alkyl, optionally substituted -CH 2 aryl, optionally substituted -CH (OH) aryl, -C (O-amido, -S (= 0) 2-amido in wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -S02R wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl , and 4-pyridyl
48. 48. The compound according to claim 47, characterized in that G is -CH2 ~; R1 and R2 are each methyl; R4 is hydrogen; R5 is -OH; and R3 is iso-propyl.
49. 49. The compound according to claim 47, characterized in that X is selected from the group consisting of -P03H2, -P (O) [-OCH2OC (0) -t-butyl] 2, -P (0) [-OCH2OC (0) 0-α-propyl] 2, -P (0) [-N (H) CH (CH 3) C (0) OCH 2 CH 3] 2, -P (0) [- N (H) C (CH 3) 2C (0) OCH2CH3] 2, -P (0) [-N (H) CH (CH3) C (0) OCH2CH3] [3,4-methylenedioxyphenyl], -P (0) [-N (H) C (CH3 ) 2C (0) OCH2CH3] [3,4-methylenedioxyphenyl], and -P (0) [-0CH (3-chlorophenyl) CH2CH20-].
50. 50. The compound according to claim 23, characterized in that T is -CH 2 -; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl, and cyano; R4 is selected from the group consisting of hydrogen and iodine; R5 is selected from the group consisting of -OH and -OC (0) Re; and R3 is selected from the group consisting of iodine, bromine, optionally substituted Ci-Cg alkyl, optionally substituted -CH2aryl, -CH (OH) optionally substituted aryl, -C (O-amido, -S (= 0) 2-amido wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -S02Re wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, and 4-pyridyl
51. 51. The compound according to claim 50, characterized in that when G is -0-, T is -CH2-, R1 and R2 are independently selected from the group consisting of iodine, bromine, chlorine, methyl, and cyano, R3 is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 6 carbons, and R5 is -OH, then R4 is not hydrogen
52. 52. The compound according to claim 50, characterized in that G is -0-, T is -CH2-, R1 and R2 are each chlorine, R4 is hydrogen, R5 is -OH, and R3 is i- propyl.
53. 53. The compound according to claim 50, characterized in that X is selected from the group consisting of -P03H2, -P (O) [-OCH2OC (O) -t-butyl] 2, -P (0) [- OCH2OC (0) 0-i-propyl] 2, -P (O) [-N (H) CH (CH3) C (O) OCH2CH3] 2, -P (0) [- N (H) C (CH3) 2C (0) OCH2CH3] 2, -P (O) [-N (H) CH (CH3) C (O) OCH2CH3] [3,4-methylenedioxyphenyl], -P (O) [-N (H) C (CH3 ) 2C (O) OCH2CH3] [3, 4-methylenedioxyphenyl], and -P (O) [-OCH (3-chlorophenyl) CH2CH20-].
54. 54. The compound according to claim 23, characterized in that T is -CH2CH-; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl, and cyano; R4 is selected from the group consisting of hydrogen and iodine; R5 is selected from the group consisting of -OH and -OC (0) Re; and R3 is selected from the group consisting of iodine, bromine, optionally substituted C-C6 alkyl, optionally substituted -CH2aryl, -CH (OH) optionally substituted aryl, -C (O) -amido, -S (= 0) 2- amido wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -SÜ2Re wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, -fluorophenyl, and 4-pyridyl.
55. 55. The compound according to claim 54, characterized in that when G is -0-; R1 and R2 are independently selected from the group consisting of iodine, bromine, chlorine and methyl; R3 is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 6 carbons; and R5 is -OH; then R4 is not hydrogen.
56. 56. The compound according to claim 54, characterized in that G is -0-; T is -CH2CH2-; R1 and R2 are each chlorine; R4 is hydrogen; R5 is -OH; and R3 is isopropyl.
57. 57. The compound according to claim 54, characterized in that X is selected from the group consisting of -P03H2, -P (0) [-0CH20C (0) -t-butyl] 2, -P (0) [- OCH2OC (0) 0-i-propyl] 2, -P (0) [-N (H) CH (CH3) C (0) 0CH2CH3] 2, -P (0) [-N (H) C (CH3) 2C (0) 0CH2CH3] 2, -P (0) [-N (H) CH (CH3) C (0) 0CH2CH3] [3,4-methylenedioxyphenyl], -P (0) [-N (H) C (CH3 ) 2C (0) OCH2CH3] [3,4-methylenedioxyphenyl], and -P (0) [-0CH (3-chlorophenyl) CH2CH20-].
58. 58. The compound according to any of claims 1, 2, 3, 4, 21, 23, 25, 27, 28, 30, 31, 33, 34, 37, 38, 40, 41, 43, 44, 46, 47, 49, 50, 53, 54 or 57, characterized in that X is P03H2.
59. 59. The compound according to claim 32, characterized in that X is selected from the group consisting of -P (0) [-0CH20C (0) -t-butyl] 2, -P (0) [-0CH20C (0) 0-i-propyl] 2.
60. 60. The compound according to claim 32, characterized in that X is selected from the group consisting of -P (0) [-0CH20C (0) 0-ethyl] 2 and -P (0) [-0CH20C (0) 0 -i-propyl] 2.
61. 61. The compound according to claim 32, characterized in that X is selected from the group consisting of -P (0) [-N (H) CH (CH3) C (0) OCH2CH3] 2, and -P (0) [- N (H) C (CH3) 2C (0) OCH2CH3] 2.
62. 62. The compound according to claim 32, characterized in that X is -P (0) [-0CH2CH2SC (0) Me] 2.
63. 63. The compound according to claim 32, characterized in that X is selected from the group consisting of -P (0) [-N (H) CH (CH3) C (0) OCH2CH3] [3, 4-ethylenedioxyphenyl] and ~ P (0 ) [-N (H) C (CH3) 2C (0) OCH2CH3] [3,4-methylenedioxyphenyl]
64. 64. The compound according to claim 32, characterized in that X is P (0) YR ^ Y'R11 wherein Y and Y 'are each independently selected from -0- and -NRV-; together R11 and R11 are the group: wherein V, W, and W are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-alkynyl; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group to the beta and gamma bound position to the Y to the phosphorus; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and W - are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl replaced; or together and W are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHRzOH, -CHRzOC (0) Ry, -CHRzOC (S) Ry, -CHRz0C (S) ORy, -CHRzOC (O) SRy, CHRzOC02Ry, -ORz, -SRZ, -CHRZN3, -CH2aryl, -CH (aryl) OH, -CH (CH = CRz2) OH, -CH (C = CRZ) OH, -Rz, -NRZ2, -OCORy, -OC02Ry, -SCOR ?, -SC02Ry, -NHC0R2, -NHC02R ?, -CH2NHaril, - (CH2) q-ORz, and - (CH2) q-SRz; q is an integer of 2 or 3; with the proviso that: a) V, Z,, W are not all -H; and b) when Z is -Rz, then at least one of V, W, and W is not -H, alkyl, aralkyl, or heterocycloalkyl; Each Rz is selected from the group consisting of Ry and -H; Each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; and Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl.
65. 65. The compound according to claim 64, characterized in that V is aryl.
66. 66. The compound in accordance with the claim 65, characterized in that Z is hydrogen, is hydrogen, and W is hydrogen.
67. 67. The compound in accordance with the claim 66, characterized in that V is selected from the group consisting of 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 3-fluorophenyl, pyrid-4-yl, pyrid-3-yl or 3,5-dichlorophenyl.
68. 68. The compound according to claim 67, characterized in that the relative stereochemistry between the substituent of group V and T in the dioxaphosphonan ring is cis.
69. 69. The compound according to claim 68, characterized in that the cis-dioxaphosphonne ring has a carbon stereochemistry R where the group V is linked.
70. 70. The compound according to claim 68, characterized in that the cis-dioxaphosphonium ring has a S-carbon stereochemistry where the V group is linked.
71. 71. The compound according to claim 19, characterized in that G is -O-, T is -CH2CH2-, R1 and R2 are each iodo, R3 is iso-propyl, R4 is hydrogen and R5 is -OH.
72. 72. The compound according to claim 71, characterized in that X is selected from the group consisting of -P (O) [-OCH (V) CH2CH20-], -P (O) [-N (H) CH (CH3) C (0) OCH2CH3] 2, and -P (O) [-N (H) C (CH3) 2C (O) OCH2CH3] 2, and V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and heteroaryl optionally substituted.
73. 73. The compound according to claim 19, characterized in that G is -0-; T is -CH2CH2-; R1 and R2 and R3 are each iodo; R4 is hydrogen; and R5 is -OH.
74. 74. The compound according to claim 73, characterized in that -P (0) [-OCH (V) CH2CH20-], -P (0) [-N (H) CH (CH3) C (0) OCH2CH3] 2 , and -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] 2, and V is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl.
75. 75. The compound in accordance with the claim 19, characterized in that G is -0-, T is -CH2-, R and R 'are each iodo, R3 is iso-propyl, R4 is hydrogen, and R5 is -OH.
76. 76. The compound according to claim 75, characterized in that X is selected from the group consisting of P (0) [-0CH (V) CH2CH20-], P (0) [- N (H) CH (CH3) C (0) OCH2CH3] 2, and -P (0) [-N (H) C (CH3) 2C (0) 0CH2CH3] 2, and V is selected from the group consisting of aryl, optionally substituted aryl, heteroaryl, and heteroaryl optionally substituted.
77. 77. The compound according to claim 19, characterized in that G is -0-; T is -CH2-; R1, R2 and R3 are each iodo; R4 is hydrogen; and R5 is -OH.
78. 78. The compound according to claim 77, characterized in that X is selected from the group consisting of -P (0) [-OCH (V) CH2CH20-], -P (0) [-N (H) CH (CH3) C (0) OCH2CH3] 2, and -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] 2, and V is selected from the group consisting of aryl, optionally substituted aryl, heteroaryl, and heteroaryl optionally substituted.
79. 79. The compueto according to claim 19, characterized in that G is -0-; T is -0CH2-; R1 and R2 are each iodo, and R4 is selected from the group consisting of hydrogen, iodo, and R3 is iso-propyl; R4 is hydrogen and R5 is -OH.
80. 80. The compound according to claim 79, characterized in that X is selected from the group consisting of -P (0) [-0CH (V) CH2CH20-], -P (0) [- N (H) CH (CH3 ) C (0) OCH2CH3] 2, and -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] 2, and V is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
81. 81. The compound according to claim 19, characterized in that G is -0-, T is -CH2-, R1 and R2 are chlorine, R3 is 4-fluorobenzyl, R4 is hydrogen and R5 is -OH.
82. 82. The compound according to claim 81, characterized in that X is selected from the group consisting of -P (0) [-0CH (V) CH2CH20-], -P (0) [-N (H) CH (CH3 ) C (0) 0CH2CH3] 2, and -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] 2, and V is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
83. 83. A method for preventing or treating a metabolic disease characterized in that it comprises administering to an animal a pharmaceutically effective amount of a compound containing phosphonic acid, a pharmaceutically acceptable salt thereof, or prodrugs thereof or pharmaceutically acceptable salts of such prodrugs, in wherein the compound characterized in that it contains phosphonic acid binds to a thyroid receptor.
84. 84. The method according to claim 83, characterized in that the phosphonic acid-containing compound is linked to a thyroid receptor with a Ki of = 1 μM.
85. 85. The method according to claim 84, characterized in that the thyroid receptor is TRal.
86. 86. The method according to claim 84, characterized in that the thyroid receptor is TRßl.
87. 87. The method according to claim 84, characterized in that the phosphonic acid-containing compound is linked to a thyroid receptor with a Ki of = 100 nM.
88. 88. The method according to claim 87, characterized in that the thyroid receptor is TRal.
89. 89. The method according to claim 87, characterized in that the thyroid receptor is TRßl.
90. 90. The method according to claim 83, characterized in that the metabolic disease is selected from the group consisting of obesity, hypercholesterolemia, hyperlipidemia, atherosclerosis, coronary heart disease, and hypertension.
91. 91. The method according to claim 90, characterized in that the metabolic disease is selected from the group consisting of obesity, hypercholesterolemia, and hyperlipidemia.
92. 92. The method according to claim 83, characterized in that the compound containing phosphonic acid activates the thyroid receptor.
93. 93. The method according to claim 92, characterized in that the thyroid receptor is TRal.
94. 94. The method according to claim 92, characterized in that the thyroid receptor is TRßl.
95. 95. The method according to claim 91, characterized in that the compound containing phosphonic acid increases the mRNA expression of a gene selected from the group consisting of the LDL, ACC, FAS, spot-14, CPT-1, CYP7A receptor, apo AI, and mGPDH.
96. 96. The method according to claim 83, characterized in that the phosphonic acid-containing compound is a compound of the formula I: wherein: G is selected from the group consisting of -O-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF-, -C (O) -, -CH (OH) -, -NH-, and -N (C? -C4 alkyl) -; T is selected from the group consisting of - (CRa2) k-, ~ CRb = CRb- (CRa2) n-, - (CRa2) n-CRb = CRb-, - (CRa2) -CRb = CRb- (CRa2) - , 0 (CRb2) (CRa2) n-, -S (CRb2) (CRa2) n-, -N (Rb) (CRb2) (CRa2) nN (Rb) C (0) (CRa2) n-, - (CRa2 ) nCH (NRbRc) -, -C (O) (CRa2) m-, (CRa2) mC (0) -, - (CRa2) C (0) (CRa2) n-, - (CRa2) nC (0) ( CRa2) -, and -C (0) NH (CR2) (CRa2) p-; k is an integer from 0-4; m is an integer from 0-3; n is an integer from 0-2; p is an integer from 0-1; Each Ra is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl, halogen, -OH, -O-C 1 -C 4 alkyl optionally substituted, -OCF 3, -S-C 4 -C 4 alkyl optionally substituted, NRbRc, optionally substituted C2-C4 alkenyl, and optionally substituted C2-C alkynyl; with the proviso that when a Ra is linked through O, S, or N, then the other Ra links to the same C that is a hydrogen, or is linked by means of a carbon atom. Each Rb is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl; Each Rc is independently selected from the group consisting of hydrogen and optionally substituted C ?C alkyl, -C (0) - optionally substituted C 1 -C 4 alkyl, and -C (0) H; R1 and R2 are each independently selected from the group consisting of halogen, optionally substituted C?-C4 alkyl, optionally substituted -S-C 1 -C 3 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, -CF 3, -0CF3, -O-C-C3 alkyl optionally substituted, and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -0CF3, cyano, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, - (CRa2) optionally substituted maryl, - (CRa2) optionally substituted cycloalkyl, (CRa2) optionally substituted metheterocycloalkyl, -0Rd, SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRfRg, -C (0) NRfRg, -C (0) 0Rh, -C (0) Re, -N (Rb) C (0) Re, -N (Rb) C (0) NRfRg, -N (Rb) S (= 0 ) 2R% N (Rb) S (= 0) 2NRfRg, and -NRfRg; Each Rd is selected from the group consisting of optionally substituted C -.- C12 alkyl, optionally substituted C2-C2-alkenyl, optionally substituted C2-Ci2 alkynyl, - (CRb2) n optionally substituted aryl, - (CR2) n cycloalkyl optionally substituted, _ (CRb2) n optionally substituted heterocycloalkyl, and -C (0) NRfRg; Each Re is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C-C? 2 alkenyl, optionally substituted C2-C? 2 alkynyl, optionally substituted - (CRa2), (CRa2) n Optionally substituted cycloalkyl, and - (CRa2) nheterocycloalkyl optionally substituted; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C2-Ci2 alkenyl, optionally substituted C2-C2 alkynyl, optionally substituted - (CRb2) naril, - (CRb2) optionally substituted cycloalkyl, and optionally substituted - (CRb2) nheterocycloalkyl, or Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second hetero group selected from the group of O, NRC, and S, wherein the heterocyclic ring optionally substituted may be substituted with 0-4 substituents selected from the group consisting of optionally substituted C 1 -C 4 alkyl, -0Rb, oxo, cyano, -CF 3, optionally substituted phenyl, and -C (0) ORh; Each Rh is selected from the group consisting of optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl, - (CR 2) n optionally substituted aryl, (CRb2) n Optionally substituted cycloalkyl, and - (CRb2) nheterocycloalkyl optionally substituted; R5 is selected from the group consisting of -OH, optionally substituted C6-C6alkyl, -OC (0) Re, -OC (0) ORh, -F, -NHC (0) Re, -NHS (= 0) Re , -NHS (= 0) 2Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); X is P (0) YRuY'Ru; Y and Y 'are each independently selected from the group consisting of -O-, and -NRV-; when Y and Y 'are -O-, R11 linked to -O- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 2OC (O) NRZ2, -NRZ-C (0) -Ry, -C (Rz) 2-OC (0) Ry, -C (R) 2-0- C (0) ORy, -C (Rz) 2OC (O) SRy, -alkyl-SC (O) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; when Y and Y 'are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-COORy, -C (Rx) 2COOR ?, - [ C (R2) 2] qC (O) SRy, and cycloalkylene-COORy; when Y is -0- and Y 'is NRV, then R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 2OC (0) NRZ2, -NRZ-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (R2) 2 -0-C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] g-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy , and -cycloalkylene-C00Ry; or when Y and Y 'are independently selected from -0- and -NRV-, then R11 and R11 together are -alkyl-S-S-alkyl to form a cyclic group, or together R11 and R11 are the group: wherein: V, W, and W are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and 1-alkynyl optionally replaced; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group to the beta and gamma bound position to the Y to the match; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and W are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHRzOH, -CHRzOC (0) Ry, -CHRzOC (S) Ry, -CHRzOC (S) ORy, -CHRzOC (O) SRy, CHRzOC02Ry, -ORz, -SRz, -CHRZN3, -CH2aryl, -CH (aryl) OH, -CH (CH = CRz2) OH, -CH (C = CRz) OH, -Rz, -NRZ2, -OCORy, -OC02Ry, -SC0Ry, -SC02Ry, -NHC0Rz, - NHC02Ry, -CH2NHaril, - (CH2) q-ORz, and - (CH2) q-SRz; q is an integer of 2 or 3; each Rz is selected from the group consisting of Ry and -H; each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; each Rx is independently selected from the group consisting of -H, and alkyl, or together Rx or Rx form a cyclic alkyl group; each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl. with the proviso that: a) when G is -0-, T is -CH2-, R1 and R2 are each bromine, R3 is iso propyl, R4 is hydrogen, and R5 is -OH, then X is not -P (0) (0H) 2 or -P (0) (OCH 2 CH 3) 2; b) V, Z, W, W are not all -H; and c) when Z is -Rz, then at least one of V,, and W are not -H, alkyl, aralkyl, or heterocycloalkyl; and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs.
