MX2007014493A - Novel phosphorus-containing thyromimetics. - Google Patents

Novel phosphorus-containing thyromimetics.

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Publication number
MX2007014493A
MX2007014493A MX2007014493A MX2007014493A MX2007014493A MX 2007014493 A MX2007014493 A MX 2007014493A MX 2007014493 A MX2007014493 A MX 2007014493A MX 2007014493 A MX2007014493 A MX 2007014493A MX 2007014493 A MX2007014493 A MX 2007014493A
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Mexico
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optionally substituted
alkyl
group
atoms
cra2
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MX2007014493A
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Spanish (es)
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Mark D Erion
Serge H Boyer
Hongjian Jiang
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Metabasis Therapeutics Inc
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Priority claimed from US11/137,773 external-priority patent/US7514419B2/en
Application filed by Metabasis Therapeutics Inc filed Critical Metabasis Therapeutics Inc
Publication of MX2007014493A publication Critical patent/MX2007014493A/en

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Abstract

The present invention relates to compounds of phosphonic acid-containing T3 mimetics and monoesters thereof, 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 syndrome x and diabetes.

Description

NOVEDIC TIROMIMETICS CONTAINING PHOSPHORUS Field of the Invention The present invention is directed towards compounds containing phosphonic acid and monoesters thereof which are ligands of the thyroid receptor, pharmaceutically acceptable salts, and prodrugs of these compounds, as well as their preparation and uses to prevent and / or treat metabolic diseases such as obesity, NASH, hypercholesterolemia and hyperlipidemia as well as associated conditions such as atherosclerosis, coronary heart disease, impaired glucose tolerance and diabetes. The invention also relates to the liver-specific delivery of thyroid receptor ligands and the use of these compounds for the prevention and treatment of diseases responsive to the modulation of genes responsive to T3 in the liver.
Background of the Invention The following description of the background is provided to assist in understanding, but it is not admitted to be, or describe, prior art. All publications and their cited references are incorporated with reference in their entirety. REF. : 186505 Thyroid hormones (TH) are synthesized in the trioids in response to thyroid stimulating hormone (TSH), which is secreted by the pituitary gland in response to various stimulants (eg, thyrotropin-releasing hormone (TRH) ) of the hypothalamus). The thyroid hormones are analogues of 0-aryl tyrosine iodinated excreted into the circulation mainly as 3, 3 ', 5, 5' -tethiodothyronine (T4). T4 rapidly defects in local tissues by thyroxine 5 'deiodinase at 3, 3', 5 '-triiodothyronine (T3), which is the most potent TH. T3 is metabolized to inactive metabolites by means of a variety of trajectories, which include trajectories involving deiodination, glucuronidation, sulfation, deamination and decarboxylation. Most of the T4 and T3 in circulation is eliminated through the liver. HT have profound physiological effects in animals and in humans. Hyperthyroidism is associated with increased body temperature, general nervousness, weight loss despite increased appetite, muscle weakness and fatigue, increased bone resorption and intensified calcification, and a variety of cardiovascular changes, including increased heart rate, attack volume increased, Increased cardiac index, cardiac hypertrophy, decreased peripheral vascular resistance, and pulse pressure increased. Hypothyroidism is usually associated with the opposite effects. The biological activity of TH is mediated mainly through the thyroid hormone receptors (TRs). The TR belong to the nuclear receptor superfamily, which, together with their common partner, the retinoid receptor X, forms heterodimers that act as transcription factors that are induced by the ligand. Like other nuclear receptors, TRs have a ligand binding domain and a DNA binding domain and regulate gene expression through ligand-dependent interactions with DNA response elements (thyroid response elements, TREs) . Currently, the literature shows that TRs are encoded by two different genes (TRa and TRβ), which produce different isoforms through an alternative splice (Williams, Mol Cell Biol. 20 (22): 8329 42 (2000); Nagaya et al., Biochem. Biophys., Res. Commun. 226 (2): 426-30 (1996)). The main isoforms that have been identified so far are TRa-1, TRa-2, TRß-1 and TRß-2. TRa-1 is particularly expressed in the rat with the highest expression in skeletal muscle and brown fat. TRß-1 is also expressed particularly with the highest expression in the liver, brain and kidney. TRß-2 is expressed in the anterior pituitary gland and specific regions of the hypothalamus as well as the developing brain and the inner ear. In the liver of rat and mouse, TRβ-1 is the predominant isoform (80%). The TR isoforms that are found in human and rat are highly homologous with respect to their amino acid sequences, which suggests that each serves a specialized function. TSH is a hormone anterior of the pituitary that regulates the production of thyroid hormone. The formation and secretion of TSH is regulated in turn by the hypothalamus (TRH). TSH controls the absorption of iodine by the thyroid, the subsequent release of iodinated thyronins from thyroglobulin (eg, T3, T4) as well as possibly the intrapituitary conversion of T4 to T3 in circulation. Compounds that mimic T3 and T4 can negatively regulate both TSH and TRH secretion resulting in the suppression of TSH levels and decreased levels of T3 and other iodinated thyronins. Negative regulation of TSH is postulated based on co-transfection and studies of inactive genes (Abel et al., J. Clin, Invest, 104: 291-300 (1999)) to appear through activation of the receptor. the TRβ thyroid, possibly the TRβ-2 isoform, which is highly expressed in the pituitary. The most widely recognized effects of HT are an increase in metabolic rate, oxygen consumption and heat production. Treatment with T3 increases the oxygen consumption in the liver isolated with perfusion and in isolated hepatocytes. (Oh et al., J. Nutr. 125 (1): 112-24 (1995); Oh et al., Proc. Soc. Exp. Biol. Med. 207 (3): 260 7 (1994)) The mitochondria of Liver of hyperthyroid rats showed an increase in oxygen consumption (Carreras et al., Am. J. Physiol. Heart Circ. Physiol. 