97. 97. The method according to claim 83 characterized in that the compound containing phosphonic acid is a compound of Formula I: wherein: G is selected from the group consisting of -0-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF-, -C (0) -, -CH (OH) -, -NH-, and -N (C 1 -C 4 alkyl) -; T is selected from the group consisting of - (CRa2) k-, -CRb = CRb- (CRa2) n-, - (CRa2) n-CRb = CRb-, - (CRa2) -CRb = CRb- (CRa2) - , 0 (CRb2) (CRa2) n-, -S (CRb2) (CRa2) n-, -N (Rb) (CRb2) (CRa2) n-, N (Rb) C (0) (CRa2) n-, - (CRa2) nCH (NRbRc) -, -C (0) (CRa2) 1: mr (CRa2) mC (0) -, - (CRa2) C (0) (CRa2) n-, - (CRa2) nC ( 0) (CRa2) -, C (0) NH (CRb2) (CRa2) p-; k is an integer from 0-4, m is an integer from 0-3, n is an integer from 0-2, p is an integer from 0-1, each Ra is independently selected from the group consisting of hydrogen, alkyl C Optionally substituted -C4, halogen, -OH, -O-C optionally substituted alkyl, -0CF3, -S-C optionally substituted alkyl, -NRbRc, optionally substituted C2-C4 alkenyl, and optionally substituted C2-C4 alkynyl; with the proviso that when a Ra is linked through O, S, or N, then the other Ra links to the same C that is a hydrogen, or is linked by means of a carbon atom. Each Rb is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl; Each Rc is independently selected from the group consisting of hydrogen and optionally substituted C? ~C alkyl, -C (O) - optionally substituted C 1 -C 4 alkyl, and -C (0) H; R1 and R2 are each independently selected from the group consisting of halogen, optionally substituted C?-C4 alkyl, optionally substituted -S-C C-C3 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, - CF 3, -OCF 3, -O-C 1 -C 3 alkyl optionally substituted, and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, C2-C? Alkynyl? optionally substituted, - (CRa2) optionally substituted maryl, (CRa2) optionally substituted cycloalkyl, (CRa2) optionally substituted mheterocycloalkyl, -ORd, SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRfRg, -C (0) NRfRg, -C (0) ORh, -C (0) Re, -N ( Rb) C (0) Re, -N (Rb) C (0) NRfRg, -N (Rb) S (= 0) 2Re, N (Rb) S (= 0) 2NRfRg, and -NRfRg; Each Rd is selected from the group consisting of optionally substituted C1-C12alkyl, optionally substituted CC ?2alkenyl, optionally substituted C2-C12alkynyl, optionally substituted aryl (CRb2), - (CRb2) n optionally substituted cycloalkyl, ~ ( CRb2) n optionally substituted heterocycloalkyl, and -C (0) NRfRg; Each Re is selected from the group consisting of optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, optionally substituted C2-C? 2 alkynyl, optionally substituted (CRa2), optionally substituted (CRa2) nCycloalkyl substituted, and - (CRa2) optionally substituted n-heterocycloalkyl; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C2-C2 alkenyl, optionally substituted C2-C2 alkynyl, optionally substituted - (CRb2) naril, - ( CRb2) optionally substituted cycloalkyl, and optionally substituted - (CRb2) nheterocycloalkyl, or Rf and Rg together can form an optionally substituted heterocyclic ring, which may contain a second hetero group selected from the group of O, NRC, and S, wherein the ring optionally substituted heterocyclic may be substituted with 0-4 substituents selected from the group consisting of optionally substituted C1-C4 alkyl, -ORb, oxo, cyano, -CF3, optionally substituted phenyl, and -C (0) ORh; Each Rh is selected from the group consisting of optionally substituted C?-C? 2 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 12 alkynyl, - (CRb 2) n optionally substituted aryl, (CRb 2) n optionally substituted cycloalkyl, and (CRb2) optionally substituted n-heterocycloalkyl; R5 is selected from the group consisting of -OH, optionally substituted C6-C6alkyl, -OC (0) Re, -OC (0) ORh, -F, -NHC (0) Re, -NHS (= 0) Re , -NHS (= 0) 2Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); X is P (O) YR ^ Y'R11; Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are -0-, R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRZ2, -NR2-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2-0- C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; when Y and Y 'are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy, and cycloalkylene-C00Ry; when Y is -0- and Y 'is NRV, then R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRZ2, -NR2-C (0) -Ry, -C (R2) 2-0C (0) Ry, -C (Rz) 2 -0-C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-COORy, -C (Rx) 2COORy, - [C (Rz) 2] qC (0) SRy , and -cycloalkylene-COORy; or when Y and Y 'are independently selected from -0- and -NRV-, then R11 and R11 together are -alkyl-S-S-alkyl to form a cyclic group, or together R11 and R11 are the group: wherein: V, W, and W are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and 1-alkynyl optionally replaced; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group to the beta and gamma bound position to the Y to the phosphorus; or together V and are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and W are connected by means of 3-5 additional atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHRz0H, -CHRzOC (0) Ry, -CHRz0C (S) Ry, -CHRzOC (S) ORy, -CHRzOC (O) SRY, CHRzOC02Ry, -ORz, -SRZ, -CHRzN3, -CH2aryl, -CH (aryl) OH, CH (CH = CR2) OH, -CH (C = CRz) OH, -R2, -NR2, -OCORy, -OC02Ry, - SCORy, -SC02Ry, -NHCORz, -NHC02Ry , -CH2NHaril, - (CH2) q-ORz, and - (CH2) q-SR; q is an integer of 2 or 3; each Rz is selected from the group consisting of R? and -H; each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; each Rx is independently selected from the group consisting of -H, and alkyl, or together Rx or Rx form a cyclic alkyl group; each R is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the proviso that: a) when G is -0-, T is -. { CR2) oi ~ r R1 and R2 are independently halogen, alkyl of 1 to 3 carbons, and cycloalkyl of 3 to 5 carbons, R3 is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 7 carbons, R4 is hydrogen, and R5 is -OH, then X is not -P (0) (0H) 2 or -P (0) (O-lower alkyl) 2; b) when G is -0-, R5 is -NHC (0) Re, -NHS (= 0)? -2Re, -NHC (S) NH (Rh), or -NHC (0) NH (Rh), T is ~ (CH2) m-, -CH = CH-, -0 (CH2)? -2-, or -NH (CH2)? _ 2-, then X is not -P (0) (0H) 2 or -P (0) (0H) NH2; c) V, Z,, W are not all -H; and d) when Z is -Rz, then at least one of V, W, and W are not -H, alkyl, aralkyl, or heterocycloalkyl; and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs.
98. 98. The method according to claim 96 characterized in that when G is -0-, T is -CH2-, R1 and R are each bromine, R3 is iso-propyl, and R5 is -OH, then R 'is not hydrogen.
99. 99. The method according to claim 97, characterized in that when G is -0-, T is - (CH2) 0-, R and R2 are independently selected from the group consisting of halogen, alkyl of 1 to 3 carbons, and cycloalkyl of 3 to 5 carbons, R3 is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 7 carbons, and R5 is -OH, then R4 is not hydrogen; and wherein when G is -0-, R5 is selected from the group consisting of NHC (0) Re, -NHS (= 0)? -2Re, NHC (= S) NH (Rh), and -NHC (0) NH (Rh); T is selected from the group consisting of - (CH2) m-, -CH = CH-, -0 (CH2)? _ 2-, and -NH (CH2)? -2-, then R4 is not hydrogen.
100. 100. A method of activating a thyroid receptor in an animal by administering a compound containing phosphonic acid, characterized in that activation results in 50% or greater increase in mRNA expression of a gene selected from the group consisting of the LDL receptor, ACC, FAS, spot-14, CPT-1, CYP7A, apo AI, and mGPDH.
101. 101. The method according to claim 100, characterized in that the phosphonic acid-containing compound binds to a thyroid receptor with a Ki of = 1 μM.
102. 102. The method according to claim 101, characterized in that the phosphonic acid-containing compound binds to a thyroid receptor with a Ki of = 100 nM.
103. 103. The method according to claim 100, characterized in that the phosphonic acid-containing compound is a compound of Formula I: wherein: G is selected from the group consisting of -O-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF-, -C (0) ~, -CH (OH) -, -NH-, and -N (C? -C4 alkyl) -; T is selected from the group consisting of - (CRa2) k-, -CRb = CRb- (CRa2) n-, - (CRa2) n-CRb = CRb-, - (CRa2) -CRb = CRb- (CRa2) - , 0 (CRb2) (CRa2) n-, -S (CRb2) (CRa2) n-, -N (Rb) (CRb2) (CRa2) n-, N (Rb) C (0) (CRa2) n-, - (CRa2) nCH (NRbRc) -, -C (O) (CRa2) m-, (CRa2) mC (0) -, - (CRa2) C (0) (CRa2) n-, - (CRa2) nC ( O) (CRa2) -, and - C (0) NH (CRb2) (CRa2) p-; k is an integer from 0-4; m is an integer from 0-3; n is an integer from 0-2; p is an integer from 0-1; Each Ra is independently selected from the group consisting of hydrogen, optionally substituted C?-C 4 alkyl, halogen, -OH, -O-C ?C 4 alkyl optionally substituted, -OCF 3, -S-C CC 4 alkyl optionally substituted, -NRbRc, optionally substituted C2-C4 alkenyl, and optionally substituted C2-C alkynyl; with the proviso that when a Ra is linked to C through O, S, or N, then the other Ra links to the same C that is a hydrogen, or is linked by means of a carbon atom. Each Rb is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl; Each Rc is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 4 alkyl, -C (O) -alkyl C 1 -C 4 optionally substituted, and -C (0) H; R1 and R2 are each independently selected from the group consisting of halogen, optionally substituted C?-C4 alkyl, optionally substituted -S-C 1 -C 3 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, -CF 3, -OCF3, -O-C-C3 alkyl optionally substituted, and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, C2-C? Alkynyl? optionally substituted, - (CRa2) optionally substituted aryl, - (CRa2) optionally substituted cycloalkyl, (CRa2) mheterocycloalkyl optionally substituted, -0Rd, SRd, -S (= 0) Re, -S (= 0) 2Re, -S ( = 0) 2NRfRg, -C (0) NRfRg, -C (0) ORh, -C (0) Re, -N (Rb) C (0) Re, -N (R) C (0) NRfRg, -N (Rb) S (= 0) 2Re, N (Rb) S (= 0) 2NRfRg, and -NRfRg; Each Rd is selected from the group consisting of optionally substituted C? ~C? 2 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl, - (CRb 2) n optionally substituted aryl, - (CRb 2) optionally substituted cycloalkyl, - (CR2) n optionally substituted heterocycloalkyl, and -C (0) NRfRg; Each Re is selected from the group consisting of optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, optionally substituted C2-C? 2 alkynyl, optionally substituted (CRa2), optionally substituted (CRa2) nCycloalkyl substituted, and - (CRa2) optionally substituted n-heterocycloalkyl; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C2 alkynyl, optionally substituted - (CRb2) naril, - (CRb2) optionally substituted cycloalkyl, and optionally substituted - (CRb2) nheterocycloalkyl, or Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second hetero group selected from the group of 0, NRC, and S, wherein the heterocyclic ring optionally substituted may be substituted with 0-4 substituents selected from the group consisting of optionally substituted C1-C4 alkyl, -ORb, oxo, cyano, -CF3, optionally substituted phenyl, and -C (0) ORh; Each Rh is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, - (CRb2) n optionally substituted aryl, (CRb2) n-cycloalkyl optionally substituted, and - (CRb2 ) optionally substituted n-heterocycloalkyl; R5 is selected from the group consisting of -OH, -O-C6alkyl optionally substituted, -0C (0) Re, -0C (0) 0Rh, -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2 Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); X is P (0) YRuY'Ru; Y and Y 'are each independently selected from the group consisting of -O-, and -NRV-; when Y and Y 'are -O-, R11 linked to -O- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 2OC (O) NRZ2, -NRZ-C (0) -Ry, -C (Rz) 2-OC (0) Ry, -C (Rz) 2-0- C (0) ORy, -C (Rz) 2OC (O) SRy, -alkyl-SC (O) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; when Y and Y 'are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-COORy, -C (Rx) 2COORy, - [C (Rz) 2] qC (O) SRy, and cycloalkylene-COORy; when Y is -O- and Y 'is NRV, then R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (O) NRZ2, -NRZ-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (R2) 2 -0-C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2COORy, - [C (Rz) 2] qC (0) SRy , and -cycloalkylene-COORy; or when Y and Y 'are independently selected from -0- and -NRV-, then R11 and R11 together are -alkyl-S-S-alkyl to form a cyclic group, or together R11 and R11 are the group: wherein: V, W, and W are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and 1-alkynyl optionally replaced; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group to the beta and gamma bound position to the Y to the phosphorus; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and W are connected by means of 3-5 additional atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHRzOH, -CHRz0C (0) Ry, -CHRz0C (S) Ry, -CHRzOC (S) ORy, -CHRzOC (O) SRy, CHRz0C02Ry, -ORz, -SRZ, -CHRZN3, -CH2aryl, -CH (aryl) OH, - CH (CH = CRz2) OH, -CH (C = CRz) OH, -Rz, -NRZ2, -OCORy, -OC02Ry, - SCORy, -SC02Ry, -NHCOR2, - NHC02Ry, -CH2NHaril, - (CH2) q-ORz, and - (CH2) q-SRz; q is an integer of 2 or 3; each Rz is selected from the group consisting of Ry and -H; each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; each Rx is independently selected from the group consisting of -H, and alkyl, or together Rx or Rx form a cyclic alkyl group; each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the proviso that: a) when G is -0-, T is -CH2-, R1 and R2 are each bromine, R3 is iso-propyl, R4 is hydrogen, and R5 is -OH, then X is not - P (0) (0H) 2 or -P (0) (OCH 2 CH 3) 2; b) V, Z,, W are not all -H; and c) when Z is -Rz, then at least one of V, W, and W are not -H, alkyl, aralkyl, or heterocycloalkyl; and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs.
104. 104. The method according to claim 100, characterized in that the phosphonic acid-containing compound is a compound of the Formula I: wherein: G is selected from the group consisting of -0-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF-, -C (0) -, -CH (OH) -, -NH-, and -N (C? -C alkyl) -; T is selected from the group consisting of - (CRa2) k-, -CRb = CRb- (CRa2) n-, - (CRa2) n-CRb = CRb-, - (CRa2) -CRb = CRb- (CRa2) - , 0 (CRb2) (CRa2) n-, -S (CRb2) (CRa2) n-, -N (Rb) (CR2) (CRa2) n-, N (Rb) C (0) (CRa2) n-, - (CRa2) nCH (NRbRc) -, -C (0) (CRa2) m-, (CRa2) mC (0) -, - (CRa2) C (0) (CRa2) n-, - (CRa2) nC ( 0) (CRa2) -, and -C (0) NH (CRb2) (CRa2) p-; k is an integer from 0-4; m is an integer from 0-3; n is an integer from 0-2; p is an integer from 0-1; Each Ra is independently selected from the group consisting of hydrogen, optionally substituted C?-C 4 alkyl, halogen, -OH, -O-C ?C alkyl optionally substituted, -0CF 3, -S-C C-C 4 alkyl optionally substituted, -NRbRc, optionally substituted C2-C alkenyl, and optionally substituted C2-C4 alkynyl; with the proviso that when a Ra is linked through O, S, or N, then the other R links to the same C that is a hydrogen, or is linked by means of a carbon atom. Each Rb is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl; Each Rc is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 4 alkyl, -C (0) -alternatively substituted C 1 -C 4 alkyl, and -C (0) H; R1 and R2 are each independently selected from the group consisting of halogen, optionally substituted C1-C4 alkyl, -S-optionally substituted C1-C3 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, -CF3, - OCF 3, -O-C 1 -C 3 alkyl optionally substituted, and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -0CF3, cyano, optionally substituted C?-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, - (CRa2 ) optionally substituted maryl, - (CRa2) optionally substituted cycloalkyl, - (CRa2) mheterocycloalkyl optionally substituted, -0Rd, SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRfRg, -C (0) NRfRg, -C (0) 0Rh, -C (0) Re, -N (Rb) C (0) Re, -N (Rb) C (0) NRfRg, -N (Rb) S ( = 0) 2Re, N (Rb) S (= 0) 2NRfRg, and -NRfRg; Each Rd is selected from the group consisting of optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl, - (CR 2) n optionally substituted aryl, - (CR 2) n cycloalkyl optionally substituted, _ (CR2) n optionally substituted heterocycloalkyl, and -C (0) NRfRg; Each Re is selected from the group consisting of optionally substituted C? ~ C12 alkyl, optionally substituted C-C? 2 alkenyl, optionally substituted C2-C? 2 alkynyl, optionally substituted - (CRa2), (CRa2) optionally substituted cycloalkyl, and - (CRa2) nheterocycloalkyl optionally substituted; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 2 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 2 alkynyl, optionally substituted - (CR 2 2) naryl, (CRb2) optionally substituted cycloalkyl, and optionally substituted - (CR2) nheterocycloalkyl, or Rf and Rg together can form an optionally substituted heterocyclic ring, which may contain a second hetero group selected from the group of O, NRC, and S, wherein the optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting of optionally substituted C? -C alkyl, -ORb, oxo, cyano, -CF3, optionally substituted phenyl, and -C (0) ORh; Each Rh is selected from the group consisting of optionally substituted C? -C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C? 2 alkynyl, optionally substituted ~ (CRb2) n aryl, (CRb2) n-cycloalkyl optionally substituted, and (CRb2) optionally substituted n-heterocycloalkyl; R5 is selected from the group consisting of -OH, -O-C6-C6 alkyl optionally substituted, -OC (0) Re, -OC (0) ORh, -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2 Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); X is P (O) YR ^ Y'R11; Y and Y 'are each independently selected from the group consisting of -O-, and -NRV-; when Y and Y 'are -O-, R11 linked to -O- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, CH2 ~ optionally substituted heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 2OC (O) NRZ2, -NR2-C (0) -Ry, -C (Rz) 2-OC (0) Ry, -C (Rz) 2-0- C (0) 0Ry, -C (Rz) 2OC (O) SRy, -alkyl-SC (O) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; when Y and Y 'are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-COORy, -C (Rx) 2COORy, - [C (Rz) 2] qC (O) SRy, and cycloalkylene-COORy; when Y is -0- and Y 'is NR, then R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRZ2, -NRZ-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2 -0-C (0) 0Ry, -C (Rz) 20C (O) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy , and -cycloalkylene-C00Ry; or when Y and Y 'are independently selected from -0- and -NRV-, then R11 and R11 together are -alkyl-S-S-alkyl to form a cyclic group, or together R11 and R11 are the group: wherein: V, W, and W are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and 1-alkynyl optionally replaced; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group to the beta and gamma bound position to the Y to the phosphorus; or together V and are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and are connected by means of 3-5 additional atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHRzOH, -CHRzOC (0) Ry, -CHRzOC (S) Ry, -CHRzOC (S) ORy, -CHRz0C (O) SRy, CHRzOC02Ry, -ORz, -SR, -CHRZN3, -CH2aryl, -CH (aryl) OH, -CH (CH = CRZ2) 0H, -CH (C = CRz) 0H, -Rz, -NRZ2, -OCORy, -OC02Ry, -SCORy, -SC02Ry, -NHC0R2, - NHC02Ry, -CH2NHaril, - (CH2) q-ORz, and - (CH2) q-SRz; q is an integer of 2 or 3; each Rz is selected from the group consisting of Ry and -H; each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; each Rx is independently selected from the group consisting of -H, and alkyl, or together Rx or Rx form a cyclic alkyl group; each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the proviso that: a) when G is -0-, T is - (CH2) 0-4-, R1 and R2 are independently halogen, alkyl of 1 to 3 carbons, and cycloalkyl of 3 to 5 carbons, R3 is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 7 carbons, R 4 is hydrogen, and R 5 is -OH, then X is not -P (0) (0H) 2 or -P (0) (O-lower alkyl) 2; b) when G is -0-, R5 is -NHC (0) Re, -NHS (= 0)? -2Re, -NHC (S) NH (Rh), or -NHC (0) NH (Rh), T is - (CH2) m-, -CH = CH-, - 0 (CH2)? _ 2-, or -NH (CH2)? _ 2-, then X is not -P (0) (0H) 2 or -P ( 0) (0H) NH2; c) V, Z, W, W are not all -H; and d) when Z is -Rz, then at least one of V, W, and W are not -H, alkyl, aralkyl, or heterocycloalkyl; and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs.
105. 105. The method according to claim 103, characterized in that when G is -0-, T is -CH2-, R1 and R2 are each bromine, R3 is iso-propyl, and R5 is -OH, then R4 is not hydrogen.
106. 106. The method according to claim 104, characterized in that when G is -0-, T is - (CH2) 0--, R1 and R2 are independently selected from the group consisting of halogen, alkyl of 1 to 3 carbons, and cycloalkyl of 3 to 5 carbons, R3 is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 7 carbons, and R5 is -OH, then R4 is not hydrogen, and wherein when G is -0-, R5 is selected from group consisting of NHC (0) Re, -NHS (= 0)? -2Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh), T is selected from the group consisting of - (CH2) m-, -CH = CH-, -0 (CH2)? _ 2-, and -NH (CH2)? -2-, then R4 is not hydrogen.
107. 107. The method according to claim 83, characterized in that the metabolic disease is NASH.
108. 108. The method according to claim 83, characterized in that the metabolic disease is selected from the group consisting of intolerance to the gucose, diabetes, and metabolic syndrome.
109. 109. The method according to claim 96, characterized in that the metabolic disease is hypercholesterolemia.
110. 110. The method according to claim 96, characterized in that the metabolic disease is obesity.
111. 111. The method according to claim 109, characterized in that the compound of Formula I is:
112. 112. The method according to claim 110, characterized in that the compound of Formula I is:
113. 113. The method according to claim 109, characterized in that the compound of Formula I is:
114. 114. The method according to claim 110, characterized in that the compound of Formula I is:
115. 115. The method according to claim 109, characterized in that the compound of Formula I is:
116. 116. The method according to claim 110, characterized in that the compound of Formula I is:
117. 117. A compound of Formula II characterized in that: A is selected from the group consisting of -NR1-, -O-, and -S-; B is selected from the group consisting of -CRb-, and -N-; R 1 is selected from the group consisting of hydrogen, -C (O) C 1 -C 4 alkyl, C 1 -C 4 alkyl, and C 1 -C 4 aryl; R b is selected from the group consisting of hydrogen and optionally substituted-C 1 -C 4 alkyl; G is selected from the group consisting of -O-, -S-, -S (= 0) 2-, -CH2-, -CF2-, -CHF-, -C (O) -, -CH (OH) - , -NH-, and -N (C? -C4 alkyl) -; D is selected from the group consisting of a bond, - (CRa2) -, and -C (O) -; Each Ra is independently selected from the group consisting of hydrogen, optionally substituted C3-C4 alkyl, halogen, -OH, optionally substituted 0-C2-C4 alkyl, -OCF3, -S-C-C4 alkyl optionally substituted, - NRbR, optionally substituted C2-C4 alkenyl, and optionally substituted C2-C4 alkynyl; with the proviso that when a Ra is linked to C through an atom 0, S, or N, then the other Ra links to the same C that is a hydrogen, or is bonded by means of a carbon atom; R1 and R2 are each independently selected from the group consisting of halogen, optionally substituted C? ~C alkyl, optionally substituted -S-C?-C alquilo alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C alkynyl, -CF 3 , -0CF3, -O-C CC3 alkyl optionally substituted, and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, optionally substituted C2-C12 alkynyl , - (CRa2) optionally substituted maryl, - (CRa2) optionally substituted cycloalkyl, (CRa2) optionally substituted metheterocycloalkyl, -0Rd, -SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRfRg, -C (0) NRfRg, -C (0) 0Rh, -C (0) Re, -N (Rb) C (0) Re, -N (Rb) C (0) NRfRg, -N ( Rb) S (= 0) 2Re, N (Rb) S (= 0) 2NRfRg, and -NRfRb; Each Rd is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2-C2 alkenyl, optionally substituted C2-C2 alkynyl, optionally substituted (CRb2) naryl, (CRb2) n optionally substituted cycloalkyl, ( CRb2) optionally substituted n-heterocycloalkyl, and C (0) NRfRg; Each Re is selected from the group consisting of optionally substituted 1-C12 alkyl, optionally substituted C2-C ?2 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted (CRa2), optionally substituted (CRa2) nCycloalkyl, and (CR2) ) optionally substituted n-heterocycloalkyl; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C?-C12 alkyl, optionally substituted C2-C? Al alkenyl, optionally substituted C2-C? Alqu alkynyl, optionally substituted - (CRb2) naril, - (CRb2) optionally substituted cycloalkyl, and - (CR2) optionally substituted n-heterocycloalkyl, or Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second hetero group selected from the group consisting of O, NRC, and S, in wherein the optionally substituted heterocyclic ring can be substituted with 0-4 substituents selected from the group consisting of optionally substituted C 1 -C 4 alkyl, -ORb, oxo, cyano, -CF 3, optionally substituted phenyl, and -C (0) ORh; Each Rh is selected from the group consisting of optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl, optionally substituted (CR 2) naryl, - (CR 2) nCycloalkyl optionally substituted, and (CRb2) optionally substituted n-heterocycloalkyl; R5 is selected from the group consisting of -OH, -0-C-C6 alkyl optionally substituted, -OC (0) Re, -OC (0) ORh, -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2 Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); X is P (O) YR ^ Y'R11; Y and Y 'are each independently selected from the group consisting of -O-, and -NRV-; when Y and Y 'are -O-, R11 linked to -O- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 2OC (O) NRZ2, -NRZ- C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2-0- C (0) ORy, -C (Rz) 2OC (O) SRy, -alkyl-SC (O) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; when Y and Y 'are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-COORy, -C (Rx) 2COORy, - [C (Rz) 2] qC (0) SRy, and cycloalkylene-COORy; when Y is -0- and Y 'is NRV, then R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains an optionally substituted carbonate or thiocarbonate, alkylaryl, -C (Rz) 20C (0) NRZ2, -NRZ-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz2) - 0-C (0) 0Ry, -C (Rz) 20C (0) SRY, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy , and -cycloalkylene-C00Ry; or when Y and Y 'are independently selected from -0- and -NRV-, then together R11 and R11 are -alkyl-S-S-alkyl to form a cyclic group, or together R11 and R11 are the group: wherein: V, W, and W are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and 1-alkynyl optionally substituted; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group to the beta and gamma bound position to the Y to the phosphorus; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and W are connected by means of 3-5 additional atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together and W are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHRz0H, -CHRzOC (0) Ry, -CHRzOC (S) Ry, -CHRzOC (S) ORy, -CHRzOC (0) SRy, CHRz0C02Ry, -0RZ, -SRZ, -CHRZN3, -CH2aryl, -CH (aryl) OH, -CH (CH = CRz2) OH, -CH (C = CRZ) OH, -Rz, -NRZ2, -OCORy, -OC02Ry, -SC0Ry, -SC02Ry, -NHC0R2, - NHC02Ry, -CH2NHaril, - (CH2) q-ORz, and - (CH2) q-SRz; q is an integer of 2 or 3; Each Rz is selected from the group consisting of Ry and -H; Each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; Each Rx is independently selected from the group consisting of -H, and alkyl, or together Rx or Rx form a cyclic alkyl group; Each R is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the proviso that: a) V, Z, W, and W are not all -H; and b) when Z is -Rz, then at least one of V, W, and W is not -H, alkyl, aralkyl, or heterocycloalkyl; and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs.
118. 118. The compound according to claim 117, characterized in that G is selected from the group consisting of -O- and -CH2-.
119. 119. The compound according to claim 117, characterized in that D is selected from the group consisting of a bond and -CH2-.
120. 120. The compound according to claim 117, characterized in that A is selected from the group consisting of -NH-, -NMe-, -O-, and -S-.
121. 121. The compound according to claim 117, characterized in that B is selected from the group consisting of -CH2-, CMe-, and -N-.
122. 122. The compound according to claim 117, characterized in that R1 and R2 are the same and are selected from the group consisting of halogen, C? -C4 alkyl, -CF3, and cyano.
123. 123. The compound according to claim 117, characterized in that R1 and R2 are different and is selected from the group consisting of halogen, -Calkyl, -CF3, and cyano.
124. 124. The compound according to claim 117, characterized in that R4 is selected from the group consisting of hydrogen, halogen, -alkyl C? ~ C4, cyano and CF3.
125. 125. The compound according to claim 117, characterized in that R5 is selected from the group consisting of -OH, -OC (0) Re, -OC (0) ORh, -F, and -NHC (0) Re.
126. 126. The compound according to claim 117, characterized in that R3 is selected from the group consisting of halogen, optionally substituted Ci-Cß alkyl, -CF3, cyano, -C (0) NRfRg, - (CRa2) optionally substituted narile, -S02NRfRg, and -S02Re.
127. 127. The compound according to claim 117, characterized in that X is selected from the group consisting of -P03H2, -P (O) [-OCRz2OC (O) Ry] 2, -P (0) [-OCRz2OC (0) ORy] 2, -P (O) [-N (H) CRz2C (0) ORy] 2, -P (0) [-N (H) CRz2C (0) ORy] [-OR11], and -P (O) ) [-OCH (V) CH2CH20-], wherein V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl.
128. 128. The compound according to claim 117, characterized in that G is selected from the group consisting of -0- and -CH2 ~; D is selected from the group consisting of a bond and -CH2-; A is selected from the group consisting of -NH-, -NMe-, -0-, and -S-; B is selected from the group consisting of -CH-, -CMe-, and -N-; R1 and R2 are each independently selected from the group consisting of halogen, C? -C4 / -CF3 alkyl, and cyano; R 4 is selected from the group consisting of hydrogen, halogen, -C 4 alkyl, cyano and CF 3; R5 is selected from the group consisting of -OH, -0C (0) Re, -0C (0) 0Rh, -F, and -NHC (0) Re; R3 is selected from the group consisting of halogen, optionally substituted Ci-Ce alkyl, -CF3, cyano, -C (0) NRfRg, (CRa2) optionally substituted naril, -S0NRfRg, and -S02Re; and X is selected from the group consisting of -P0H2, -P (0) [-0CRz20C (0) Ry] 2, -P (0) [-0CRz20C (0) 0Ry] 2, -P (0) [-N (H) CRZ2C (0) 0Ry] 2, -P (0) [-N (H) CRz2C (0) 0Ry] [-0R11], and -P (0) [-0CH (V) CH2CH20-], in where V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl.
129. 129. The compound according to claim 128, characterized in that G is selected from the group consisting of -0- and -CH2; D is selected from the group consisting of a bond and -CH2-; A is selected from the group consisting of -NH-, -NMe-, -0-, and -S-; B is selected from the group consisting of -CH-, -CMe- and -N-; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl, and cyano; R4 is selected from the group consisting of hydrogen and halogen; R5 is selected from the group consisting of -OH and -OC (0) Re; and R3 is selected from the group consisting of halogen, optionally substituted Ci-Cg alkyl, optionally substituted -CH2aryl, optionally substituted -CH (OH) aryl, -C (0) -amido, -S (= 0) 2-amido, wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-ethylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -S02Re wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, 4- fluorophenyl, and 4-pyridyl.
130. 130. The compound according to claim 129, characterized in that G is -0-; D is a link; A is selected from the group consisting of -NH- and -NMe-; B is selected from the group consisting of -CH- and -CMe-; R1 and R2 are each bromine; R4 is selected from the group consisting of hydrogen and iodine; R5 is -OH; and R3 is isopropyl.
131. 131. The compound according to claim 130 characterized in that X is selected from the group consisting of -P03H2, -P (0) [-OCH2OC (0) -t-butyl] 2, -P (0) [-OCH2OC ( 0) 0-i-propyl] 2, -P (0) [-N (H) CH (CH3) C (0) 0CH2CH3] 2, -P (0) [-N (H) C (CH3) 2C ( 0) OCH2CH3] 2, -P (0) [-N (H) CH (CH3) C (0) 0CH2CH3] [3,4-methylenedioxyphenyl], -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] [3,4-methylenedioxyphenyl], and -P (0) [-0CH (3-chlorophenyl) CH2CH20-].
132. 132. The compound according to claim 129 characterized in that G is -0-; D is a link; A is -0-; B is selected from the group consisting of -CH- and -CMe; R1 and R2 are each bromine; R4 is selected from the group consisting of hydrogen and iodine; R5 is -OH; and R3 is isoprolyl.
133. 133. The compound according to claim 132, characterized in that X is selected from the group consisting of -P03H2, -P (0) [-OCH2OC (0) -t-butyl] 2, -P (0) [- OCH2OC (0) 0-i-propyl] 2, -P (0) [-N (H) CH (CH3) C (0) 0CH2CH3] 2, -P (0) [- N (H) C (CH3) 2C (0) OCH2CH3] 2, -P (0) [-N (H) CH (CH3) C (0) 0CH2CH3] [3,4-methylenedioxyphenyl], -P (0) [-N (H) C (CH3 ) 2C (0) 0CH2CH3] [3,4-methylenedioxyphenyl], and -P (0) [-0CH (3-chlorophenyl) CH2CH20-].
134. 134. The compound according to any of claims 117, 128, 129, 131, and 133, characterized in that X is -P03H2.
135. 135. The method according to claim 83, characterized in that the phosphonic acid-containing compound is a compound of the Formula II: wherein: A is selected from the group consisting of -NRX-, -0-, and -S-; B is selected from the group consisting of -CRb-, and -N-; R 1 is selected from the group consisting of hydrogen, -C (0) C 1 -C 4 alkyl, C 1 -C 4 alkyl, and C 1 -C 4 aryl; R b is selected from the group consisting of hydrogen and optionally substituted C 1 -C 4 alkyl; G is selected from the group consisting of -0-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF-, -C (0) -, -CH (OH) -, -NH-, and -N (C 1 -C 4 alkyl) -; D is selected from the group consisting of a bond, - (CRa2) -, and -C (0) -; Each Ra is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl, halogen, -OH, optionally substituted 0-C 2 -C 4 alkyl, -0CF 3, -S-optionally substituted C 1 -C 4 alkyl, NRbRc, optionally substituted C2-C alkenyl, and optionally substituted C2-C4 alkynyl; with the proviso that when a Ra is linked to C through an atom 0, S, or N, then the other Ra links to the same C that is a hydrogen, or is bonded by means of a carbon atom; R1 and R2 are each independently selected from the group consisting of halogen, optionally substituted C?-C4 alkyl, optionally substituted -S-alkyl Cj.-C3, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, -CF3 , -0CF3, -O-C-C3 alkyl optionally substituted, and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, C2-C? Alkynyl? optionally substituted, - (CRa2) optionally substituted maryl, (CRa2) optionally substituted cycloalkyl, (CRa2) optionally substituted metheterocycloalkyl, -0Rd, SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRfRg, -C (0) NRfRg, -C (0) ORh, -C (0) Re, -N (Rb) C (0) Re, -N (R) C (0) NRfRg, -N ( Rb) S (= 0) 2Re, N (Rb) S (= 0) 2NRfRg, and -NRfRb; Each Rd is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2-C2 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted - (CRb2), optionally substituted - (CRb2) nCycloalkyl, - ( CRb2) optionally substituted n-heterocycloalkyl, and -C (0) NRfRg; Each Re is selected from the group consisting of optionally substituted C 1 -C 2 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted - (CRa 2) naryl, - (CR a 2) n optionally substituted Cycloalkyl, and (CRa2) optionally substituted n-heterocycloalkyl; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C2-C2 alkenyl, optionally substituted C2-C12 alkynyl, - (CRb2) optionally substituted naril, - (CRb2) optionally substituted cycloalkyl, and optionally substituted - (CRb2) nheterocycloalkyl, or Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second hetero group selected from the group consisting of 0, NRC, and S, wherein the ring optionally substituted heterocyclic may be substituted with 0-4 substituents selected from the group consisting of optionally substituted C? -C alkyl, -0R, oxo, cyano, -CF3, optionally substituted phenyl, and -C (0) 0Rh; Each Rh is selected from the group consisting of optionally substituted C?-C? 2 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 12 alkynyl, (CRb 2) optionally substituted naryl, - (CRb 2) n optionally substituted Cycloalkyl, and (CRb2) optionally substituted n-heterocycloalkyl; R5 is selected from the group consisting of -OH, -0-alkyl optionally substituted Ca-C6, -0C (0) Re, -OC (0) ORh, -F, -NHC (0) Re, -NHS (= 0 ) Re, -NHS (= 0) 2 Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); X is P (0) YR ^ Y'R11; And e 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are -0-, R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRz2, -NRZ-C (0) -R ?, -C (Rz) 2-0C (0) Ry, -C (Rz) 2-0 -C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; when Y and Y 'are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy, and cycloalkylene-C00Ry; when Y is -0- and Y 'is NRV, then R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains an optionally substituted carbonate or thiocarbonate, alkylaryl, -C (Rz) 20C (0) NRZ2, -NRZ-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz2) - 0-C (0) 0Ry, -C (Rz) 0C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2COORy, - [C (Rz) 2] qC (0) SRy , and -cycloalkylene-COORy; or when Y and Y 'are independently selected from -O- and -NRV-, then together R11 and R11 are -alkyl-S-S-alkyl to form a cyclic group, or together Ru and R11 are the group: wherein: V, W, and W are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and 1-alkynyl optionally substituted; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; ooj untos V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group at the beta and gamma position And linked to phosphorus; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and are connected by means of 3-5 additional atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHRzOH, -CHRzOC (0) Ry, -CHRzOC (S) Ry, -CHRz0C (S) ORy, -CHRzOC (O) SRy, CHRzOC02Ry, -ORz, -SRz, -CHRzN3, -CH2aryl, -CH (aryl) OH, -CH (CH = CRz2) 0H, -CH (C = CRz) OH, -Rz, -NRZ2, -0C0Ry, -OC02Ry, -SCORy, -SC02Ry, -NHCORz, - NHC02Ry, -CH2NHaril, - (CH2) q-ORz, and -i (CH2) q-SRz; q is an integer of 2 or 3; Each Rz is selected from the group consisting of Ry and -H; Each R? is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; Each Rx is independently selected from the group consisting of -H, and alkyl, or together Rx or Rx form a cyclic alkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the proviso that: a) V, Z, W, and W 'are not all -H; and b) when Z is -Rz, then at least one of V, W, and W is not -H, alkyl, aralkyl, or heterocycloalkyl. and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs.
136. 136. The method according to claim 100, characterized in that the phosphonic acid-containing compound is a compound of the Formula II: where: A is selected from the group consisting of -NRX-, -0-, and -S-; B is selected from the group consisting of -CRb-, and -N-; R 1 is selected from the group consisting of hydrogen, -C (0) C 1 -C 4 alkyl, C 1 -C alkyl, and C 1 -C 4 aryl; Rb is selected from the group consisting of hydrogen and optionally substituted C ?C alkyl; G is selected from the group consisting of -0-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF-, -C (0) -, -CH (OH) -, -NH-, and -N (C? -C alkyl) -; D is selected from the group consisting of a bond, - (CRa2) -, and -C (0) -; Each Ra is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl, halogen, -OH, optionally substituted 0 -C 2 -C 4 alkyl, -0CF 3, -S-optionally substituted C 1 -C 4 alkyl, -NRbRc optionally substituted C2-C4 alkenyl, and optionally substituted C2-C4 alkynyl; with the proviso that when a Ra is linked to C through an atom O, S, or N, then the other Ra links to the same C that is a hydrogen, or is bonded by means of a carbon atom; R1 and R2 are each independently selected from the group consisting of halogen, optionally substituted C? -C alkyl, optionally substituted -S? -C3 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, -CF3 , -OCF3, -O-C-C3 alkyl optionally substituted, and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, C2-C2 alkynyl. 2 optionally substituted, - (CRa2) optionally substituted maryl, - (CRa2) optionally substituted cycloalkyl, (CRa2) mheterocycloalkyl optionally substituted, -0Rd, SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRfRg, -C (0) NRfRg, -C (0) ORh, -C (0) Re, -N (Rb) C (0) Re, -N (Rb) C (0) NRfRg, - N (Rb) S (= 0) 2Re, N (Rb) S (= 0) 2NRfRg, and -NRfRg; Each Rd is selected from the group consisting of optionally substituted C 1 -C 2 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl, optionally substituted (CR 2) naryl, (CR 2) nCycloalkyl optionally substituted , - (CRb2) optionally substituted n-heterocycloalkyl, and C (0) NRfRg; Each Re is selected from the group consisting of optionally substituted? -C? Alkyl, optionally substituted C2-C? 2 alkenyl, optionally substituted C2-C? 2 alkynyl, optionally substituted (CRa2), optionally substituted (CRa2) n-cycloalkyl , and (CRa2) optionally substituted n-heterocycloalkyl; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, optionally substituted C2-C? 2 alkynyl, optionally substituted - (CR2) , - (CRb2) optionally substituted cycloalkyl, and - (CRb) optionally substituted n-heterocycloalkyl, or Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second hetero group selected from the group consisting of O, NRC, and S , wherein the optionally substituted heterocyclic ring can be substituted with 0-4 substituents selected from the group consisting of optionally substituted C? ~C alkyl, -ORb, oxo, cyano, -CF3, optionally substituted phenyl, and -C (0) ORh; Each Rh is selected from the group consisting of optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, optionally substituted C2-C? 2 alkynyl, optionally substituted (CRb2) naryl, optionally substituted (CRb2) n-cycloalkyl , and (CRb2) optionally substituted n-heterocycloalkyl; R5 is selected from the group consisting of -OH, -0-C-C6 alkyl optionally substituted, -0C (0) Re, -0C (0) 0Rh, -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2 Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); X is P (0) YRuY'Ra ?; Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are -0-, R linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRZ2, -NRz-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2-0- C (0) 0Ry, -C (RZ) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; when Y and Y 'are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy, and cycloalkylene-C00Ry; when Y is -0- and Y 'is NRV, then R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains an optionally substituted carbonate or thiocarbonate, alkylaryl, -C (Rz) 20C (0) NRZ2, -NRZ-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz2) - 0-C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-COORy, - C (Rx) 2COORy, - [C (Rz) 2] qC (0) SRy , and -cycloalkylene-COORy; or when Y and Y 'are independently selected from -0- and -NRV-, then together R11 and R11 are -alkyl-S-S-alkyl to form a cyclic group, or together R11 and R11 are the group: wherein: V, W, and W are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and 1-alkynyl optionally replaced; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group to the beta and gamma bound position to the Y to the match; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and W are connected by means of 3-5 additional atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHRzOH, -CHRzOC (0) Ry, -CHRzOC (S) Ry, -CHRzOC (S) 0Ry, -CHRzOC (O) SRy, CHRzOC02Ry, -0RZ, -SRZ, -CHRZN3, -CH2aryl, -CH (aryl) OH, CH (CH = CRz2) OH, -CH (C = CRz) OH, -RZ, -NRZ2, -OCORy, -OC02Ry, - SCORy, -SC02Ry, -NHCORz, -NHC02Ry , -CH2NHaril, - (CH2) q-ORz, and - (CH2) q-SRz; q is an integer of 2 or 3; Each Rz is selected from the group consisting of Ry and -H; Each R? is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; Each Rx is independently selected from the group consisting of -H, and alkyl, or together Rx or Rx form a cyclic alkyl group; Each R is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; a) V, Z, W, and W are not all -H; and b) when Z is -Rz, then at least one of V, W, and W is not -H, alkyl, aralkyl, or heterocycloalkyl. and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs.