281 (6): H2282 8 (2001) and higher activities of enzymes in oxidative trajectories (Dummler et al., Biochem J. 317 (3): 913-8 (1996), Schmehl et al., FEBS Lett 375 (3): 206-10 (1995), Harper et al., Can. J. Physiol. 72 (8): 899 908 (1994)) Conversely, the mitochondria of hypothyroid rats showed decreased oxygen consumption.The increasing metabolic relationships are associated with increased mitochondria biogenesis and the associated increment of 2 to 8 Sometimes in mitochondria mRNA levels Some of the energy produced from the increased metabolic ratio is captured as ATP (adenosine 5'-triphosphate), which is stored or used to drive biosynthetic trajectories (for example, gluconeogenesis, lipogenesis, lipoprotein synthesis). Much of the energy, however, is lost in the form of heat (thermogenesis), which is associated with an increase in proton leakage from the mitochondria that possibly results from the effects mediated by TH in the membrane of the mitochondria. , decoupling proteins, enzymes involved in an inefficient transfer of sn-glycerol 3 phosphate such as sn-glycerol 3 mitochondrial phosphate dehydrogenase (mGPDH), and / or enzymes associated with proton leakage 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 levels of cholesterol in plasma, which is probably due to an increased expression of the LDL hepatic receptor. Hypothyroidism is a well-established cause of hypercholesterolemia and elevated LDL in serum. L-T3 is known to lower plasma cholesterol levels. The effects of T3 are attributed to TRβ since the mice deficient in TRβ are resistant to the reduction induced by T3 in cholesterol levels. Effects on cholesterol levels have been postulated to result from the direct effects on the expression of the LDL receptor, enzymes involved in the conversion of cholesterol to bile acids such as the cholesterol-limiting 7α-hydroxylase enzyme of the ratio (CYP7A) and / or possibly enzymes involved in the synthesis of cholesterol 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 secretion of apo AI in HDL while reducing apo B100. In this way, it would be expected that T3 and T3 mimetics inhibit the atherosclerotic process in the animal fed cholesterol. THs simultaneously increase the synthesis of de novo fatty acids and oxidation through the effects on enzymes such as ACC, FAS, and spot 14. TH increase the levels of free fatty acids (FFA) in circulation, in part at increase the production of FFA of adipose tissue by means of TH-induced lipolysis. In addition, THs increase enzyme levels in the mitochondria involved in the oxidation of FFA, for example, carnitine palmitoyltransferase 1 (CPT 1) and enzymes involved in storage and energy consumption. The liver represents an important target organ of HT. The microconfiguration analysis of hepatic liver gene expression of hypothyroid mice and mice treated with T3 showed changes in mRNA levels for 55 genes (14 positively regulated and 41 negatively regulated) (Feng et al., Mol. Endocrinol. 14 (7): 947 55 (2000) Others have estimated that approximately 8% of liver genes are regulated by T3, many of which are important for fatty acids and for cholesterol synthesis and metabolism. It is known to have other effects on the liver, including effects on carbohydrates, through increased glycogenolysis and gluconeogenesis and decreased insulin action.
The heart is also an important objective organ of HT. TH decreases systemic vascular resistance, increases blood volume and produces inotropic and chronotropic effects. In general, HT results in increased cardiac output, which may suggest that T3 or T3 mimetics may be of use to treat patients with compromised cardiac function (eg, patients undergoing grafts for coronary artery bypass). CABG) or cardiac arrest) (U.S. Patent No. 5,158,978). Changes in cardiac function are the result of changes in the cardiac expression of genes. The increasing synthesis of proteins and the increasing weight of the cardiac organ are easily observed in animals treated with T3 and represent the side effect of T3 that limits its therapeutic use. Mice with inactivated TRβ genes show high levels of TSH and T4 and increased heart rate suggesting that they retain a cardiac sensitivity and therefore that the cardiac effects are by means of TRa. Those inactivated with TRa showed reduced cardiac rhythms. THs also play a role in the development and function of brown and white adipose tissue. Both TRa and TRß are expressed in brown adipose tissue (BAT). TH induces the differentiation of white adipose tissue (WAT) as well as a variety of lipogenic genes, including ACC, FAS, glucose 6 phosphate dehydrogenase and spot 14. In general, TH 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)). TH 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 dietary intake but is also associated with an overall increase in basal metabolic rate (BMR). Hyperthyroidism is also associated with decreased body weight (ca. 15%) while hypothyroidism is associated with an increase of 25-30% in body weight. The treatment of patients with hypothyroidism with T3 leads to a decrease in body weight for most patients but not all (17% of patients retain 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 of body mass. Long-term therapy has also been associated with bone loss. With these side effects, the medical community has tended to use thyroxine at low doses as an adjuvant in dietary treatments. At these doses, TH has little effect on body weight or BMR.