137. 137. The method according to claim 135, characterized in that the metabolic disease is hypercholesterolemia.
138. 138. The method according to claim 135, characterized in that the metabolic disease is obesity.
139. 139. A compound of Formula III: characterized in that: G is selected from the group consisting of -O-, -S-, -S (= 0) -, -S (= 0) 2 ~, -CH2-, -CF2-, -CHF-, -C (O) -, -CH (OH) -, -NH-, and - (CC-) - alkyl-; T is selected from the group consisting of - (CRa2) k-, -CR = CRb- (CRa2) n, - (CRa2) n-CRb = CRb-, - (CRa2) -CRb = CRb- (CRa2) -, 0 (CRb2) (CRa2) n-, -S (CRb2) (CRa2) n-, -N (RC) (CRb2) (CRa2) n-, N (Rb) C (0) (CRa2) n-, - (CRa2) nCH (NRbRc) -, -C (O) (CR ^ -, (CRa2) mC (0) -, - (CRa2) C (0) (CRa2) n-, - (CRa2) nC0) (CRa2 ) -, and C (0) NH (CRb2) (CRa2) p-; k. is an integer from 0-4, m is an integer from 0-3 n is an integer from 0-2, p is an integer from 0-1, Each Ra is independently selected from the group consisting of hydrogen, alkyl C? - Optionally substituted C4, halogen, -OH, -O-C optionally substituted-C4 alkyl, -0CF3, -S-optionally substituted Cx-j alkyl, -NRbRc, optionally substituted C2-C4 alkenyl, and optionally substituted C2-C alkynyl; with the proviso that when a Ra is linked to C through an atom O, S, or N, then the other Ra links to the same C that is a hydrogen, or is bonded by means of a carbon atom; Each Rb is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 4 alkyl; Each Rc is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 4 alkyl, -C (O) -alternatively substituted C 1 -C 4 alkyl, and -C (0) H; R1 and R2 are each independently selected from the group consisting of halogen, optionally substituted C1-C4 alkyl, -S-optionally substituted C1-C3 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, -CF3, - OCF3, -O-C-C3 alkyl optionally substituted, and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, C2-C? Alkynyl? optionally substituted, - (CRa2) optionally substituted maryl, - (CRa2) optionally substituted cycloalkyl, (CRa2) optionally substituted metheterocycloalkyl, -ORd, -SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NHfRg, -C (0) NRfRg, -C (0) ORh, -C (0) Re, -N (Rb) C (0) Re, -N (Rb) C (O) NRfRg, - N (Rb) S (= 0) 2Re, N (Rb) S (= 0) 2NRfRg, and -NRfRg; Each Rd is selected from the group consisting of optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, optionally substituted C2-C? 2 alkynyl, optionally substituted - (CRb2) naril, - (CRb2) n optionally substituted cycloalkyl, - (CRb2) nheterocycloalkyl optionally substituted, and -C (0) NRfRg; Each Re is selected from the group consisting of optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted - (CR a 2) naryl, - (CR b 2) n Optionally substituted cycloalkyl, and ( CRa2) optionally substituted n-heterocycloalkyl; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C? -C? 2 alkyl, optionally substituted C? 2 alkenyl, optionally substituted C2-Ci2 alkynyl, - (CRb2) optionally substituted null, - (CRb2 optionally substituted cycloalkyl, and optionally substituted (CRb2) nheterocycloalkyl, or Rf and Rg together can form an optionally substituted heterocyclic ring, which may contain a second hetero group selected from the group consisting of 0, NRC, and S, wherein the ring optionally substituted heterocyclic may be substituted with 0-4 substituents selected from the group consisting of optionally substituted C1-C4 alkyl, -0Rb, oxo, cyano, -CF3, optionally substituted phenyl, and -C (0) 0Rh; Each Rh is selected from the group consisting of optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -Ci 2 alkynyl, optionally substituted - (CR 2) naryl, - (CR 2) n optionally substituted Cycloalkyl, and (CR 2) optionally substituted n-heterocycloalkyl; R5 is selected from the group consisting of -OH, - optionally substituted C6-C6alkyl, -OC (0) Re, -OC (0) ORh, -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2 Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); R7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, -0-C? -C4 alkyl, -SH and -S-C1-C4 alkyl; X is P IO YR ^ Y 'R11; Y and Y 'are each independently selected from the group consisting of -O-, and -NRV-; when Y and Y 'are -O-, R11 linked to -O- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 2OC (0) NRz2, -NRz-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (R2) 2-0- C (0) ORy, -C (Rz) 2OC (O) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; when Y and Y 'are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-COORy, -C (Rx) 2COORy, - [C (Rz) 2] qC (O) SRy, and cycloalkylene-COORy; when Y is -O- and Y 'is NRV, then R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRZ2, -NRZ-C (0) -Ry, -C (R2) 2-0C (0) Ry, -C (RZ) 2 -0-C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy and -cycloalkylene-COORy; or when Y and Y 'are independently selected from -0- and -NRV-, then together R11 and R11 are -alkyl-S-S-alkyl to form a cyclic group, or together R11 and R11 are the group: wherein: V, W, and W are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and 1-alkynyl optionally replaced; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group to the beta and gamma bound position to the Y to the phosphorus; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and are connected by means of 3-5 additional atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHRzOH, -CHRzOC (0) Ry, -CHRzOC (S) Ry, -CHRz0C (S) ORy, -CHRzOC (0) SRy, CHRz0C02Ry, -0RZ, -SRZ, -CHRZN3, -CH2aryl, -CH (aryl) OH, CH (CH = CRz2) 0H, -CH (C = CRZ) 0H, -RZ, -NRZ2, -0C0Ry, -0C02Ry, -SC0Ry, -SC02Ry, -NHC0Rz, -NHC02Ry, -CH2NHaril, - (CH2) q- 0Rz, and - (CH2) q-SRz; q is an integer of 2 or 3; Each Rz is selected from the group consisting of Ry and -H; Each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; Each Rx is independently selected from the group consisting of -H, and alkyl, or together Rx and Rx form a cyclic alkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the proviso that: -a) when G is -O-, T is -NH-CH2-, R1 and R2 are each chlorine, R3 is iso-propyl, R4 is hydrogen, R7 is fluorine, and R5 is - OH, then X is not P (O) (OH) 2, P (O) (OH) (OCH3) or P (O) (OCH3) 2; b) V, Z,, and W are not all -H; and c) when Z is -Rz, then at least one of V, W, and W is not -H, alkyl, aralkyl, or heterocycloalkyl; and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs.
140. 140. A compound of formula III: characterized in that: G is selected from the group consisting of -O-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF-, -C (O) -, -CH (OH) -, -NH-, and -N (C? -C alkyl) -; T is selected from the group consisting of - (CRa2) k-, -CR = CRb- (CRa2) n, - (CRa2) n-CRb = CRb-, - (CRa2) -CRb = CRb- (CRa2) -, 0 (CRb2) (CRa2) n-, -S (CRb2) (CRa2) n-, -N (Rc) (CRb2) (CRa2) n-, N (Rb) C (0) (CRa2) n-, - (CRa2) nCH (NRbRc) -, -C (O) (CRa2) m-, (CRa2) mC (0) -, - (CRa2) C (0) (CRa2) n-, - (CRa2) nCO) ( CRa2) -, and -C (0) NH (CRb2) (CRa2) p-; k is an integer from 0-4; m is an integer from 0-3; n is an integer from 0-2; p is an integer from 0-1; Each Ra is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl, halogen, -OH, -O-C 1 -C 4 alkyl optionally substituted, -0CF 3, -S-C 4 -C 4 alkyl optionally substituted, -NR b R c , optionally substituted C2-C4 alkenyl, and optionally substituted C2-C4 alkynyl; with the proviso that when a Ra is linked to C through an atom O, S, or N, then the other Ra links to the same C that is a hydrogen, or is bonded by means of a carbon atom; Each Rb is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 4 alkyl; Each Rc is independently selected from the group consisting of hydrogen and optionally substituted d-C4 alkyl, -C (O) -alternatively substituted C1-C4 alkyl, and -C (0) H; R1 and R2 are each independently selected from the group consisting of halogen, optionally substituted C3-C4 alkyl, -S-C3-C3 alkyl optionally substituted, C2-C4 alkenyl optionally substituted, C2-C4 alkynyl optionally substituted, -CF3, -0CF3, -O-C-C3 alkyl optionally substituted, and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted C?-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C ?2 alkynyl, - - (CRa2) optionally substituted maryl, - (CRa2) optionally substituted cycloalkyl, (CRa2) optionally substituted metheterocycloalkyl, -ORd, SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NHfRg, -C (0) NRfRg, -C (0) ORh, -C (0) Re, -N (Rb) C (0) Re, -N (Rb) C (0) NRfRg, -N (Rb) S (= 0) 2Re, N (Rb) S (= 0) 2NRfRg, and -NRfRg; Each Rd is selected from the group consisting of optionally substituted C 1 -C 2 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl, optionally substituted (CR 2) naryl, - (CR b 2) n cycloalkyl optionally substituted, (CRb2) optionally substituted n-heterocycloalkyl, and -C (0) NRfRg; Each Re is selected from the group consisting of optionally substituted C? ~C? Alquilo alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted (CRa 2) naryl, (CRb 2) n optionally substituted Cycloalkyl, and - (CRa2) optionally substituted n-heterocycloalkyl; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C? ~C? 2 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C -C? Alkynyl, optionally substituted (-) , - (CRb2) optionally substituted cycloalkyl, and - (CRb2) nheterocycloalkyl optionally substituted, or Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second hetero group selected from the group consisting of O, NRC, and S , wherein the optionally substituted heterocyclic ring can be substituted with 0-4 substituents selected from the group consisting of optionally substituted C? -C alkyl, -ORb, oxo, cyano, -CF, optionally substituted phenyl, and -C (0) ORh; Each Rh is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2-C2 alkenyl, optionally substituted C2-C2 alkynyl, optionally substituted (CRb2) naryl, optionally substituted - (CRb2) n-cycloalkyl, and - (CRb2) optionally substituted n-heterocycloalkyl; R5 is selected from the group consisting of -OH, - optionally substituted C6-C6alkyl, -OC (0) Re, -OC (0) ORh, -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2 Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); R7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, -O-C1-C4 alkyl, -SH and -S-C1-C4 alkyl; X is P (0) YR ^ Y'R11; Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are -0-, R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRz2, -NRz-C (0) -Ry, -C (RZ) 2-0C (0) Ry, -C (Rz) 2-0- C (0) 0Ry, -C (RZ) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; when Y and Y 'are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy, and cycloalkylene-C00Ry; when Y is -0- and Y 'is NRV, then R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRZ2, -NRZ-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2 -0-C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-COORy, - C (Rz) 2COORy, - [C (Rz) 2] qC (0) SRy and -cycloalkylene-COORy; or when Y and Y 'are independently selected from -0- and -NR-, then together R11 and R11 are -alkyl-S-S-alkyl to form a cyclic group, or together R11 and R11 are the group: wherein: V, W, and W are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and 1-alkynyl optionally replaced; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group to the beta and gamma bound position to the Y to the phosphorus; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and W are connected by means of 3-5 additional atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHRz0H, CHRzOC (0) Ry, -CHRzOC (S) Ry, -CHRz0C (S) ORy, -CHRz0C (O) SRY, CHRzOC02Ry, -ORz, -SRZ, -CHR2N3, ~ CH2aryl, -CH (aryl) OH, - CH (CH = CRz2) OH, -CH (C = CRz) OH, -Rz, -NRZ2, -OCORy, -OC02Ry, - SCORy, -SC02Ry, -NHCORz, -NHC02Ry , -CH2NHaril, - (CH2) q-ORz, and - (CH2) q-SRz; q is an integer of 2 or 3; Each Rz is selected from the group consisting of Ry and -H; Each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; Each Rx is independently selected from the group consisting of -H, and alkyl, or together Rx and Rx form a cyclic alkyl group; Each is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the proviso that: a) when G is selected from the group consisting of -O-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -C (O ) - and -NR-; T is -A-B- wherein A is selected from the group consisting of -NRb-, -O-, -CH2- and -S- and B is selected from the group consisting of a bond and substituted or unsubstituted C1-C3 alkyl; R 3 is selected from the group consisting of halogen, trifluoromethyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aryloxy, substituted amide, sulfone, sulfonamide and C 3 -C 7 cycloalkyl, wherein the aryl, heteroaryl or cycloalkyl rings are bonded or fused to the aromatic; R4 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R1 and R2 are each independently selected from the group consisting of halogen, substituted or unsubstituted C?-C4 alkyl, and substituted or unsubstituted C3-C5 cycloalkyl; R7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, -O-C C-C4 alkyl, -SH and -S-C?-C4 alkyl; and R5 is selected from the group consisting of hydroxyl, -O-Cg alkyl optionally substituted, and -OC (0) Re; then X is not -P (O) (OH) 2; b) V, Z, W, and W are not all -H; and c) when Z is -Rz, then at least one of V,, and W is not -H, alkyl, aralkyl, or heterocycloalkyl; and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs.
141. 141. The compound according to claim 139, characterized in that G is -O-, T is -NH-CH2-, R1 and R2 are each chlorine, R3 is iso-propyl, R7 is fluoro and R5 is -OH , then R4 is not hydrogen.
142. 142. The compound according to claim 140, characterized in that when G is selected from the group consisting of oxygen, sulfur, sulfoxide, sulfonyl, -CH2-, -C (0) - and -NRb-; T is -AB- where A is selected from the group consisting of -NRb-, -0-, -CH2- and -S- and B is selected from the group consisting of a bond and substituted or unsubstituted C?-C3 alkyl; R3 is selected from the group consisting of halogen, trifluoromethyl, substituted or unsubstituted Ci-Cß alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aryloxy, substituted amide, sulfone, sulfonamide and C3-C7 cycloalkyl, wherein the aryl, heteroaryl or cycloalkyl rings are linked or fused to the aromatic; R4 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted Ci-Cß alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R 1 and R 2 are each independently selected from the group consisting of halogen, substituted or unsubstituted C 1 -C 4 alkyl, and substituted and unsubstituted C 3 -C 5 cycloalkyl; and R7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, -O-C1-C4 alkyl, -SH and -S-C-C4 alkyl; then R5 is not hydroxyl, optionally substituted Ci-CdOalkyl, or -0C (0) Re.
143. 143. The compound according to claim 139, characterized in that G is selected from the group consisting of -O- and -CH2-.
144. 144. The compound according to claim 140, characterized in that G is selected from the group consisting of -O- "and -CH2-.
145. 145. The compound according to claim 139, characterized in that T is selected from the group consisting of - (CRa2) n-, -0 (CRb2) (CRa2) p-, -N (Rc) (CRb2) (CRa2) p-, - S (CRb2) ( CRa2) p-, -NRb (C0) -, and -CH2CH (NRcR) -.
146. 146. The compound in accordance with the claim 140, characterized in that T is selected from the group consisting of - (CRa2) n-, -0 (CRb2) (CRa2) p-, -N (Rc) (CRb2) (CRa2) p-, -S (CRb2) ( CRa2) p-, -NRb (C0) -, and -CH2CH (NRcRb) -.
147. 147. The compound according to claim 139, characterized in that R1 and R2 are the same and are selected from the group consisting of halogen, Ci-C4 alkyl, CF3, and cyano.
148. 148. The compound according to claim 140, characterized in that R1 and R2 are the same and are selected from the group consisting of halogen, C? -C4 alkyl, CF3, and cyano.
149. 149. The compound in accordance with the claim 139, characterized in that R1 and R2 are different and are selected from the group consisting of halogen, C -.- C, CF3, and cyano alkyl.
150. 150. The compound in accordance with the claim 140, characterized in that R1 and R2 are different and are selected from the group consisting of halogen, Ci-C4 alkyl, CF3, and cyano. ilf
151. 151. The compound according to claim 139, characterized in that R 4 is selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, cyano and CF 3.
152. 152. The compound according to claim 140, characterized in that R4 is selected from the group consisting of hydrogen, halogen, C? -C4 alkyl, cyano and CF3.
153. 153. The compound according to claim 139, characterized in that R5 is selected from the group consisting of -OH, -OC (0) Re, -0C (0) 0Rh, -F, and -NHC (0) Re.
154. 154. The compound according to claim 140, characterized in that R5 is selected from the group consisting of -OH, -OC (0) Re, -OC (0) ORh, -F, and -NHC (0) Re.
155. 155. The compound in accordance with the claim 139, characterized in that R3 is selected from the group consisting of halogen, optionally substituted Ci-Ce alkyl, CF3, cyano, -C (0) NRfRg, - (CRa2) optionally substituted naril, -S02NRfRg and -S02Re.
156. 156. The compound in accordance with the claim 140, characterized in that R3 is selected from the group consisting of halogen, optionally substituted Ci-Cß alkyl, CF3, cyano, -C (0) NRfRg, - (CRa2) optionally substituted naril, -S02NRfRg and -S02Re.
157. 157. The compound according to claim 139, characterized in that X is selected from the group consisting of -P03H2, -P (0) [-OCRz2OC (O) Ry] 2, -P (0) [- OCRz2OC (O) 0Ry] 2, ~ P (O) [-N (H) CRz2C (O) 0Ry] 2, -P (O) [- N (H) CRz2C (0) ORy] [-0R11] and -P (O) [-OCH (V) CH2CH20-], wherein V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl.
158. 158. The compound according to claim 140, characterized in that X is selected from the group consisting of -P03H2, -P (O) [-OCRz2OC (0) Ry] 2, -P (0) [- 0CRz20C (0) 0Ry] 2, -P (0) [-N (H) CRZ2C (0) 0Ry] 2, -P (0) [-N (H) CRz2C (0) 0Ry] [-0R11] and -P (0) [-0CH (V) CH2CH20-], wherein V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl.
159. 159. The compound according to claim 139, characterized in that R7 is selected from the group consisting of hydrogen, fluoro, chloro, amino, hydroxyl and -0-CH3.
160. 160. The compound according to claim 140, characterized in that R7 is selected from the group consisting of hydrogen, fluoro, chloro, amino, hydroxyl and -0-CH3.
161. 161. The compound according to claim 139, characterized in that T is selected from the group consisting of - (CRa2) n-, -0 (CRb2) (CRa2) p-, -N (Rc) (CRb2) (CRa2) p-, -S (CRb2) (CRa2) p-, -NRb (C0) -, and -CH2CH (NRcRb) -; R1 and R2 are each independently selected from the group consisting of halogen, -C1-C4 alkyl, -CF3 and cyano; R 4 is selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, cyano and CF 3; R5 is selected from the group consisting of -OH, -OC (0) Re, -0C (0) 0Rh, -F, and -NHC (0) Re; R3 is selected from the group consisting of halogen, optionally substituted C-β alkyl, CF3, cyano, -C (0) NRfRg, (CRa2) optionally substituted naril, -S02NRfRg and -S02Re; R7 is selected from the group consisting of hydrogen, fluoro, chloro, amino, hydroxyl and -0-CH; and X is selected from the group consisting of -P03H2, -P (O) [-0CRz20C (O) R?] 2, -P (O) [-OCRz2OC (0) ORy] 2, -P (0) [- N (H) CRz2C (0) OR?] 2, -P (0) [-N (H) CRz2C (0) ORy] [-OR11] and -P (O) [-OCH (V) CH2CH20-], wherein V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl.
162. 162. The compound according to claim 161, characterized in that when G is -O-, T is -CH2-, R1 and R2 are chlorine, R3 is iso-propyl, R7 is fluoro and R5 is -OH, then R4 is not It is hydrogen.
163. 163. The compound according to claim 140, characterized in that G is selected from the group consisting of -O- and -CH2-; T is selected from the group consisting of - (CRa2) n-, -0 (CRb2) (CRa2) p-, -N (Rc) (CRb2) (CRa2) p-, -S (CRb2) (CRa2) p- , -NRb (CO) -, and -CH2CH (NRcRb) -; R1 and R2 are each independently selected from the group consisting of halogen, -C? -C4 alkyl, -CF3 and cyano; R 4 is selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, cyano and CF 3; R5 is selected from the group consisting of -OH, -OC (0) Re, -OC (0) ORb, -F, and -NHC (0) Re; R3 is selected from the group consisting of halogen, optionally substituted Ci-Ce alkyl, CF3, cyano, -C (0) NRfRg, - (CRa2) optionally substituted naril, -S02NRfRg and -S02Re; R7 is selected from the group consisting of hydrogen, fluoro, chloro, amino, hydroxyl and -0-CH3; and X is selected from the group consisting of -P03H2, -P (O) [-OCRz2OC (0) Ry] 2, -P (O) [-OCRz2OC (O) ORy] 2, P (O) [-N ( H) CRz2C (0) ORy] 2, -P (O) [-N (H) CRZ2C (O) ORy] [-OR11] and P (O) [-OCH (V) CH2CH20-], wherein V is selects from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl.
164. 164. The compound according to claim 163, characterized in that G is selected from the group consisting of -O- and -CH2-; T is -AB- wherein A is selected from the group consisting of -NRb-, -O-, -CH2- and -S- and B are selected from the group consisting of a bond and substituted or unsubstituted C?-C3 alkyl; R 3 is selected from the group consisting of halogen, trifluoromethyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aryloxy, substituted amide, sulfone, sulfonamide and C 3 -C 7 cycloalkyl, wherein the aryl, heteroaryl or cycloalkyl rings are bonded or fused to the aromatic; R 4 is selected from the group consisting of hydrogen, halogen and substituted or unsubstituted C 1 -C 4 alkyl; R1 and R2 are each independently selected from the group consisting of halogen and substituted or unsubstituted C1-C4 alkyl; and R7 is selected from the group consisting of hydrogen, fluoro, chloro, amino, hydroxyl and -0-CH3; then R5 is not hydroxyl, -0 optionally substituted C6-C6 alkyl or -0C (0) Re.
165. 165. The compound according to claim 161, characterized in that T is -N (H) C (0) -; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl and cyano; R4 is selected from the group consisting of hydrogen and iodine; R5 is selected from the group consisting of -OH and -0C (0) Re; R 3 is selected from the group consisting of iodine, bromine, optionally substituted C 1 -C 6 alkyl, optionally substituted -CH 2 aryl, optionally substituted aryl CH (OH), -C (0) -amido, -S (= 0) -amido, wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperzinyl, morpholinyl, cyclohexylamino, anilinyl and indolyl and -S02Re wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl and 4-pyridyl; and R7 is selected from the group consisting of hydrogen and fluoro.
166. 166. The compound according to claim 165, characterized in that G is -0-; R1 and R2 are each chlorine; R4 is hydrogen; R5 is -OH; R7 is fluoro; and R3 is iso-propyl.
167. 167. The compound in accordance with the claim 166, characterized in that X is selected from the group consisting of -P03H2, -P (0) [-OCH2OC (0) -t-butyl] 2, -P (0) [- 0CH20C (0) 0-i-propyl] 2, -P (0) [-N (H) CH (CH3) C (0) OCH2CH3] 2, -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] 2, -P (0) [-N (H) CH (CH3) C (0) 0CH2CH3] [3, 4-methylenedioxyphenyl], -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] [3 , 4-ethylenedioxyphenyl], and -P (0) [-0CH (3-chlorophenyl) CH2CH20-].
168. 168. The compound according to claim 161, characterized in that T is -0CH2-; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl and cyano; R4 is selected from the group consisting of hydrogen and iodine; R5 is selected from the group consisting of -OH and -0C (0) Re; R 3 is selected from the group consisting of iodine, bromine, optionally substituted C 1 -C 6 alkyl, optionally substituted -CH 2 aryl, optionally substituted aryl CH (OH), -C (0) -amido, -S (= 0) 2-a gone, wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperzinyl, morpholinyl, cyclohexylamino, anilinyl and indolinyl and -S02Re wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, 4- fluorophenyl and 4-pyridyl; and R7 is selected from the group consisting of hydrogen and fluoro.
169. 169. The compound according to claim 168, characterized in that G is -0-; R1 and R2 are each chlorine; R4 is hydrogen; R7 is fluoro; R5 is -OH; and R3 is iso-propyl.
170. 170. The compound in accordance with the claim 169, characterized in that X is selected from the group consisting of -P03H2, -P (O) [-OCH2OC (O) -t-butyl] 2, -P (0) [-OCH2OC (0) 0-i-propyl] 2, -P (0) [-N (H) CH (CH3) C (0) 0CH2CH3] 2, -P (0) [-N (H) C (CH3) 2C (0) 0CH2CH3] 2, -P (0) [-N (H) CH (CH3) C (0) 0CH2CH3] [3,4-ethylenedioxyphenyl], -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] [3 , 4-methylenedioxyphenyl], and -P (0) [-0CH (3-chlorophenyl) CH2CH20-].
171. 171. The compound according to claim 161, characterized in that T is -CH2-; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl and cyano; R4 is selected from the group consisting of hydrogen and iodine; R5 is selected from the group consisting of -OH and -0C (0) Re; R 3 is selected from the group consisting of iodine, bromine, optionally substituted C 1 -C 6 alkyl, optionally substituted -CH 2 aryl, optionally substituted aryl CH (OH), -C (0) -amido, -S (= 0) 2-amido , wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperzinyl, morpholinyl, cyclohexylamino, anilinyl and indolinyl and -S02Re wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl and 4-pyridyl; and R7 is selected from the group consisting of hydrogen and fluoro.
172. 172. The compound according to claim 171, characterized in that G is -0-; R1 and R2 are each chlorine; R4 is hydrogen; R7 is fluoro; R5 is -OH; and R3 is iso-propyl.
173. 173. The compound in accordance with the claim 172, characterized in that X is selected from the group consisting of ~ P03H2, -P (0) [-OCH2OC (0) -t-butyl] 2, -P (0) [- 0CH20C (0) 0-i-propyl] 2, -P (0) [-N (H) CH (CH3) C (0) OCH2CH3] 2, -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] 2, -P (0) [-N (H) CH (CH3) C (O) OCH2CH3] [3,4-methylenedioxyphenyl], -P (0) [-N (H) C (CH3) 2C (0) 0CH2CH3] [3 , 4-methylenedioxyphenyl], and -P (0) [-0CH (3-chlorophenyl) CH2CH20-].
174. 174. The compound according to claim 161, characterized in that T is -CH2CH2-; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl and cyano; R4 is selected from the group consisting of hydrogen and iodine; R5 is selected from the group consisting of -OH and -0C (0) Re; R 3 is selected from the group consisting of iodine, bromine, optionally substituted C 1 -C 6 alkyl, optionally substituted -CH 2 aryl, optionally substituted aryl CH (OH), -C (0) -amido, -S (= 0) 2-amido , wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperzinyl, morpholinyl, cyclohexylamino, anilinyl and indolinyl and -S02Re wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl and 4-pyridyl; and R7 is selected from the group consisting of hydrogen and fluoro.
175. 175. The compound according to claim 174, characterized in that G is -0-; R1 and R2 are each chlorine; R4 is hydrogen; R7 is fluoro; R5 is -OH; and R3 is iso-propyl.
176. 176. The compound in accordance with the claim 175, characterized in that X is selected from the group consisting of ~ P03H2, -P (0) [-OCH2OC (0) -t-butyl] 2, -P (0) [- 0CH20C (0) 0-i-propyl] 2, -P (0) [-N (H) CH (CH3) C (0) OCH2CH3] 2, -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] 2, -P (0) [-N (H) CH (CH3) C (0) 0CH2CH3] [3,4-methylenedioxyphenyl], -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] [3 , 4-methylenedioxyphenyl], and -P (0) [-0CH (3-chlorophenyl) CH2CH20-].
177. 177. The compound according to claim 161, characterized in that T is -NHCH2-; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl and cyano; R4 is selected from the group consisting of hydrogen and iodine; R5 is selected from the group consisting of -OH and -0C (0) Re; R 3 is selected from the group consisting of iodine, bromine, optionally substituted C 1 -C 6 alkyl, optionally substituted -CH 2 aryl, optionally substituted aryl CH (OH), -C (0) -amido, -S (= 0) 2-amido , wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperzinyl, morpholinyl, cyclohexylamino, anilinyl and indolinyl and -S02Re wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl and 4-pyridyl; and R7 is selected from the group consisting of hydrogen and fluoro.
178. 178. The compound according to claim 177, characterized in that G is -0-; R1 and R2 are each chlorine; R7 is fluoro; R5 is -OH; and R3 is iso-propyl, then R4 is not hydrogen.
179. 179. The compound according to claim 177, characterized in that G is -0-; R1 and R2 are each bromine; R4 is hydrogen; R7 is fluoro; R5 is -OH; and R3 is iso-propyl.
180. 180. The compound according to claim 179, characterized in that X is selected from the group consisting of -P03H2, -P (O) [-OCH2OC (O) -t-butyl] 2, -P (0) [- OCH2OC (O) Oi-propyl] 2, -P (O) [-N (H) CH (CH3) C (O) OCH2CH3] 2, -P (O) [-N (H) C (CH3) 2C (O ) OCH2CH3] 2, -P (O) [-N (H) CH (CH3) C (O) OCH2CH3] [3,4-methylenedioxyphenyl], -P (O) [-N (H) C (CH3) 2C (O) OCH2CH3] [3,4-methylenedioxyphenyl], and -P (O) [-OCH (3-chlorophenyl) CH2CH20-].
181. 181. The compound according to claim 163, characterized in that T is -N (H) C (0) -; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl and cyano; R4 is selected from the group consisting of hydrogen and iodine; R5 is selected from the group consisting of -OH and -OC (0) Re; R3 is selected from the group consisting of iodine, bromine, optionally substituted Ci-Ce alkyl, optionally substituted -CH2aryl, CH (OH) optionally substituted aryl, -C (O) -amido, -S (= 0) 2-amido, wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperzinyl, morpholinyl, cyclohexylamino, anilinyl and indolinyl and -S02Re wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl and 4-pyridyl; and R7 is selected from the group consisting of hydrogen and fluoro.
182. 182. The compound according to claim 181, characterized in that G is -0-; R1 and R2 are each chlorine; R7 is fluoro; R4 is hydrogen; R5 is -OH; and R3 is iso-propyl.
183. 183. The compound according to claim 181, characterized in that X is selected from the group consisting of -P03H2, -P (0) [-OCH2OC (0) -t-butyl] 2, -P (0) [- 0CH20C (0) 0-i-propyl] 2, -P (0) [-N (H) CH (CH3) C (0) 0CH2CH3] 2, -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] 2, -P (0) [-N (H) CH (CH3) C (0) 0CH2CH3] [3,4-methylenedioxyphenyl], -P (0) [-N (H) C (CH3 ) 2C (0) OCH2CH3] [3, 4-methylenedioxyphenyl], and -P (0) [-0CH (3-chlorophenyl) CH2CH20-].
184. 184. The compound according to claim 163, characterized in that T is -0CH2-; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl and cyano; R4 is selected from the group consisting of hydrogen and iodine; R5 is selected from the group consisting of -OH and -0C (0) Re; R 3 is selected from the group consisting of iodine, bromine, optionally substituted C 1 -C 6 alkyl, optionally substituted -CH 2 aryl, CH (OH) optionally substituted aryl, -C (0) -amido, -S (= 0) 2-amido, wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperzinyl, morpholinyl, cyclohexyl , anilinyl and indolinyl and -S02Re wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl and 4-pyridyl; and R7 is selected from the group consisting of hydrogen and fluoro.
185. 185. The compound according to claim 184, characterized in that G is -0-; R1 and R2 are each chlorine; R4 is hydrogen; R7 is fluoro; R5 is -OH; and R3 is iso-propyl.
186. 186. The compound according to claim 184, characterized in that X is selected from the group consisting of -P03H2, -P (0) [-OCH2OC (0) -t-butyl] 2, -P (0) [- 0CH20C (0) 0-i-? Ropil] 2, -P (0) [-N (H) CH (CH3) C (0) 0CH2CH3] 2, -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] 2, -P (0) [-N (H) CH (CH3) C (0) OCH2CH3] [3,4-methylenedioxyphenyl], -P (0) [-N (H) C ( CH3) 2C (0) OCH2CH3] [3,4-methylenedioxyphenyl], and -P (0) [-0CH (3-chlorophenyl) CH2CH20-].
187. 187. The compound according to claim 163, characterized in that T is -CH2-; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl and cyano; R4 is selected from the group consisting of hydrogen and iodine; R5 is selected from the group consisting of -OH and -0C (0) Re; R 3 is selected from the group consisting of iodine, bromine, optionally substituted C 1 -C 6 alkyl, optionally substituted -CH 2 aryl, CH (OH) optionally substituted aryl, -C (0) -amido, -S (= 0) 2-amido, wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperzinyl, morpholinyl, cyclohexylamino, anilinyl and indolinyl and -S02Re wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl and 4-pyridyl; and R7 is selected from the group consisting of hydrogen and fluoro.
188. 188. The compound according to claim 187, characterized in that G is -0-; R1 and R2 are each chlorine; R7 is fluoro; R4 is hydrogen; R5 is -OH; and R3 is i-propyl.
189. 189. The compound according to claim 187, characterized in that X is selected from the group consisting of -P03H2, -P (O) [-OCH2OC (O) -t-butyl] 2, -P (0) [- OCH2OC (0) 0-i-propyl] 2, -P (O) [-N (H) CH (CH3) C (O) OCH2CH3] 2, -P (0) [- N (H) C (CH3) 2C (0) OCH2CH3] 2, -P (O) [-N (H) CH (CH3) C (O) OCH2CH3] [3,4-methylenedioxyphenyl], -P (O) [-N (H) C (CH3 ) 2C (O) OCH2CH3] [3,4-methylenedioxyphenyl], and -P (O) [-OCH (3-chlorophenyl) CH2CH20-].
190. 190. The compound according to claim 163, characterized in that T is -CH2CH2-; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl, and cyano; R4 is selected from the group consisting of hydrogen and iodine; R5 is selected from the group consisting of -OH and -0C (0) Re; R3 is selected from the group consisting of iodine, bromine, optionally substituted Ci-Cg alkyl, optionally substituted -CH2aryl, optionally substituted aryl CH (OH), -C (O) -amido, -S (= 0) 2-amido, wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperizinyl, morpholinyl , cuclohexylamino, anilinyl, and indolinyl, wherein the amido group is selected from the group consisting of phenylamino, piperidinyl, 4-methylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -S02Re wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, and 4-pyridyl; and R7 is selected from the group consisting of hydrogen and fluoro.
191. 191. The compound according to claim 190, characterized in that G is -0-; T is -CH2CH2-; R1 and R2 are each chlorine; R4 is hydrogen; R7 is fluoro; R5 is -OH; and R3 is iso-propyl.
192. 192. The compound according to claim 190, characterized in that X is selected from the group consisting of -P03H2, -P (O) [-OCH2OC (O) -t-butyl] 2, -P (0) [-OCH2OC (O) 0-i-propyl] 2 , -P (O) [-N (H) CH (CH3) C (0) 0CH2CH3] 2, -P (O) [-N (H) C (CH3) 2C (O) OCH2CH3] 2, -P ( O) [-N (H) CH (CH3) C (O) OCH2CH3] [3,4-methylenedioxyphenyl], -P (O) [-N (H) C (CH3) 2C (O) OCH2CH3] [3, 4-methylenedioxyphenyl], and -P (O) [-0CH (3-chlorophenyl) CH2CH20-].
193. 193. The compound according to claim 163, characterized in that T is -NHCH2-; R1 and R2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl, and cyano; R4 is selected from the group consisting of hydrogen and iodine; R5 is selected from the group consisting of -OH, and -OC (0) Re; R 3 is selected from the group consisting of iodine, bromine, optionally substituted C 1 -C 6 alkyl, optionally substituted -CH 2 aryl, optionally substituted -CH (OH) aryl, C (0) -amido, -S (= 0) 2-amido , wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -S02Re wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, -fluorophenyl, and 4-pyridyl; and R7 is selected from the group consisting of hydrogen and fluoro.
194. 194. The compound according to claim 193, characterized in that G is -0-; R1 and R2 are each chlorine; R7 is fluoro; R5 is -OH; and R3 is isopropyl, then R4 is not hydrogen.
195. 195. The compound according to claim 193, characterized in that G is -0-; R1 and R2 are each bromine; R4 is hydrogen; R7 is fluoro; R5 is -OH; and R3 is isopropyl.
196. 196. The compound according to claim 195, characterized in that X is selected from the group consisting of -P03H2, -P (O) [-0CH20C (0) -t-butyl] 2, -P (0) [- OCH2OC (0) 0-i-propyl] 2, -P (0) [-N (H) CH (CH3) C (0) OCH2CH3] 2, -P (0) [-N (H) C (CH3) 2C (0) 0CH2CH3] 2, -P (0) [-N (H) CH (CH3) C (0) 0CH2CH3] [3,4-methylenedioxyphenyl], -P (0) [-N (H) C (CH3 ) 2C (0) OCH2CH3] [3, 4-methylenedioxyphenyl], and -P (O) [-OCH (3-chlorophenyl) CH2CH20-].
197. 197. The compound according to any of claims 139, 140, 141, 142, 161, 163, 165, 167, 168, 170, 171, 173, 174, 176, 177, 180, 181, 183, 184, 186 , 187, 189, 190, or 193, characterized in that X is -P03H2.