The effectiveness of T3 to induce weight loss can be mitigated by defects in the action of TH. Compared with normal animals, higher doses of T3 were required in ob / ob mice to affect oxygen consumption, which was only observed in the muscles without any changes in liver and BAT. (Oh et al., J. Nutr. 125 (1): 112-24 (1995); Oh et al., Proc. Soc. Exp. Biol. Med. 207 (3): 260 7 (1994)). These effects were at least partially attributed to a decreased absorption of T3 by the liver. T3 analogues have been reported. Many were designed for use as agents that lower cholesterol. Analogs that lower cholesterol and various lipoproteins (eg, LDL and Lp (a) cholesterol) without generating adverse cardiac effects have been reported (eg, Underwood et al., Nature 324: 425 9 (1986)). In some cases, the improved therapeutic profile is attributed to an increased specificity for TR-ß where in other cases it may be due to an increased distribution in the liver. (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 mimetics are thought to inhibit atherosclerosis by modulating the levels of certain lipoproteins that are known to be independent risk factors or potential risk factors. atherosclerosis, including low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, apoAI, which is an important apoprotein constituent of high-density lipoprotein (HDL) and lipoprotein (a) particles or Lp (a). Lp (a) is an important risk factor, elevated in many patients with premature atherosclerosis. Lp (a) is considered highly atherogenic (de Bruin et al., J. Clin Endocrinol, Metab 76: 121-126 (1993)). In humans, Lp (a) is an acute phase hepatic protein that promotes the binding of LDL to cell surfaces independent of LDL receptors. Thus, Lp (a) is thought to provide cholesterol complementary 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 main component of HDL, which is an independent risk factor in atherosclerosis. ApoAI is thought to promote the release of cholesterol from peripheral tissues and higher levels of HDL (or apoAI) result in a decreased risk of atherosclerosis. Hyperthyroidism worsens glycemic control in type 2 diabetics. TH therapy is reported to be stimulates hepatic gluconeogenesis. The enzymes specific for gluconeogenesis and important for controlling the trajectory and its physiological role of glucose production 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 have found that glucose 6-phosphatase is over-regulated (Feng et al., Mol. Endocrinol 14: 947 (2000)). TH therapy is also associated with reduced levels of glycogen. TH therapy results in an insulin-stimulated glucose utilization not stimulated by insulin and a decreased insulin resistance in the muscle of ob / ob mice. (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 The figure details the bond of T3 to the TRal receiver when using a homologous displacement reaction. Figure lb details the binding of T3 to the TRβ receptor by using a homologous shift reaction. Figure lc details the link from Compound 17 to TRal receptor when using a heterologous displacement reaction. Figure 1d details the binding of Compound 17 to the TRβ receptor by using a heterologous shift reaction. The figure details the binding of Compound 7 to the TRal receptor when using a heterologous shift reaction. Figure 1 details the binding of Compound 7 to the TRβ receptor by 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 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 activity GPDH in rats fed cholesterol.
Figure 5 details the dose response of serum cholesterol levels for Compound 13-1-cis in rats fed with cholesterol. ANOVA test < 0.0001; Dunnett 's: All groups.
Brief Description of the Invention The present invention relates to phosphonic acid-containing compounds and phosphonic acid monoesters that bind to thyroid receptors in the liver. The activation of these receptors results in the modulation of gene expression of genes 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 and phosphonic acid monoesters are useful for improving efficacy, improving the therapeutic index, for example, decreasing non-liver related toxicities and side effects, or for improving liver selectivity, that is, increasing the distribution of an active drug to the liver relative to the extrahepatic tissues and more specifically increasing the distribution of an active drug to the nucleus of the liver cells relative to the nucleus of extrahepatic tissue cells (including heart, kidney and pituitary).
Prodrugs of the compounds containing phosphonic acid and phosphonic acid monoesters are useful for increasing the oral bioavailability and sustained supply of the phosphorus-containing compounds. In other aspects, the present invention relates to compounds of the formula I, II, III, VIII and X. The compounds of the formula I, II, III, VIII and X can be an 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, VIII and X. Compounds of compounds are also included in the present invention of the formula I, II, III, VIII and X which are active forms, and pharmaceutically acceptable salts, including but not limited to acid addition salts and physiological salts, and co-crystals thereof. Further elaboration methods are included when using the compounds of the present invention.
Formula I Formula I I Formula I I I Formula VIII (Arl) -G- (Ar2) -T-X Formula X Some of the compounds of formula I, II, III, VIII and X have asymmetric centers. Thus included in the present invention are racemic mixtures, enantiomerically enriched mixtures, diastereomeric mixtures, including enriched diastereomeric mixtures, and individual stereoisomers of the compounds of formula I, II, III, VIII and X and prodrugs thereof.