198. 198. The method according to claim 83, characterized in that the phosphonic acid-containing compound is a compound of Formula III: wherein: G is selected from the group consisting of -O-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF-, -C (O) -, -CH (OH) -, -NH-, and -N (C? -C alkyl) -; T is selected from the group consisting of ~ (CRa2) k-, -CR = CRb- (CRa2) n, - (CRa2) n-CRb = CRb-, - (CRa2) -CRb = CRb- (CRa2) -, 0 (CRb2) (CRa2) n-, -S (CRb2) (CRa2) n-, -N (Rc) (CRb2) (CRa2) n-, N (Rb) C (0) (CRa2) n-, - (CRa2) nCH (NRbRc) -, -C (O) (CRa2) m-, (CRa2) mC (0) -, - (CRa2) C (0) (CRa2) n-, - (CRa2) nCO) (CRa2) -, and C (0) NH (CRb2) (CRa2) p-; k is an integer from 0-4; m is an integer from 0-3; n is an integer from 0-2; p is an integer from 0-1; Each Ra is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl, halogen, -OH, -O-C 1 -C 4 alkyl optionally substituted, -OCF 3, -S-C 1 -C 4 alkyl optionally substituted, -NR b R c, optionally substituted C2-C4 alkenyl, and optionally substituted C2-C alkynyl; with the proviso that when a Ra is linked to C through an atom 0, S, or N, then the other Ra links to the same C is a hydrogen, or is bonded by means of a carbon atom; Each Rb is independently selected from the group consisting of hydrogen and optionally substituted Cx-C alkyl; Each Rc is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 4 alkyl, -C (O) -alkyl C 1 -C 4 optionally substituted, and -C (0) H; R1 and R2 are each independently selected from the group consisting of halogen, optionally substituted C1-C4 alkyl, -S-optionally substituted C1-C3 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C alkynyl, -CF3, - OCF 3, -O-C 1 -C 3 alkyl optionally substituted, and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -0CF, cyano, optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, optionally substituted C2-C12 alkynyl , - (CRa2) optionally substituted maryl, (CRa2) optionally substituted cycloalkyl, (CRa2) optionally substituted metheterocycloalkyl, -0Rd, SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NHfRg, -C (0) NRfRg, -C (0) ORh, -C (0) Re, -N (Rb) C (0) Re, -N (Rb) C (0) NRfRg, -N (Rb) S (= 0) 2Re, N (Rb) S (= 0) 2NRfRg, and -NRfRg; Each Rd is selected from the group consisting of optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, optionally substituted C2-C1 alkynyl, optionally substituted (CRb2) naryl, ~ (CRb2) n cycloalkyl optionally substituted, - (CRb2) optionally substituted n-heterocycloalkyl, and -C (0) NRfRg; Each Re is selected from the group consisting of optionally substituted C? ~C? Alquilo alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted (CRa 2) naryl, (CRb 2) n optionally substituted Cycloalkyl, and (CR2) optionally substituted n-heterocycloalkyl; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C1-C12 alkyl, C2-C alkenyl? optionally substituted, optionally substituted C2-C2 alkynyl, optionally substituted - (CRb2) naryl, optionally substituted - (CRb2) n-cycloalkyl, and optionally substituted - (CRb2) nheterocycloalkyl, or Rf and Rg together can form an optionally substituted heterocyclic ring, which may contain a second heterogroup selected from the group consisting of 0, NRC, and S, wherein the optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting of optionally substituted C 1 -C 4 alkyl, -ORb, oxo, cyano, -CF3, optionally substituted phenyl, and -C (0) 0Rh; Each Rh is selected from the group consisting of optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 2 alkynyl, optionally substituted - (CR 2) naryl, - (CR 2) n optionally substituted Cycloalkyl, and - (CRb2) optionally substituted n-heterocycloalkyl; R5 is selected from the group consisting of -OH, optionally substituted Cx-C6alkyl, -OC (0) Re, -OC (0) ORh, -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2 Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); R7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, -O-C1-C4 alkyl, -SH and -S-C1-C4 alkyl; X is P (0) YR1: LY'R1: L; Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are -0-, R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRZ2, -NRZ-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2-0- C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; when Y and Y 'are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy, and cycloalkylene-COORy; when Y is -0- and Y 'is NRV, then R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRZ2, -NRZ-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2 -0-C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, - C (Rz) 2COORy, - [C (Rz) 2] qC (0) SRy and -cycloalkylene-COORy; or when Y and Y 'are independently selected from -0- and -NRV-, then together R11 and R11 are -alkyl-S-S-alkyl to form a cyclic group, or together R11 and R11 are the group: wherein: V,, and W are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-alkynyl; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group to the beta and gamma position Y linked to phosphorus; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and W are connected by means of 3-5 additional atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or heteroaryl replaced; or together W and W are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHRzOH, CHRzOC (0) Ry, -CHRzOC (S) Ry, -CHRzOC (S) ORy, -CHRzOC (O) SRy, CHRzOC02Ry, -ORz, -SRZ, -CHRZN3, - CH2aryl, -CH (aryl) OH, -CH (CH = CRz2) 0H, -CH (C = CRz) 0H, -Rz, -NRZ2, -OCORy, -OC02Ry, -SCORy, -SC02Ry, -NHCORz, -NHC02Ry , -CH2NHaril, - (CH2) q-0Rz, and - (CH2) q-SRz; q is an integer of 2 or 3; Each Rz is selected from the group consisting of Ry and -H; Each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; Each Rx is independently selected from the group consisting of -H, and alkyl, or together W and W form a cyclic alkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the proviso that: a) when G is -O-, T is -NH-CH2-, R1 and R2 are each chlorine, R3 is iso-propyl, R4 is hydrogen, R7 is fluorine, and R5 is -OH , then X is not P (0) (OH) 2, P (O) (OH) (OCH3) or P (O) (OCH3) 2; b) V, Z,, and W are not all -H; and c) when Z is -Rz, then at least one of V, W, and W is not -H, alkyl, aralkyl, or heterocycloalkyl; and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs.
199. 199. The method according to claim 83, characterized in that the compound containing phosphonic acid is a compound of Formula III: wherein: G is selected from the group consisting of -0-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF-, -C (0) -, -CH (OH) -, -NH-, and -N (C 1 -C 4 alkyl) -; T is selected from the group consisting of - (CRa2) k ~, -CR = CRb- (CRa2) n, - (CRa2) n-CRb = CRb-, - (CRa2) -CRb = CRb- (CRa2) -, 0 (CRb2) (CRa2) n-, -S (CRb2) (CRa2) n-, -N (Rc) (CRb2) (CRa2) n-, N (R) C (0) (CRa2) n-, - (CRa2) nCH (NRbRc) -, -C (0) (CRa2) m-, (CRa2) mC (0) -, - (CRa2) C (0) (CRa2) n-, - (CRa2) nC (0 ) (CRa2) -, and -C (0) NH (CRb2) (Ra2) p-; k is an integer from 0-4; m is an integer from 0-3; n is an integer from 0-2; p is an integer from 0-1; Each Ra is independently selected from the group consisting of hydrogen, optionally substituted C1-C4 alkyl, halogen, -OH, -O-C optionally substituted alkyl, -OCF3, -S-optionally substituted C1-C4 alkyl, -NRbRc , optionally substituted C2-C4 alkenyl, and optionally substituted C2-C4 alkynyl; with the proviso that when an R is linked to C through an atom 0, S, or N, then the other Ra binds to the same C that is a hydrogen, or is bonded by means of a carbon atom; Each Rb is independently selected from the group consisting of hydrogen and optionally substituted C? -C alkyl; Each Rc is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl, -C (0) - optionally substituted C 1 -C 4 alkyl, and -C (0) H; R1 and R2 are each independently selected from the group consisting of halogen, optionally substituted C1-C4 alkyl, -S-optionally substituted C1-C3 alkyl, optionally substituted C2-C alkenyl, optionally substituted C2-C4 alkynyl, -CF3, - 0CF3, -O-C1-C3 alkyl optionally substituted, and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -0CF3, cyano, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, - (CRa) optionally substituted maryl, - (CRa2) optionally substituted cycloalkyl, (CRa2) optionally substituted -heterocycloalkyl, -0Rd, -SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRfRg, -C (0) NRfRg, -C (0) 0Rh , - C (0) Re, -N (Rb) C (0) Re, -N (Rb) C (0) NRfRg, -N (Rb) S (= 0) 2Re, N (Rb) S (= 0 ) 2NRfRg, and -NRfRg; Each Rd is selected from the group consisting of optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted (CRb2), optionally substituted (CRb2) nCycloalkyl, (CRb2) optionally substituted n-heterocycloalkyl, and C (0) NRfRg; Each Re is optionally substituted C? -C? 2 alkyl, optionally substituted C2-C1 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted - (CRb2) naril, optionally substituted - (CRb2) n-cycloalkyl, and - (CRb2) nheterocycloalkyl optionally replaced; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C? -C? 2 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C? 2 alkynyl, optionally substituted - (CRb2) naril, - (CRb2) optionally substituted cycloalkyl, and optionally substituted - (CR2) nheterocycloalkyl, or Rf and Rg together can form an optionally substituted heterocyclic ring, which may contain a second hetero group selected from the group of O, NRC, and S, wherein the optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting of optionally substituted C? ~C alkyl, -ORb, oxo, cyano, -CF3, optionally substituted phenyl, and -C (0) ORh; Each Rh is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2-C2 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted (CRb2), optionally substituted (CRb2) nCycloalkyl, and (CRb2) nheterocycloalkyl; R5 is selected from the group consisting of -OH, -O-C6 alkyl optionally substituted, -OC (0) Re, -OC (0) ORh, -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2 Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); R7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, -O-C1-C4 alkyl, -SH and -S-C-C4 alkyl; X is P (0) YRuY'Ru; Y and Y 'are each independently selected from the group consisting of -O-, and -NRV ~; when Y and Y 'are -O-, R11 linked to -O- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 2OC (O) NRz2, -NRz-C (0) -Ry, -C (Rz) 2-OC (0) Ry, -C (Rz) 2-0- C (0) ORy, -C (Rz) 2OC (O) SRy, -alkyl-SC (O) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; when Y and Y 'are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-COORy, -C (Rx) 2COORy, - [C (Rz) 2] qC (0) SRy, and cycloalkylene-COORy; When Y is -0- and Y 'is NRV, then R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRZ2, -NRZ-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2 -0-C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy , and -cycloalkylene-C00Ry; or when Y and Y 'are independently selected from -0- and NRV, then R11 and R11 together are -alkyl-S-S-alkyl to form a cyclic group, or together R11 and R11 are the group: wherein: V,, and W are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-alkynyl; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group at the beta and gamma position And linked to phosphorus; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and are connected by means of 3-5 additional atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHRzOH, CHRzOC (0) Ry, -CHRz0C (S) Ry, -CHRz0C (S) ORy, -CHRz0C (O) SRy, CHRzOC02Ry, -0RZ, -SRZ, -CHRZN3, - CH2aryl, -CH (aryl) OH, CH (CH = CRz2) OH, -CH (C = CRz) OH, -Rz, -NRZ2, -OCORy, -OC02Ry, -SCORy, -SC02Ry, -NHCOR \ -NHC02Ry, -CH2NHaril, - (CH2) q- ORz, and - (CH2) q-SRz; q is an integer of 2 or 3; Each Rz is selected from the group consisting of Ry and -H; Each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; Each Rx is independently selected from the group consisting of -H, and alkyl, or together Rx or Rx form a cyclic alkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the proviso that: a) when G is selected from the group consisting of -0-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -C (0 ) - and -NR-; T is -A-B- wherein A is selected from the group consisting of -NRb-, -0-, -CH2- and -S- and B is selected from the group consisting of a bond and substituted or unsubstituted C1-C3 alkyl; R3 is selected from the group consisting of halogen, trifluoromethyl, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aryloxy, substituted amide, sulfone, sulfonamide and C3 ~ C7 cycloalkyl, wherein the aryl, heteroaryl or cycloalkyl rings are linked or fused to the aromatic; R4 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted Ci-Cß alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R1 and R2 are each independently selected from the group consisting of halogen, substituted or unsubstituted C1-C4 alkyl, and substituted or unsubstituted C3-C5 cycloalkyl; R7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, -O-C1-C4 alkyl, -SH and -S-C1-C alkyl; and R5 is selected from the group consisting of hydroxyl, - optionally substituted Ci-Cd O-alkyl, and -OC (0) Re; then X is not -P (0) (0H) 2; b) V, Z,, and W are not all -H; and c) when Z is -R2, then at least one of V,, and W is not -H, alkyl, aralkyl, or heterocycloalkyl; and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs.
200. 200. The method according to claim 198, characterized in that when G is -O-, T is -NH-CH2-, R1 and R2 are each chlorine, R3 is iso-propyl, R7 is fluoro and R5 is -OH , then R4 is not hydrogen.
201. 201. The method according to claim 199, characterized in that G is selected from the group consisting of -O-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -C (O) - and -NRb-; T is -A-B- wherein A is selected from the group consisting of -NRb-, -O-, -CH2- and -S- and B is selected from the group consisting of a bond and substituted or unsubstituted C1-C3 alkyl; R 3 is selected from the group consisting of halogen, trifluoromethyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aryloxy, substituted amide, sulfone, sulfonamide and C 3 -C 7 cycloalkyl, wherein the aryl, heteroaryl or cycloalkyl rings are bonded or fused to the aromatic; R4 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted Ci-Cß alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R1 and R2 are each independently selected from the group consisting of halogen, substituted or unsubstituted C1-C4 alkyl, and substituted and unsubstituted C3-C5 cycloalkyl; and R7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, -O-C1-C4 alkyl, -SH and -S-C1-C4 alkyl; then R5 is not hydroxyl, optionally substituted Ci-C3alkyl, or -OC (0) Re.
202. 202. The method according to claim 100, characterized in that the phosphonic acid-containing compound is a compound of Formula III: wherein: G is selected from the group consisting of -0-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF-, -C (O) -, -CH (OH) -, -NH-, and -N (C, L-C4 alkyl) -; T is selected from the group consisting of ~ (CRa2) k-, -CRb = CRb- (CRa2) n, - (CRa2) n-CRb = CRb-, - (CRa2) -CRb = CRb- (CRa2) -, 0 (CRb2) (CRa2) n-, -S (CRb2) (CRa2) n-, -N (Rc) (CRb2) (CRa2) n-, N (Rb) C (0) (CRa2) n-, - (CRa2) nCH (NRbRc) -, -C (O) (CRa2) m-, (CRa2) mC (0) -, - (CRa2) C (0) (CRa2) n-, - (CRa2) nC (0 ) (CRa2) -, and -C (0) NH (CRb2) (Ra2) p-; k is an integer from 0-4; m is an integer from 0-3; n is an integer from 0-2; p is an integer from 0-1; Each Ra is independently selected from the group consisting of hydrogen, optionally substituted C?-C 4 alkyl, halogen, -OH, -O-C opcional-C 4 alkyl optionally substituted, -OCF 3, -.S-C C-C 4 alkyl optionally substituted , -NRbRc, optionally substituted C2-C4 alkenyl, and optionally substituted C2-C4 alkynyl; with the proviso that when a Ra is linked to C through an atom O, S, or N, then the other Ra links to the same C that is a hydrogen, or is bonded by means of a carbon atom; Each Rb is independently selected from the group consisting of hydrogen and optionally substituted C? -C alkyl; Each Rc is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl, -C (O) -alternatively substituted C 1 -C 4 alkyl, and -C (0) H; R1 and R2 are each independently selected from the group consisting of halogen, optionally substituted C?-C4 alkyl, optionally substituted -S-C 1 -C 3 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, -CF 3, -OCF3, -O-C1-C3 alkyl optionally substituted, and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted CC2alkyl, optionally substituted C2-C2alkenyl, optionally substituted C2-C2alkynyl, - (CRa2) optionally substituted maryl, (CRa2) optionally substituted cycloalkyl, (CRa2) optionally substituted -heterocycloalkyl, -ORd, SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRfRg, -C (0) NRfRg, -C (0) ORh, -C (0) Re, -N ( Rb) C (0) Re, -N (Rb) C (0) NRfRg, -N (Rb) S (= 0) 2Re, N (Rb) S (= 0) 2NRfRg, and -NRfR; Each Rd is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C2 alkynyl, optionally substituted - (CRb2) naril, - (CRb2) n optionally substituted cycloalkyl, (CRb2 optionally substituted n-heterocycloalkyl, and C (0) NRfRg; Each Re is optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl, optionally substituted - (CR 2) naryl, optionally substituted - (CR 2) n -Cycloalkyl, and - (CR 2) nheterocycloalkyl optionally substituted; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, optionally substituted C2-C? 2 alkynyl, optionally substituted - (CRb2) , - (CRb2) optionally substituted cycloalkyl, and - (CRb2) nheterocycloalkyl optionally substituted, or Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second hetero group selected from the group of 0, NRC, and S, in wherein the optionally substituted heterocyclic ring can be substituted with 0-4 substituents selected from the group consisting of optionally substituted C? ~C alkyl, -0Rb, oxo, cyano, -CF3, optionally substituted phenyl, and -C (0) ORh; Each Rh is selected from the group consisting of optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, optionally substituted C2-C? 2 alkynyl, optionally substituted (CRb2) naryl, (CRb2) nCycloalkyl optionally substituted, and - (CRb2) nheterocycloalkyl; R5 is selected from the group consisting of -OH, optionally substituted C6-C6alkyl, -0C (0) Re, -0C (0) 0Rh, -F, -NHC (0) Re, -NHS (= 0) Re , -NHS (= 0) 2Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); R7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, -O-C C-C4 alkyl, -SH and -S-C?-C4 alkyl; X is P (0) YRu? 'Ru; Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are -0-, R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRZ2, -NRZ-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2-0- C (0) 0Ry, -C (R2) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; when Y and Y 'are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy, and cycloalkylene-C00Ry; When Y is -0- and Y 'is NRV, then R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRZ2, -NRz- C (0) -Ry, -C (Rz) 2-OC (0) Ry, -C (Rz) 2 -0-C (0) ORy, -C (Rz) 2OC (O) SRy, - alkyl-SC (O) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-COORy, -C (Rx) 2COORy, - [C (Rz) 2] qC (0) SRy , and -cycloalkylene-COORy; or when Y and Y 'are independently selected from -O- and NRV then R11 and R11 together are -alkyl-S-S-alkyl to form a cyclic group, or together R11 and R11 are the group: wherein: V, W, and W are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and 1-alkynyl optionally replaced; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group at the beta and gamma position And linked to phosphorus; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and W are connected by means of 3-5 additional atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together and W are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHRzOH, CHRzOC (0) Ry, -CHRzOC (S) Ry, -CHRzOC (S) 0Ry, -CHRzOC (0) SRy, CHRz0C02Ry, -0RZ, -SRZ, -CHRZN3, - CH2aryl, -CH (aryl) OH, -CH (CH = CRz2) 0H, -CH (C = CRz) 0H, -Rz, -NRZ2, -0C0Ry, -0C02Ry, -SC0Ry, -SC02Ry, -NHC0R, -NHC02Ry , -CH2NHaril, - (CH2) q-0Rz, and - (CH2) q-SRz; q is an integer of 2 or 3; Each Rz is selected from the group consisting of Ry and -H; Each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; Each Rx is independently selected from the group consisting of -H, and alkyl, or together Rx or Rx form a cyclic alkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the proviso that: a) when G is selected from the group consisting of -O-, T is -NH-CH2-, R1 and R2 are each chlorine, R3 is iso-propyl, R4 is hydrogen, R7 is fluoro and R5 is -OH, then X is not P (0) (0H) 2, P (0) (OH) (0CH3) or -P (0) (OCH3) 2; b) V, Z, W, and W are not all -H; and c) when Z is -Rz, then at least one of V, W, and W or is -H, alkyl, aralkyl, or heterocycloalkyl; and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs.