Definitions As used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise. T groups having more than one atom are read from left to right where the left atom of group T is connected to the phenyl group bearing the groups R1 and R2, and the right atom of group T is linked to the atom of phosphorus in X. For example, when T is -0-CH2 or -N (H) C (0) means -phenyl-0-CH2-P (O) YR Y 'R11 and -phenyl-N (H) C ( O) -P (O) YR ^ Y'R11. The term "alkyl" refers to a straight or branched chain or cyclic hydrocarbon radical with only carbon-carbon single 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? -C20. The term "aryl" refers to aromatic groups which have 5-14 ring atoms and at least one ring has a conjugated pi electron system and includes heterocyclic carbocyclic, aryl and biaryl aryl groups, all of which may be optionally substituted . Carbocyclic aryl groups are groups which they have 6-14 atoms in the ring where the atoms in the ring on the aromatic ring are carbon atoms. Carbocyclic aryl groups include carbocyclic and polycyclic monocyclic aryl groups or fused compounds such as optionally substituted naphthyl groups. Heterocyclic or heteroaryl aryl groups are groups which have 5-14 ring atoms where 1 to 4 heteroatoms are ring atoms in the aromatic ring and the remaining 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, N-oxide pyridyl, pyrimidyl, pyrazinyl, imidazolyl, and the like, all optionally substituted. The term "biaryl" represents aryl groups which have 5-14 atoms containing more than one aromatic ring including both fused ring systems and substituted aryl groups 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 one, two, three, four, five or six substituents, independently selected from lower alkyl, lower aryl, lower aralkyl, alkyl lower cyclic, 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 esters, carboxyl , carboxamide, 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 arylalkyloxyalkyl. "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 group heteroaryl. The term "alkylaryl-" refers to an aryl group substituted with an alkyl group. "Lower alkyl" refers to such groups where alkyl is lower alkyl. The term "lower" referred to herein in conjunction with organic compounds or radicals respectively refers to 6 carbon atoms or less. Such groups may be straight chain, branched, or cyclic. The term "higher" referred to herein in conjunction with organic compounds or radicals respectively refers to 7 carbon atoms or more. Such groups may be straight chain, branched, or cyclic. 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" refer to cyclic groups of 3 to 10 atoms, and in one aspect are 3 to 6 atoms, which contain at least one heteroatom, in a further aspect are 1 to 3 heteroatoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. Heterocyclic groups can be attached through a nitrogen or through a carbon atom in the ring. The heterocyclic alkyl groups include groups cyclic unsaturated, cyclic fused and spirocyclic. Suitable heterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl, 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 a -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 unsaturated groups which have 2 to 12 atoms and contain at least one carbon-carbon double bond and include straight chain, branched chain and cyclic groups. Alkenyl groups may be optionally substituted. Suitable alkenyl groups include allyl. "1-alkenyl" refers to alkenyl groups wherein the double bond is between the first and second carbon atoms. If the 1-alkenyl group is joined to another group, for example, is a substituent W attached to the cyclic phosphonate, it is attached to the first carbon. The term "alkynyl" refers to unsaturated groups which have 2 to 12 atoms and contain at least one carbon-carbon triple bond and includes straight chain, branched chain and cyclic groups. 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 second carbon atoms. If the 1-alkynyl group is bound to another group, for example, it is a substituent W attached to the cyclic phosphonate, it is attached to the first carbon. The term "alkylene" refers to a straight-chain, branched-chain or saturated cyclic divalent aliphatic group. In one aspect the alkylene group contains up to and including 10 atoms. In other aspects the alkylene group contains up to and including 6 atoms. In a further aspect the alkylene group contains up to and including 4 atoms. The alkylene group can be either linear, 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 alkyl-NR-alk group where 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- where "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 aryl-alk-O-alk group wherein "alk" is an alkylene group. "Aralkyloxyalkyl lower" refers to such groups wherein the alkylene groups are lower alkylene. The term "alkoxy" or "alkyloxy" refers to the alkyl-O- group. The term "alkoxyalkyl" or "alkyloxyalkyl" is refers to the alkyl-O-alk group wherein "alk" is an alkylene group. In "lower alkoxyalkyl" each alkyl and alkylene is lower alkyl and alkylene, respectively. The term "alkylthio" refers 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 lower alkyl and 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 close to an acyl or sulfonyl group as in 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 (O) - and RCtOJ-NR1-, where R and R1 include H, alkyl, aryl, aralkyl, and heterocycloalkyl. The term does not include urea, -NR-C (0) -NR-. The terms "sulfonamido" or "sulfonamido" refer to -NR2-S (= 0) 2- and RS (= 0) 2-NR1-, where R and Rl include H, alkyl, aryl, aralkyl, and heterocycloalkyl. The term it does not include sulfonylurea, -NR-S (= 0) 2-NR-. The term "carboxamidoalkylaryl" and "carboxamidoaryl" refers to an aryl-alk-NR ^ C (0), and ar-NR ^ C (0) -alq, 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-NR1-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 halo. The term "cyano" refers to -C = N. The term "nitro" refers to -N02. The term "acylalkyl" refers to an alkyl-C (0) -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 a group alkylene substituted with a heteroaryl group. The term "perhalo" refers to groups wherein each C-H bond has been replaced with a C-halo bond on an aliphatic or aryl group. Suitable perhaloalkyl groups include -CF3 and -CFC12. The term "carboxylic acid moiety" refers to a compound having a carboxylic acid group (-COOH), and salts thereof, a carboxylic acid ester, or a carboxylic acid substitute. The term "carboxylic acid substitutes" refers to groups that have nearly identical molecular forms and volumes such as the carboxylic acid and which exhibit similar physical and biological properties. Examples of carboxylic acid substitutes include, but are not limited to, tetrazole, 6-azauracil, aciisulfonamides, sulfonates, thiazolidinedione, hydroxamic acid, oxamic acid, malonamic acid, and carboxylic acid amides. Because phosphorus-containing thyromimetics (for example, compounds containing phosphonic acid, phosphonic acid monoester, and compounds containing phosphonic acid) have a markedly different biological activity compared to the carboxylic acid-containing thyromimetics, phosphonic acid, Monoester of phosphonic acid, and phosphonic acid are not considered to be substitutes for carboxylic acid in these compounds.
The term "co-crystal" as used herein means a crystalline material comprising two or more unique solids at room temperature, each containing distinctive physical characteristics, such as structure, melting point and heats of fusion. The co-crystals of the present invention comprise a co-crystal former linked to H to a compound of the present invention. The co-crystal former can be linked directly to H to the compound of the present invention or can be linked in H to an additional molecule which binds to the compound of the present invention. The additional molecule can be linked in H to the compound of the present invention or ionically linked to the compound of the present invention. The additional molecule can also be a second API. Solvates of compounds of the present invention which do not further comprise a co-crystal former are not "co-crystals" according to the present invention. The co-crystals may, however, include one or more solvate molecules in the crystalline matrix. That is, solvates of co-crystals, or a co-crystal further comprising a solvent or compound that is liquid at room temperature, is included in the present invention as a co-crystal. The co-crystals can 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 invention and the co-crystal former are constructed or linked together through 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 above-listed interactions, hydrogen bonding is the dominant interaction in co-crystal formation, (and an interaction required 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 acceptor of the other. Crystalline material comprising the 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 where the solvent is water. Other forms of the present invention include, but are not limited to, anhydrous forms and desolvated solvates. The ratio of the compound of the present invention to the co-crystal former or solvent can be specified as stoichiometric or non-stoichiometric. Relationships of 1: 1, 1.5: 1, 1: 1.5, 2: 1, 1: 2, and 1: 3 of API: co-crystals / solvent former are examples of stoichiometric ratios. The term "link" means the specific association of the compound of interest to the hormone receptor of the thyroid. One method of measuring the binding in this invention is the ability of the compound to inhibit the association of 125I-T3 with a mixture of thyroid hormone receptors by using purified or partially purified nuclear extracts or thyroid hormone receptors ( for example, alpha or beta) in a heterologous assay. The term "energy expenditure" means basal or resting metabolic ratio as defined by Schoeller et al., J Appl Physiol. 53 (4): 955 9 (1982). Increases in the resting metabolic rate can also be measured by using increases in the consumption of 02 and / or output of C02 and / or increases in body or organ temperature. The phrase "therapeutically effective amount" means an amount of a compound or a combination of compounds that improves, 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 the 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, adipic acid, benzenesulfonic acid, (+) - 7, 7-dimethyl-2-oxo-bicyclo [2.2.1] heptane-1-methanesulfonic acid, citric acid, 1,2-ethanedisulfonic acid, dodecyl sulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, hippuric acid, hemietanolic acid hydrochloride, HBr, HCl, Hl, 2-hydroxyethane sulfonic acid, lactic acid, lactobionic acid, maleic acid , methanesulfonic acid, methyl bromide acid, methyl sulfuric acid, 2-naphthalenesulfonic acid, nitric acid, oleic acid, acid, 4'-methylenebis [3-hydroxy-2-naphthalene carboxy], phosphoric acid, polygalacturonic acid, stearic acid, succinic acid , sulfuric acid, sulfosalicylic acid, tannic acid, tartaric acid, terephthalic 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 a chemically spontaneous reaction (s), chemical reaction (s) catalyzed by enzymes, and / or reaction (s) metabolic chemistries, or a combination of each. Standard prodrugs are formed by using groups attached to the functionality, for example, HO-, HS-, HOOC-, R2N-, associated with the drug, which are divided in vivo. Standard prodrugs include but are not limited to carboxylate esters where the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl as well as hydroxyl esters, thiol and amines where the group attached is an acyl group, an alkoxycarbonyl, aminocarbonyl, phosphate or sulfate. Illustrated groups are exemplary, not exhaustive, and other known varieties of prodrugs may be prepared by one skilled in the art. Such prodrugs of the compounds of the present invention 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 itself, and serves to improve the efficacy or safety of the drug through improved oral bioavailability, and / or pharmacodynamic half-life, etc. Forms of prodrugs of compounds can be used, for example, to improve bioavailability, improve the acceptability of the subject such as by concealing or reducing unpleasant characteristics such as bitter taste or gastrointestinal irritability, altering solubility such as for intravenous use, providing release or sustained or prolonged supply, improve the ease of formulation, or provide a specific supply of the compound site. 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 break 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 an alkyl cyclic ring is formed. These esters have been shown to generate phosphorus-containing nucleotides within cells through a postulated sequence of reactions that begin 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); a review see Ferres, H., Drugs of Today, 19: 499 (1983).) More recently, MS et al. (Summary of AAPS Western Regional Meeting, April, 1997) showed that these prodrugs of the alkyloxycarbonyloxymethyl ester on (9) - [(R) -2-phosphonomethoxy) propyl] adenine (PMPA) are bioavailable up to 30% in dogs.