203. 203. The method according to claim 100, characterized in that the phosphonic acid-containing compound is a compound of Formula III: wherein: G is selected from the group consisting of -0-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF-, -C (O) -, -CH (OH) -, -NH-, and -N (C? -C4 alkyl) -; T is selected from the group consisting of - (CRa2) k-, -CRb = CRb- (CRa2) n, - (CRa2) n-CRb = CRb-, - (CR2) -CRb = CRb- (CRa2) -, 0 (CRb2) (CRa2) n-, -S (CR2) (CRa2) n-, -N (Rc) (CRb2) (CRa2) n-, N (Rb) C (0) (CRa2) n-, ~ (CRa2) nCH (NRbRc) -, -C (O) (CRa2) m-, (CRa2) mC (0) -, - (CRa2) C (0) (CRa2) n-, - (CRa2) nC (0 ) (CRa2) -, and -C (0) NH (CRb2) (Ra2) p-; k is an integer from 0-4; m is an integer from 0-3; n is an integer from 0-2; p is an integer from 0-1; Each Ra is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl, halogen, -OH, -O-optionally substituted C 1 -C 4 alkyl, -OCF 3, -S-optionally substituted C 1 -C 4 alkyl, -NRbRc optionally substituted C2-C4 alkenyl, and optionally substituted C2-C4 alkynyl; with the proviso that when a Ra is linked to C through an atom 0, S, or N, then the other Ra links to the same C that is a hydrogen, or is bonded by means of a carbon atom; Each Rb is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 4 alkyl; Each Rc is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl, -C (O) -alternatively substituted C 1 -C 4 alkyl, and -C (0) H; R1 and R2 are each independently selected from the group consisting of halogen, optionally substituted C1-C4 alkyl, -S-optionally substituted C1-C3 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, ~ CF3, - 0CF3, -O-C1-C3 alkyl optionally substituted, and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -0CF3, cyano, optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, optionally substituted C-C12 alkynyl , - (CRa2) optionally substituted maryl, - (CRa2) optionally substituted cycloalkyl, (CRa2) optionally substituted metheterocycloalkyl, -ORd, SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0 ) 2NRfRg, -C (0) NRfRg, -C (0) ORh, - C (0) R \ -N (Rb) C (0) Re, -N (Rb) C (0) NRfRg, -N (Rb) ) S (= 0) 2Re, N (R) S (= 0) 2NRfRg, and -NRfRg; Each Rd is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2-C2 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted (CRb2), optionally substituted (CRb2) n-cycloalkyl, (CRb2) optionally substituted n-heterocycloalkyl, and C (0) NRfRg; Each Re is optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl, optionally substituted - (CR 2) naryl, optionally substituted - (CR 2) n-cycloalkyl, and - (CR 2) nheterocycloalkyl optionally substituted; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, optionally substituted C2-C? 2 alkynyl, optionally substituted - (CRb2) , - (CRb2) n Optionally substituted cycloalkyl, and - (CRb2) nheterocycloalkyl optionally substituted, or Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second hetero group selected from the group of 0, NRC, and S, in wherein the optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting of optionally substituted C 1 -C 4 alkyl, -0Rb, oxo, cyano, -CF 3, optionally substituted phenyl, and -C (0) 0Rh; Each Rh is selected from the group consisting of optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, optionally substituted C2-C? 2 alkynyl, - (CRb2) optionally substituted narile, - (CRb2) nCycloalkyl optionally substituted, and (CRb2) nheterocycloalkyl; R5 is selected from the group consisting of -OH, optionally substituted O-alkylC-C5, -0C (0) Re, -0C (0) 0Rh, -F, -NHC (0) Re, -NHS (= 0) Re , -NHS (= 0) 2Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); R7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, -O-C1-C4 alkyl, -SH and -S-C-C4 alkyl; X is P (0) YRuY'Ru; Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are -0-, R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, CH2- optionally substituted heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRZ2, -NRZ- C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2-0- C (0) 0Ry, -C (Rz) 20C (0) SRy, - alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; when Y and Y 'are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy, and cycloalkylene-C00Ry; when Y is -0- and Y 'is NRV, then R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) RZ2, NRz-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2- 0-C (0) 0Ry, C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy , and -cycloalkylene-C00Ry; or when Y and Y 'are independently selected from -0- and then R11 and R11 together are -alkyl-S-S-alkyl to form a cyclic group, or together R11 and R11 are the group: wherein: V, W, and W are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and 1-alkynyl optionally replaced; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group at the beta and gamma position And linked to phosphorus; or together V and are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and W are connected by means of 3-5 additional atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHRzOH, CHRzOC (0) Ry, -CHROC (S) Ry, -CHRzOC (S) ORy, -CHRzOC (O) SRy, CHRzOC02Ry, -ORz, -SRZ, -CHRZN3, -CH2aryl, -CH (aryl) OH, - CH (CH = CRz2) OH, -CH (C = CRz) 0H, -Rz, -NRZ2, -OCORy, -OC02Ry, - SCORy, -SC02Ry, -NHC0R2, -NHC02Ry, -CH2NHaril, - (CH2) q-0R2 , and - (CH2) q-SRz; q is an integer of 2 or 3; Each R2 is selected from the group consisting of Ry and -H; Each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; Each Rx is independently selected from the group consisting of -H, and alkyl, or together Rx or Rx form a cyclic alkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the proviso that: a) when G is selected from the group consisting of -O-, -S-, -S (= 0) -, S (= 0) 2-, -CH2, C (O) and - NRb; T is -A-B- A is selected from the group consisting of -NRb-, -0-, -CH2- and -S- and B is selected from the group consisting of a bond and substituted or unsubstituted C?-C3 alkyl; R3 is selected from the group consisting of halogen, trifluoromethyl, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aryloxy, substituted amide, sulfone, sulfonamide and C3-C7 cycloalkyl, wherein the aryl, heteroaryl or cycloalkyl rings are linked or fused to the aromatic; R4 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R and R are each independently selected from the group consisting of halogen, substituted or unsubstituted C? -C alkyl, and substituted or unsubstituted C3-Cs cycloalkyl; R7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, -O-C CC alkyl, -SH and -S-C?-C 4 alkyl; and R5 is selected from the group consisting of hydroxyl, optionally substituted-O-alkyl Ci-Cβ, and OC (0) Re; then X is not -P (0) (0H) 2; c) V, Z, W, W 'are not all -H; and d) when Z is -Rz, then at least one of V, W, and W is not -H, alkyl, aralkyl, or heterocycloalkyl; and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs.
204. 204. The method according to claim 202, characterized in that G is -0-, T is -NH-CH2-, R1 and R2 are each chlorine, R3 is iso-propyl, R7 is fluorine and R5 is -OH, then R4 is not hydrogen.
205. 205. The method according to claim 203, characterized in that when G is selected from the group consisting of -O-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2- , -C (O) - and -NRb-; T is -AB- where A is selected from the group consisting of -NRb-, -O-, -CH2- and -S- and B is selected from the group consisting of a bond and substituted or unsubstituted C? -C3 alkyl; R3 is selected from the group consisting of halogen, trifluoromethyl, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aryloxy, substituted amide, sulfone, sulfonamide and C3-C7 cycloalkyl, wherein the aryl, heteroaryl or cycloalkyl rings are linked or fused to the aromatic; R 4 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R1 and R2 are each independently selected from the group consisting of halogen, substituted or unsubstituted C? -C alkyl, and substituted or unsubstituted C3-Cs cycloalkyl; R7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, -O-C-C alkyl, -SH and -S-C-alkyl- C4; then R5 is not hydroxyl, optionally substituted-Oalkyl C? -C6, and -OC (0) Re.
206. 206. A pharmaceutical composition, characterized in that it comprises a pharmaceutically effective amount of a compound of Formula I: characterized in that: G is selected from the group consisting of -O-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF-, -C (O) -, -CH (OH) -, -NH-, and -N (C 1 -C 4 alkyl) -; T is selected from the group consisting of ~ (CR2) k-, CRb = CRb- (CRa2) n-, - (CRa2) n-CRb = CRb-, - (CRa2) -CRb = CRb- (CRa2) -, 0 (CRb2) (CRa2) n-, -S (CRb2) (CRa2) n-, -N (Rb) (CRb2) (CRa2) n-, N (R) C (0) (CRa2) n-, - (CRa2) nCH (NRbRc) -, -C (0) (CRa2) a-, (CRa2) mC (0) -, - (CRa2) C (0) (CRa2) n-, - (CRa2) nC (0) (CRa2) -, and -C (0) NH (CRb2) (CRa2) p -; k is an integer from 0-4; m is an integer from 0-3; n is an integer from 0-2; p is an integer from 0-1; Each Ra is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl, halogen, -OH, -O-C 1 -C 4 alkyl optionally substituted, -OCF 3, -S-C 4 -C 4 alkyl optionally substituted, -NR b R c optionally substituted C2-C4 alkenyl, and optionally substituted C2-C4 alkynyl; with the proviso that when a Ra is linked through O, S, or N, then the other Ra links to the same C that is a hydrogen, or is linked by means of a carbon atom. Each Rb is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl; Each Rc is independently selected from the group consisting of hydrogen and optionally substituted C4-C4 alkyl, optionally substituted -C (0) -alkyl, and -C (0) H; R1 and R2 are each independently selected from the group consisting of halogen, optionally substituted C1-C4 alkyl, -S-optionally substituted C1-C3 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C alkynyl, -CF3, - 0CF3, -O-C1-C3 alkyl optionally substituted, and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -0CF3, cyano, optionally substituted C1-C12 alkyl, optionally substituted C2-C2 alkenyl, optionally substituted C2-C2 alkynyl, - (CRa2) optionally substituted aryl, - (CRa2) m optionally substituted cycloalkyl, _ (CRa2) m optionally substituted heterocycloalkyl, -0Rd, -SRd, S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRfRg, -C (0) NRfRg, -C (0) 0Rh, -C (0) Re, -N (Rb) C (0) Re, -N (Rb) C (0) NRfRg, -N (Rb) S (= 0) 2Re, -N (Rb) S (= 0) 2NRfRg, and -NRfRg; Each Rd is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2-C2 alkenyl, optionally substituted C2-C2 alkynyl, - (CRb2) n optionally substituted aryl, - (CRb2) n cycloalkyl optionally substituted, _ (CRb2) n optionally substituted heterocycloalkyl, and -C (0) NRfRg; Each Re is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2-C2 alkenyl, optionally substituted C2-C12 alkynyl, - (CRa2) n optionally substituted aryl, - (CRa2) n optionally substituted cycloalkyl, and _ (CRa) n optionally substituted heterocycloalkyl; R f and R g are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl, - (CR 2) n optionally substituted aryl, - (CRb2) n optionally substituted cycloalkyl, and - (CRb2) n optionally substituted heterocycloalkyl, or Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second heterogroup selected from the group of O, NRC, and S, in wherein the optionally substituted heterocyclic ring can be substituted with 0-4 substituents selected from the group consisting of optionally substituted C1-C4 alkyl, -0Rb, oxo, cyano, -CF3, optionally substituted phenyl, and -C (0) 0Rh; Each Rh is selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, - (CRb2) n optionally substituted aryl, - (CRb2) n optionally substituted cycloalkyl, and - (CRb2) n optionally substituted heterocycloalkyl; R5 is selected from the group consisting of -OH, - optionally substituted C6-C6alkyl, -OC (0) Re, -OC (0) ORh, -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2 Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); X is P (0) YR Y'R?: L; Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are -0-, R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRZ2, -NRZ-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (R2) 2-0- C (0) 0Ry, -C (RZ) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, nd-alkyl-SSS-alkylhydroxy; when Y and Y 'are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy, and cycloalkylene-C00Ry; when Y is -0- and Y 'is NRV, then R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRZ2, NRz-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2- 0-C (0) 0Ry, C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy , and -cycloalkylene-C00Ry; or when Y and Y 'are independently selected from -0- and -NRV-, then R11 and R11 together are -alkyl-S-S-alkyl to form a cyclic group, or together R11 and R11 are the group: wherein: V, W, and W are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and 1-alkynyl optionally replaced; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group at the beta and gamma position And linked to phosphorus; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and W are connected by means of 3-5 additional atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHRz0H, CHRzOC (0) Ry, -CHRzOC (S) Ry, -CHRZ0C (S) 0Ry, -CHRzOC (0) SRy, CHRz0C02Ry, -0RZ, -SRZ, -CHRZN3, - CH2aryl, -CH (aryl) OH, CH (CH = CRz2) 0H, -CH (C = CRZ) 0H, -RZ, -NRZ2, -0C0Ry, -0C02Ry, -SC0Ry, - SC02Ry, -NHC0R2, -NHC02Ry, -CH2NHarÍlo, - (CH2) q-0Rz, and - (CH2) q-SRz; q is an integer of 2 or 3; each Rz is selected from the group consisting of Ry and -H; each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; each Rx is independently selected from the group consisting of -H, and alkyl, or together Rx or Rx form a cyclic alkyl group; each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the proviso that: a) V, Z, W, W are not all -H; and b) when Z is -Rz, then at least one of V, W, and W is not -H, alkyl, aralkyl, or heterocycloalkyl; and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs and a pharmaceutically acceptable carrier.
207. 207. A pharmaceutical composition, characterized in that it comprises a pharmaceutically effective amount of the compound of the Formula II: characterized in that: A is selected from the group consisting of -NR1-, -O-, and -S-; B is selected from the group consisting of -CRb-, and -N-; R1 is selected from the group consisting of hydrogen, -C (O) C1-C4 alkyl, C, L-C4 alkyl, and Ci-C4 aryl; R b is selected from the group consisting of hydrogen and optionally substituted C 1 -C 4 alkyl; G is selected from the group consisting of -O-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF-, -C (0) -r -CH (OH) -, -NH-, and -N (C 1 -C 4 alkyl) -; D is selected from the group consisting of a bond, - (CRa2) -, and -C (O) -; Each Ra is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl, halogen, -OH, optionally substituted 0-C 2 -C 4 alkyl, -OCF 3, -S-optionally substituted C 1 -C 4 alkyl, -NRbRc optionally substituted C2-C4 alkenyl, and optionally substituted C2-C4 alkynyl; with the proviso that when a Ra is linked to C through an atom 0, S, or N, then the other Ra links to the same C that is a hydrogen, or is bonded by means of a carbon atom; R1 and R2 are each independently selected from the group consisting of halogen, optionally substituted C?-C4 alkyl, optionally substituted -S-C?-C3 alkyl, optionally substituted C2-C alkenyl, optionally substituted C2-C alkynyl, -CF3 , -0CF3, -O-C1-C3 alkyl optionally substituted, and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -0CF3, cyano, C-alkyl, optionally substituted C2, optionally substituted C2-C2 alkenyl, optionally substituted CC2 alkynyl, - (CRa2) optionally substituted maryl, (CRa2) Optionally substituted cycloalkyl, (CRa2) optionally substituted metheterocycloalkyl, -0Rd, SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRfRg , -C (0) NRfRg, -C (0) 0Rh, -C (0) Re, -N (Rb) C (0) Re, -N (Rb) C (0) NRfRg, -N (Rb) S (= 0) 2Re, N (Rb) S (= 0) 2NRfRg, and -NRfRb; Each Rd is selected from the group consisting of optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl, optionally substituted (CR 2) naryl, (CR 2) n Cycloalkyl optionally substituted, (CRb2) optionally substituted n-heterocycloalkyl, and C (0) NRfRg; Each Re is selected from the group consisting of optionally substituted C? ~C? Alquilo alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C alkynyl, optionally substituted (CRa 2) naryl, (CRa 2) nCycloalkyl optionally substituted, and (CRa2) optionally substituted n-heterocycloalkyl; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, optionally substituted C2-C? 2 alkynyl, optionally substituted - (CRb2) , - (CRb2) optionally substituted cycloalkyl, and - (CRb2) nheterocycloalkyl optionally substituted, or Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second hetero group selected from the group consisting of O, NRC, and S , wherein the optionally substituted heterocyclic ring can be substituted with 0-4 substituents selected from the group consisting of optionally substituted C 1 -C 4 alkyl, -ORb, oxo, cyano, -CF 3, optionally substituted phenyl, and -C (0) ORh; Each Rh is selected from the group consisting of optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, optionally substituted C2-C? 2 alkynyl, optionally substituted (CRb2) naryl, (CRb2) n optionally substituted cycloalkyl , and (CRb2) optionally substituted n-heterocycloalkyl; R5 is selected from the group consisting of -OH, -0-C-C6 alkyl optionally substituted, -0C (0) Re, -0C (0) 0Rh, -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); X is P (0) YRuY'Ru; Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are -0-, R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRZ2, -NR2-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2-0- C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-SC (O) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; when Y and Y 'are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy, and cycloalkylene-C00Ry; when Y is -0- and Y 'is NRV, then R11 linked to -O- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRZ2, -NRz-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz2) - 0-C (0) 0Ry, C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NR- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] qC (0) SRy , and -cycloalkylene-C00R ?; or when Y and Y 'are independently selected from -0- and -NR11-, then together R11 and R11 are -alkyl-S-S-alkyl to form a cyclic group, or together R11 and R11 are the group: wherein: V, W, and W are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and 1-alkynyl optionally replaced; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group to the beta and gamma bound position to the Y to the phosphorus; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and W are connected by means of 3-5 atoms II additional to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHRz0H, -CHRzOC (O) Ry, -CHRz0C (S) Ry, -CHRz0C (S) ORy, -CHRzOC (0) SRy, CHRz0C02Ry, -ORz, -SRZ, -CHRZN3, -CH2aryl, -CH (aryl) OH, -CH (CH = CRz2) OH, -CH (C = CRz) OH, -Rz, -NRZ2, -OCORy, -OC02Ry, -SCORy, -SC02Ry, -NHC0R2, - NHC02Ry, -CH2NHaril, - (CH2) q-ORz, and - (CH2) q-SRz; q is an integer of 2 or 3; Each Rz is selected from the group consisting of Ry and -H; Each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; Each Rx is independently selected from the group consisting of -H, and alkyl, or together Rx or Rx form a cyclic alkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the proviso that: a) V, Z, W, and W are not all -H; and b) when Z is -Rz, then at least one of V, W, and W is not -H, alkyl, aralkyl, or heterocycloalkyl; and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs and a pharmaceutically acceptable carrier.