Formula 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 an alkyl ring Cyclic is formed as shown in formula B. These esters are shown to generate phosphorus-containing nucleotides instead of cells through a sequence of reactions started with deesterification and followed by a series of elimination reactions (eg, Freed et al., Biochem. Pharm. 38: 3193-3198 (1989)).
Formula B Where R is -H, alkyl, aryl, alkylaryl, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino or cycloalkyl. Aryl esters have also been used as 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 probes as well as mono- and poly-substituted phenyl have been generated from the phosphonic acid precursor in studies carried out on animals and humans (Formula C). Another methodology 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 in the para position can accelerate hydrolysis. Benzyl analogs with 4-acyloxy or 4-alkyloxy group [Formula D, X = -H, 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 Phosphonate containing thiophosphonate proesters may also be useful in the delivery of drugs to hepatocytes.
These proesters contain a protected thioethyl portion as shown in Formula E. One or more of the oxygens of the phosphonate 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, bisulfide is reduced by a process mediated by reductase (Puech et al., Antiviral Res. 22: 155-174 (1993)). Thioesters will also generate free thiolates after hydrolysis mediated by esterase Benzaria, et al., J. Med. Chem. 39 (25): 4958-65. (nineteen ninety six) ) . Cyclic analogues are also possible and are shown to liberate the phosphonate in hepatocytes from isolated rats. The cyclic disulfide shown below is not previously described and is novel.
Formula E wherein Z is alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, or alkylthio. Other examples of suitable prodrugs include classes of proesters exemplified by Biller and Magnin (U.S. Patent No. 5,157,027); Serafinowska et al., J. Med. Chem. 38 (8): 1372-9 (1995); Starrett et al., J. Med. Chem. 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 described they are optionally substituted, including fused lactose bound to the omega position (formulas El and E-2) and optionally substituted 2-oxo-l, 3-dioxolees bonded through a methylene to phosphorus oxygen (Formula E-3) such as : omega 3-phthalidyl 2-oxotetrahydrofuran-5-yl 2-oxo-4,5-didehydro-1, 3-dioxolanmethyl E-l? -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. Prodrugs of Formula E-3 are an example of "optionally substituted heterocycloalkyl where the cyclic portion contains a carbonate or thiocarbonate." Propyl phosphonate proesters may also be used to deliver drugs within hepatocytes. These proesters may contain derivatives of a hydroxyl and hydroxyl group in the 3-position of the propyl group as shown in Formula F. The R and X groups can 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 (eg, McGuigan et al., J. Med. Chem. 42: 393 (1999) and references cited therein) as shown in Formula G and H.
Formula G Formula H Cyclic phosphoramidates have also been studied as phosphonate prodrugs due to their stability higher speculated compared to non-cyclic phosphoramidates (for example, Starrett et al., J. Med. Chem. 37: 1857 (1994)). Another type 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 ethylones, for example, bis (trichloroethyl) esters as described by McGuigan, et al., Bioorg Med. Chem. Lett. 3: 1207-1210 (1993), and the combined phenyl and benzyl nucleotide esters reported by Meier, C. et al., Bioorg. Med. Chem. Lett. 7:99 104 (1997). The structure It has a symmetry run plane through the double phosphorus oxygen bond when R6 = R6, V = W, and V and W either pointing both upwards or downwards both. The same of the structures where each -NR6 is replaced with -O-. The term "cyclic phosphonate ester of 1,3-propanol diol", "cyclic phosphonate diester of 1,3-propane diol", "2 oxo 2? 5 [1, 3, 2] dioxaphosphonane", "2 oxo [ 1, 3, 2] dioxaphosphonane "," dioxaphosphonane "refers to the following: The phrase "V and Z together are connected by means of 3-5 additional atoms to form a cyclic group containing 5-7 atoms, optionally containing 1 heteroatom, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy linked to an atom of carbon that is 3 atoms of both Y groups bound to phosphorus "includes 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 to be oxidized. The phrase "V and Z together are connected by means of 3-5 additional atoms to form a cyclic group, optionally containing a heteroatom, which is fused to an aryl group bonded in the beta position and gamma in the Y position linked to phosphorus "includes the following: The phrase "V and W together are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and are substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyl, alkylthiocarbonyloxy and aryloxycarbonyloxy, bonded to one of the additional carbon atoms that are three atoms of a Y linked to phosphorus "includes the following: The structure above has an acyloxy substituent which is 3 carbon atoms of a Y and an optional substituent, -CH 3, in the 6-membered ring. These have at least one hydrogen in each of the following positions: carbon bonded to Z; both alpha carbons on the carbon labeled "3" and the carbon bonded to "0C (0) CH3" above. The phrase "W and W 'together are connected by means of 2-5 additional atoms to form a cyclic group, which optionally contains 0-2 heteroatoms and V can be aryl, substituted aryl, heteroaryl or substituted heteroaryl" and includes the following: The structure above has V = aryl and a fused cyclopropyl group for W and W '. The term "cyclic phosphon (amide)" refers to Where Y is independently -O- u -NRV-. The carbon bonded to V may have a C-H bond. The carbon bonded to Z may also have a C-H bond. The compounds are named by having the ring carrying the groups R5 and R3 as a substituent on the ring bearing the groups R1 and R2. The naming of the prodrugs is done by having the diaryl system with its ligation T (Formula I, III or VIII) or D (Formula II) which is a substituent on the phosphorus atom contained in X. For example: Acid [3 -R1-5-R2-4- (4'-R6-3'-R3-benzyl) phenoxy] methyl phosphonic represents the formula: Acid [3-R1-5-R2-4- (4 '-R5-3' -R3-phenoxy) phenoxy] methyl phosphonic represents the formula: N- [3-Rx-5-R2-4- (4 '-R5-3' -R3-phenoxy) phenyl] carbamoyl phosphonic acid represents the formula: 2- [(3-Rx-5-R2-4- (4 '-R5-3' -R3-benzyl) phenoxy) methyl] -4-aryl-2-oxo-2? 5- [l, 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 ] -dioxaphosphonane: The term "cis" stereochemistry refers to the space ratio of group V and the carbon bonded to the phosphorus atoms in the 6-membered ring. The formula below shows a cis stereochemistry, The term "trans" stereochemistry refers to a space ratio of group V and carbon, linked to the phosphorus atoms in the 6-membered ring. The formula below shows a trans stereochemistry. V The formula below shows another trans stereochemistry.
The terms "S configuration", "S isomer" and "prodrug S" refers to the absolute S configuration of carbon C. "The formula below shows the S stereochemistry.
The terms "R configuration", "R isomers" 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. It 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 chiral compound consisting of more than one enantiomer than the other. The degree to which a sample is enantiomerically enriched is quantified by the enantiomeric ratio or the enantiomeric excess. The term "liver" refers to the organ of the liver. The term "enhance" refers to increasing or improving a specific property.
The term "liver specificity" refers to the relationship: [drug or a metabolite of the drug in liver tissue] [drug or a metabolite of the drug in the blood or other tissue] When measured in animals treated with the drug or a prodrug. The relationship can be determined by measuring tissue levels at a specified time or it can represent an AUC based on the measured values at three or more time points. The term "phosphorus-containing compounds" refers to compounds containing P03H2, P03"2, P02HR, P02R_1, and monoesters thereof." The term "fructose-1, 6-biphosphatase inhibitor" or "FBPase inhibitor" refers to to compounds that inhibit the activity of the enzyme FBPase and thereby block the conversion of fructose 1,6-bisphosphate, the substrate of the enzyme, to fructose 6-phosphate These compounds have an IC 50 of equal to or less than 50 μM on the Human liver FBPase measured according to the procedure found in US 6,489,476 The term "enhanced or enhanced liver specificity" refers to an increase in the ratio of liver specificity in treated animals to a liver. composed 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 phosphorus-containing compound of the present invention. In another embodiment, the control compound is the corresponding carboxylic acid derivative of the phosphorus-containing test compound. The term "improved oral bioavailability" refers to an increase of at least 50% in the absorption of the dose of the precursor drug, unless otherwise specified. In a further aspect, the increase in bioavailability of the prodrug (compared to the precursor drug) is at least 100%, which is twice the absorption. The oral bioavailability measurement usually refers to measurements of the prodrug, drug, or drug metabolite in blood, plasma, tissues, or urine following oral administration as compared to measurements following systemic administration of the orally administered compound. The terms "treat" or "treatment" of a disease include a decrease in the progress or development of a disease after the onset or currently reverse some or all of the effects of the disease. The treatment also includes palliative treatment. The term "prevention" includes a decrease in the progress or development of a disease before the onset or exclude the onset of a disease. The term "thyroid hormone receptors" (TR) refers to intracellular proteins located in the nuclei of cells that, after the binding of the thyroid hormone, they stimulate the transcription of specific genes by binding to the DNA sequences called thyroid hormone response elements (TRE). In this way, TRs regulate the expression of a wide variety of genes involved in metabolic processes (eg, 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 it is postulated that it plays a role in the stimulation of the hormone of the Thyroid lipogenesis. (Campbell, MC et al., Endocrinology 10: 1210 (2003) .The term "CPT 1" refers to carnitine palmitoyltransferase 1. The term "CYP7A" refers to cholesterol 7 alpha hydroxylase, 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 ferrihemoprotein reductase of NADPH.This enzyme CYP7A encoded by CYP7, converts cholesterol to 7 alpha hydroxycholesterol which is the first and limiting stage of the speed in the synthesis of bile acids The term "apoAI" refers to Apolipoprotein AI found in HDL and chylomicrons.It