208. 208. A pharmaceutical composition characterized in that it comprises a pharmaceutically effective amount of a compound of Formula III: wherein: G is selected from the group consisting of -O-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF-, -C (O) -, -CH (OH) -, -NH-, and -N (C-alkyl; LC) -; T is selected from the group consisting of ~ (CRa2) k-, -CRb = CRb- (CRa2) n, ~ (CRa2) n-CRb = CRb-, - (CRa2) -CRb = CR- (CRa2) -, 0 (CRb2) (CRa2) n-, -S (CRb2) (CRa2) n-, -N (Rc) (CRb2) (CRa2) n ~, N (Rb) C (0) (CRa2) n-, - (CRa2) nCH (NRbRc) -, -C (O) (CRa2) m-, (CRa2) mC (0) -, - (CRa2) C (0) (CRa2) n-, - (CRa2) nCO) ( CRa2) -, and -C (0) NH (CRb2) (CRa2) p-; k is an integer from 0-4; m is an integer from 0-3; n is an integer from 0-2; p is an integer from 0-1; Each Ra is independently selected from the group consisting of hydrogen, optionally substituted C? -C 4 alkyl, halogen, -OH, -O-C ?C alkyl optionally substituted, -OCF 3, -S-C C-C 4 alkyl optionally substituted, - NRbRc, optionally substituted C2-C alkenyl, and optionally substituted C2-C4 alkynyl; with the proviso that when a Ra is linked to C through an atom O, S, or N, then the other Ra links to the same C that is a hydrogen, or is bonded by means of a carbon atom; Each Rb is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 4 alkyl; Each Rc is independently selected from the group consisting of hydrogen and optionally substituted C? -C4 alkyl, optionally substituted C (O) -alkyl C? -C4, and -C (0) H; R1 and R2 are each independently selected from the group consisting of halogen, optionally substituted Ci-C alkyl, -S-optionally substituted C3-C3 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, -CF3, -0CF3, -O-C-C3 alkyl optionally substituted, and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, optionally substituted C2-C12 alkynyl , - (CRa2) optionally substituted maryl, - (CRa2) optionally substituted cycloalkyl, (CRa2) optionally substituted metheterocycloalkyl, -0Rd, SRd, -S (= 0) Re, -S (= 0) 2Re, -S (-0 ) 2NHfRg, -C (0) NRfRg, -C (0) ORh, -C (0) Re, -N (Rb) C (0) Re, -N (Rb) C (0) NRfRg, -N (Rb) ) S (= 0) 2Re, N (Rb) S (= 0) 2NRfRg, and -NRfRg; Each Rd is selected from the group consisting of optionally substituted C? -C12 alkyl, optionally substituted C2-C? 2 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted (CRb2) naryl, - (CR2) n optionally substituted cycloalkyl, - (CRb2) optionally substituted n-heterocycloalkyl, and C (0) NRfRg; Each Re is selected from the group consisting of optionally substituted C? -C? 2 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted (CRa2), optionally substituted (CRa2) nCycloalkyl, and ( CRa2) optionally substituted n-heterocycloalkyl; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, optionally substituted C2-C? 2 alkynyl, optionally substituted - (CRb2) , - (CRb2) optionally substituted cycloalkyl, and - (CRb2) nheterocycloalkyl optionally substituted, or Rf and Rg together may form an optionally substituted heterocyclic ring, which may contain a second hetero group selected from the group consisting of 0, NRC, and S , wherein the optionally substituted heterocyclic ring can be substituted with 0-4 substituents selected from the group consisting of optionally substituted C 1 -C 4 alkyl, -0Rb, oxo, cyano, -CF 3, optionally substituted phenyl, and -C (0) 0Rh; Each Rh is selected from the group consisting of optionally substituted C? -C? 2 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted (CRb2) naryl, - (CRb2) n optionally substituted cycloalkyl, and - (CR 2) optionally substituted n-heterocycloalkyl; R5 is selected from the group consisting of -OH, -O-alkyl optionally substituted CL-C6, -0C (0) Re, -0C (0) 0Rh, -F, -NHC (0) Re, -NHS (= 0) Re , -NHS (= 0) 2R% -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); R7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, -O-C1-C4 alkyl, -SH and -S-alkyl, -C-C4; X is P (0)? RuY 'Ru; Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are -0-, R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 2OC (0) NRz2, -NRZ-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2-0- C (0) 0Ry, C (Rz) 2CC (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; when Y and Y 'are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, [C (Rz) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C ( Rz) 2] qC (0) SRy, and -cycloalkylene-COORy; when Y is -0- and Y 'is NRV, then R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 20C (0) NRz2, -NR2-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) 2 -0-C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-C00Ry, -C (Rz) 2C00Ry, - [C (R2) 2] qC (0) SRy and -cycloalkylene-C00Ry; or when Y and Y 'are independently selected from -0- and -NRV-, then together R11 and R11 are -alkyl-S-S-alkyl to form a cyclic group, or together R11 and R11 are the group: wherein: V, W, and W are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and 1-alkynyl optionally replaced; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are 3 atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group to the beta and gamma bound position to the Y to the phosphorus; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms that are 3 atoms of a Y bond to phosphorus; or together Z and W are connected by means of 3-5 additional atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHR20H, -CHRz0C (0) Ry, -CHRzOC (S) Ry, -CHRzOC (S) 0Ry, -CHRzOC (O) SRy, CHRz0C02Ry, -0RZ, -SRZ, -CHRZN3 , -CH2aryl, -CH (aryl) OH, -CH (CH = CRZ2) 0H, -CH (C = CRz) 0H, -Rz, -NRZ2, -OCORy, -OC02Ry, -SCORy, -SC02Ry, -NHC0Rz, -NHC02Ry, -CH2NHaril, - (CH2) q-ORz, and - (CH2) q-SRz; q is an integer of 2 or 3; Each Rz is selected from the group consisting of Ry and -H; Each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; Each Rx is independently selected from the group consisting of -H, and alkyl, or together Rx and Rx form a cyclic alkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the proviso that: a) V, Z, W, and W are not all -H; and b) when Z is -Rz, then at least one of V, W, and W is not -H, alkyl, aralkyl, or heterocycloalkyl; and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs. and a pharmaceutically acceptable carrier.
209. 209. The pharmaceutical composition according to any of claims 206, 207 or 208, characterized in that the pharmaceutical composition is a controlled release form.
210. 210. The pharmaceutical composition according to any of claims 206, 207 or 208 characterized in that the pharmaceutical composition is in the form of a transdermal patch.
211. 211. The pharmaceutical composition according to any of claims 206, 207 or 208 characterized in that the pharmaceutical composition is in the form of a tablet.
212. 212. The pharmaceutical composition according to any one of claims 206, 207 or 208 characterized in that the pharmaceutical composition is in the form of a hard capsule.
213. 213. The pharmaceutical composition according to any of claims 206, 207 or 208 characterized in that the pharmaceutical composition is in the form of a soft capsule.
214. 214. The pharmaceutical composition according to any of claims 206, 207 or 208 characterized in that the pharmaceutical composition comprises a crystalline form of the compound of Formula I, II or III.
215. 215. The pharmaceutical composition according to any of claims 206, 207 or 208 characterized in that the pharmaceutical composition comprises a salt form of the compound of Formula I, II or III.
216. 216. The pharmaceutical composition according to any of claims 206, 207 or 208 characterized in that the pharmaceutical composition is administered orally in a unit dose of about 0.375 μg / kg to 3,375 mg / kg.
217. 217. The pharmaceutical composition according to claim 216 characterized in that the unit dose is from about 3.75 μg / kg to 0.375 mg / kg.
218. 218. The pharmaceutical composition according to claim 216 characterized in that the unit dose is from about 3.75 μg / kg to 37.5 μg / kg.
219. 219. The pharmaceutical composition according to claim 216 characterized in that the unit dose is from about 3.75 μg / kg up to 60 μg / kg.
220. 220. The pharmaceutical composition according to claim 216, characterized in that the unit dose is around 0.188 μg / kg up to 1.88 mg / kg.
221. 221. The pharmaceutical composition according to claim 216 characterized in that the unit dose is from about 1.88 μg / kg to .188 mg / kg.
222. 222. The pharmaceutical composition according to claim 216 characterized in that the unit dose is about 1.88 μg / kg up to 18.8 μg / kg.
223. 223. The pharmaceutical composition according to claim 216 characterized in that the unit dose is about 1.88 μg / kg to 30 μg / kg.
224. 224. The pharmaceutical composition according to any of claims 206, 207 or 208 characterized in that the pharmaceutical composition is administered orally in a total daily dose of about 0.375 μg / kg / day to about 3.75 mg / kg / day, equivalent of the free acid.
225. 225. The pharmaceutical composition according to claim 224 characterized in that the total daily dose is from about 3.75 μg / kg / day to about 0.375 mg / kg / day, equivalent of the free acid.
226. 226. The pharmaceutical composition according to claim 224 characterized in that the total daily dose is from about 30 μg / kg / day to about 3.0 mg / kg / day, equivalent of the free acid.
227. 227. A phosphonic acid containing a thyromimetic compound of the Formula X: { ? r1) -G- (? r2) -T-X characterized in that: Ar1 and Ar2 are aryl groups; G is an atom or group of atoms that bind Ar1 and Ar2 through a single C, S, O or N atom; T is an atom or group of atoms that bind Ar2 to X through 1-4 contiguous atoms or are absent; X is a -P (O) (0H) 2 or prodrug thereof. wherein (Ar1) -G- (Ar2) -T-P (O) (OH) 2 has a Ki < 150 nM relative to T3; with the proviso that P (0) (0H) 2 contains a thyromimetic compound that is not:
228. 228. A method for improving liver-to-heart selectivity of a thyromimetic compound of formula Y: (Ar1) -G- (Ar2) -T-E characterized in that: Ar1 and Ar2 are aryl groups; G is an atom or group of atoms that bind Ar1 and Ar2 through a C, S, 0, or single N atom; T is an atom or group of atoms that bind Ar2 to E through 1-4 contiguous atoms or is absent; E is selected from the group consisting of a functional group or a portion with a pKa < 7.4, a carboxylic acid moiety or an atom or group of atoms containing a 0 u N that binds the thyroid hormone binding cavity of a TRa or TRβ, comprising the step of replacing E with a -P ( 0) (0H) 2 or prodrug thereof
229. 229. A method for improving the therapeutic index of a thyromimetic compound of formula Y: . { Rr1) -G-. { Ar2) -T-E characterized in that: Ar1 and Ar2 are aryl groups; G is an atom or group of atoms that bind Ar1 and Ar2 through a C, S, 0, or single N atom; T is an atom or group of atoms that bind Ar2 to E through 1-4 contiguous atoms or is absent; E is selected from the group consisting of a functional group or a portion with a pKa < 7.4, a carboxylic acid moiety or an atom or group of atoms containing a 0 u N that binds to the thyroid hormone binding cavity of a TRa or TRβ, comprising the step of replacing E with a -P (0) (0H) 2 or prodrug thereof.
230. 230. A method for designing a thyromimetic compound with improved liver-to-heart selectivity, characterized in that it comprises the steps of: obtaining a molecular formula for a thyromimetic of formula Y: (Ar ^ -G-ÍAr ^ -T-E wherein: Ar1 and Ar2 are aryl groups; G is an atom or group of atoms that bind Ar1 and Ar2 through a C, S, 0, or single N atom; T is an atom or group of atoms that bind Ar2 to E through 1-4 contiguous atoms or is absent; E is selected from the group consisting of a functional group or a portion with a pKa < 7.4, a portion of carboxylic acid or an atom or group of atoms containing an O or N that binds to the thyroid hormone binding cavity of a TRa or TRβ, comprising the step of replacing E with a -P (0) (0H) 2 or prodrug thereof; and synthesizing a compound of Formula X wherein X is - P (0) (0H) 2 acid or prodrug thereof.
231. 231. A method for designing a thyromimetic compound with an improvement in the therapeutic index characterized in that it comprises the steps of: obtaining a molecular formula for a thyromimetic of the formula Y: (Arx) -G- (Ar2) -T-E wherein: Ar1 and Ar2 are aryl groups; G is an atom or group of atoms that bind Ar1 and Ar2 through a C, S, 0, or single N atom; T is an atom or group of atoms that bind Ar2 to E through 1-4 contiguous atoms or is absent; E is selected from the group consisting of a functional group or a portion with a pKa < 7.4, a portion of carboxylic acid or an atom or group of atoms containing an O or N that binds to the thyroid hormone binding cavity of a TRa or TRβ, comprising the step of replacing E with a -P (0) (0H) 2 or prodrug thereof; and synthesizing a compound of Formula X wherein X is P (0) (OH) 2 acid or prodrug thereof.
232. 232. A compound of Formula VIII: Formula VIII characterized in that: G is selected from the group consisting of -0-, ~ S-, -S (= 0) -, -S (= 0) 2-, -Se-, -CH2-, -CF2-, -CHF-, -C (0) -, -CH (OH) -, -CH (C 1 -C 4 alkyl) -, -CH (C 1 -C 4 alkoxy) -, -C (= CH 2) -, -NH- , and -N (C1-C4 alkyl) -; T is selected from the group consisting of ~ (CRa2) k-, -CRb = CRb- (CR2) n-, - (CRa2) n-CRb = CRb-, - (CRa2) -CRb = CRb- (CRa2) - , 0 (CRb2) (CRa2) n-, -S (CR2) (CRa2) n-, -N (Rc) (CRb2) (CRa2) n-, N (Rb) C (0) (CRa2) n-, - (CRa2) nCH (NRbRc) -, -C (0) (CRa2) m-, (CRa2) mC (0) -, - (CRa2) C (0) (CRa2) n-, - (CRa2) nC ( 0) (CRa2) -, and -C (0) NH (CRb2) (CRa2) p-; k is an integer from 0-4; m is an integer from 0-3; n is an integer from 0-2; p is an integer from 0-1; Each Ra is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl, halogen, -OH, -O-C 1 -C 4 alkyl optionally substituted, -OCF 3, -S-C 4 -C 4 alkyl optionally substituted, -NR b R c optionally substituted C2-C4 alkenyl, and optionally substituted C2-C4 alkynyl; with the proviso that when a Ra is linked to C through an atom 0, S, or N, then the other Ra links to the same C that is a hydrogen, or is bonded by means of a carbon atom; Each Rb is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 4 alkyl; Each Rc is independently selected from the group consisting of hydrogen and optionally substituted C ?C alkyl, -C (0) -alkyl C ?C optionally substituted, and -C (0) H; R1, R2, R6, R7, R8, and R9 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted C?-C4 alkyl, optionally substituted -S-C alquiloC3 alkyl, optionally C2-C4 alkenyl substituted, optionally substituted C2-C4 alkynyl, -CF3, -0CF3, -O-C3-C3 alkyl optionally substituted, and cyano; with the proviso that at least one of R1 and R2 are not hydrogen; or R6 and T are taken together, together with the carbons and are bonded to form a ring of 5 to 6 atoms, 0 to 2 heteroatoms independently selected from -NRX-, -0-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have been separated by at least one carbon atom; and X is linked to this ring by a direct bond to a carbon in the ring, or by linking - (CRa2) - to a carbon in the ring or to a nitrogen in the ring; R1 is selected from the group consisting of hydrogen, -C (0) C? -C4 alkyl, -C? -C4 alkyl, and C? -C aryl; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted C? -C? 2 alkyl, optionally substituted C2-C? 2 alkenyl, C2-C alkynyl? optionally substituted, - (CRa2) optionally substituted maryl, - (CRa2) optionally substituted cycloalkyl, (CRa2) optionally substituted metheterocycloalkyl, -ORd, SRd, -S (= 0) Re, -S (= 0) 2Re, -S ( = 0) 2NRfRg, -C (0) NRfRg, -C (0) ORh, -C (0) Re, -N (Rb) C (0) Re, -N (Rb) C (0) NRfRg, -N (Rb) S (= 0) 2Re, N (Rb) S (= 0) 2NRfRg, and -NRfRg; Each Rd is selected from the group consisting of optionally substituted C? ~C? 2 alkyl, optionally substituted C?? Al alkenyl, optionally substituted C2-C? Alqu alkynyl, optionally substituted - (CRb2) naril, - (CRb2) n cycloalkyl optionally substituted, - (CRb2) optionally substituted n-heterocycloalkyl, and -C (0) NRfRg; Each Re is selected from the group consisting of optionally substituted C? -C12 alkyl, optionally substituted C2-C? 2 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted (CRa2), optionally substituted (CRa2) nCycloalkyl, and ( CRa2) optionally substituted n-heterocycloalkyl; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C2-C2 alkenyl, optionally substituted C2-C2 alkynyl, optionally substituted (CRb2) naril, - ( CR2) optionally substituted cycloalkyl, and - (CRb2) nheterocycloalkyl optionally substituted, or Rf and Rg together may form an optionally substituted heterocyclic ring, the heterocyclic ring may contain a second hetero group within the ring selected from the group consisting of O, NRC, and S, wherein the optionally substituted heterocyclic ring can be substituted with 0-4 substituents selected from the group consisting of optionally substituted C? -C alkyl, -ORb, oxo, cyano, -CF3, optionally substituted phenyl, and -C (0) ORh; Each Rh is selected from the group consisting of alkyl Optionally substituted C? -C? 2, optionally substituted C2-C? 2 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted (CRb2) naryl, (CRb2) n optionally substituted cycloalkyl, and optionally substituted (CRb2) nheterocycloalkyl; R5 is selected from the group consisting of -OH, optionally substituted C6-C6alkyl, -OC (0) Re, -OC (0) ORh, -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2 Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); X is P (0) YRuY'Rn; Y and Y 'are each independently selected from the group consisting of -O-, and -NRV-; when Y and Y 'are -O-, R11 linked to -O- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (Rz) 2OC (O) NRZ2, -NRz-C (0) -Ry, -C (Rz) 2-OC (0) Ry, -C (Rz) 2-0- C (0) ORy, -C (Rz) 2OC (O) SRy, -alkyl-SC (O) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; when Y and Y 'are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-COORy, -C (Rx) 2COORy, - [C (Rz) 2] qC (O) SRy, and cycloalkylene-COORy; when Y is -O- and Y 'is NRV, then R11 linked to -0- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains an optionally substituted carbonate or thiocarbonate, alkylaryl, -C (Rz) 2OC (O) NRZ2, -NRZ-C (0) -Ry, -C (Rz) 2-OC (0) Ry, -C (RZ) 2 -0-C (0) 0Ry, -C (RZ) 20C (O) SRy, -alkyl-SC (O) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] q-COORy, -C (Rx) 2COORy, - [C (Rz) 2] qC (0) SRy , and -cycloalkylene-COORy; or when Y and Y 'are independently selected from -O- and -NRV-, then together R11 and R11 are -alkyl-S-S-alkyl to form a cyclic group, or together R11 and R11 are the group: wherein: V,, and W are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-alkynyl; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which are three atoms of both Y groups bonded to phosphorus; or together V and Z are connected by means of 3-5 additional atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which are fused to an aryl group to the beta and gamma bound position to the Y to the phosphorus; or together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, linked to one of the carbon atoms which are three atoms of a Y bond to phosphorus; or together Z and W are connected by means of 3-5 additional atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W are connected by means of 2-5 additional atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHRzOH, -CHRzOC (0) Ry, -CHRzOC (S) Ry, -CHRz0C (S) 0Ry, -CHRz0C (0) SRy, -CHRz0C02Ry, -0RZ, -SRZ, -CHRZN3 , -CH2aryl, -CH (aryl) OH, -CH (CH = CRz2) 0H, -CH (C = CRZ2) OH, -Rz, -NRZ2, -OCORy, -0C02Ry, -SC0Ry, -SC02Ry, -NHC0R2, -NHC02Ry, -CH2NHaril, - (CH2) q-0Rz, and - (CH2) q-SRz; q is an integer of 2 or 3; Each Rz is selected from the group consisting of Ry and -H; Each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; Each Rx is independently selected from the group consisting of -H, and alkyl, or together Rx or Rx form a cyclic alkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the proviso that: a) when G is -0-, T is -CH2-, R1 and R2 are each bromine, R3 is iso-propyl, R4 is hydrogen, and R5 is -OH, then X is not P (0) (OH) 2 or P (0) (OCH2CH3) 2; b) V, Z,, and W are not all -H; and c) when Z is -Rz, then at least one of V, • W, and W are not -H, alkyl, aralkyl, or heterocycloalkyl; d) when G is -0-, T is - (CH2) or -4- R1 and R2 are independently halogen, alkyl of 1 to 3 carbons, and cycloalkyl of 3 to 5 carbons, R3 is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 7 carbons, R 4 is hydrogen, and R 5 is -OH, then X is not -P (O) (OH) 2 or -P (O) (O lower alkyl) 2; and e) when G is -O-, R5 is -NHC (0) Re, -NHS (= 0) a_2Re, -NHC (S) NH (Rh), or -NHC (0) NH (Rh), T is - (CH2) m-, -CH = CH-, -0 (CH2)? _ 2-, or - E. { CR2)? -2 ~ r then X is not -P (0) (0H) 2 or -P (0) (0H) NH2; and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs.
233. 233. A method for increasing the liver specificity for a mimetic T3 having a carboxylic acid moiety, characterized in that it comprises the preparation of a compound that is an analogue of the mimetic T3, characterized in that the carboxylic acid moiety is replaced by P ( 0) (0H) 2 and prodrugs thereof.
234. 234. A method for selecting a mimetic T3 to increase liver specificity, characterized in that it comprises the steps of: a) measuring the specificity of liver to a mimetic T3 having a carboxylic acid moiety; b) measuring the liver specificity of a compound that is an analogue of the mimetic T3 having a carboxylic acid moiety, wherein the carboxylic acid moiety is replaced by a P (0) (0H) 2 or prodrug thereof; c) compare the hepatic liver specificities of steps a) and b).
235. 235. A method for separating by exclusion T3 mimetics, characterized in that it comprises the steps of: a) measuring a biological effect of T3 mimetics having a carboxylic acid moiety, characterized in that the biological effect is selected from the group consisting of the relative Ki up to T3, effects on blood glucose levels, effects on serum cholesterol levels, effects on liver fat, liver specificity and therapeutic index; b) measuring the same biological effect measured in a) of a mimetic T3 having a phosphonic acid or prodrug portion thereof; and c) compare the results in stages a) and b). d) select the mimetic T3 from stage b) for additional scientific evaluation.
236. 236. The compound according to any of claims 1, 2, 117, 139, 140 or 232, characterized in that the compound is in the form of a co-crystal.
237. 237. The method according to claim 135, characterized in that the metabolic disease is NASH.
238. 238. The method according to claim 135, characterized in that the metabolic disease is selected from the group consisting of impaired tolerance of glucose, diabetes and metabolic syndrome X.