is an activator of LCAT and a ligand for the HDL receptor.The term "mGPDH" refers to glycerol 3 phosphate dehydrogenase. The term "hypercholesterolemia" refers to the presence of an abnormally large amount of cholesterol in cells and circulating blood plasma. "Lipemia" refers to the presence of an abnormally large amount of circulating blood lipids. The term "atherosclerosis" refers to a condition characterized by distributed lipid deposits irregularly in the intima of medium-sized and large arteries where such deposits cause fibrosis and calcification. Atherosclerosis raises 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 body mass index (BMI) of 30.0 or greater; and extreme obesity is defined as a BMI of 40 or greater. "Overweight" is defined as a body mass index of 25.0 to 29.9 (This is generally around 10 percent above an ideal body weight) The term "coronary heart disease" or "coronary disease" refers to an imbalance between the functional requirements of the myocardium 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 terms "fatty liver" and "liver steatosis" are interchangeable and refer to a disease or disorder characterized by significant deposition of lipids in hepatocytes of the liver (parenchymal cells). Simple fatty liver or steatosis of the liver is not associated with some other abnormalities of the liver such as scarring or inflammation. Fatty liver or Steatosis of the liver is common in patients who are quite overweight or have diabetes mellitus. The term "Stearate Non-Alcoholic Hepatitis (NASH)" refers to a disease or disorder characterized by inflammation of the liver in combination with fatty liver. NASH is a possible diagnosis when other causes of liver inflammation such as hepatitis B and C viruses, autoimmune disorders, alcohol, drug toxicity, and the accumulation of copper (Wilson's disease) or iron (hemochromatosis) are excluded. The term "Non-Alcoholic Fatty Liver Disease (NAFLD) refers to a broad spectrum of liver disease that ranges from (and including) simple fatty liver (steatosis) to non-alcoholic steatohepatitis (NASH), to cirrhosis (advanced scar formation) in the liver.) All stages of NAFLD have fatty liver in common.In NASH, the accumulation of fat is associated with varying degrees of inflammation (hepatitis) which can lead to scarring (fibrosis) of the liver. more easily diagnosed with non-invasive imaging modalities, such as ultrasound, magnetic resonance imaging, or computed tomography as examples, or after a percutaneous biopsy.Using ultrasound as an example of an imaging diagnostic tool do not Invasive: sonographic findings of diffuse fatty change include a diffuse hyperechoic ecotexture (shiny liver), increased eczexture of the liver compared to the kidneys, vascular deterioration, and deep attenuation (Yajima et al., Tohoku J Exp Med 139 (1): 43 -50 (1983)). When using percutaneous biopsy, the histological aspects of NAFLD are indistinguishable from those of alcohol-induced liver disease, of which, macrovesicular steatosis predominantly alone in > 33% of the hepatocytes will be used as the definition. Other histological features, such as variable amounts of cytological balloon formation and stained necrosis, scattered mixed neutrophilic-lymphocytic inflammation, glycogen nuclei, Mallory's hyaline, and perisinusoidal fibrosis may be present, but are not required for a diagnosis of NAFLD. The term "nephrotic syndrome" refers to a condition of heavy glomerular proteinuria which is associated with hyperlipidemia, increased risk of cardiovascular disease, and impaired renal function. Nephrotic dyslipidemia is noted for hypercholesterolemia, hypertriglyceridemia, elevated plasma concentration and weakened clearance of LDL, VLDL, and IDL. These abnormalities are mainly a result of deregulation of the key enzymes and receptors involved in lipid metabolism, including LDL receptor deficiency, lecithin-cholesterol acyl transferase (LCAT) deficiency, ester transfer protein in elevated plasma cholesterol, decreased HDL receptor, dysregulation of HMG-CoA reductase and 7a-hydroxylase, catabolism decreased apo B-100, increased production of Lp (a), down regulation of the lipoprotein lipase VLDL receptor and hepatic lipase, and overregulation of acyl-coenzyme A: diacylglycerol acyltransferase hepatic, acetyl-coenzyme A carboxylase, and fatty acid synthase . The term "chronic renal failure" refers to a chronic condition of the kidney that leads to abnormalities of lipid metabolism and a marked alteration of the plasma lipid profile. Typical dyslipidemia associated with chronic renal failure includes hypertriglyceridemia, elevated level and weakened clearance of VLDL, IDL, and LDL, inadequately reduced HDL cholesterol, and weakened maturation of HDL-3 low in cholesterol to HDL-2-rich cardioprotective cholesterol ester. The primary mechanisms of dyslipidemia include down regulation of lipoprotein lipase, VLDL receptor, hepatic triglyceride lipase, and LCAT. The term "diabetes" refers to a heterogeneous group of disorders that share glucose intolerance in common. It refers to disorders in which the use of carbohydrates and increases that of lipids and proteins; 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 weakened insulin secretion 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: impaired glucose tolerance, fasting hyperglycemia, glycosuria, increased hepatic glucose production, reduced hepatic glucose uptake and glycogen storage, absorption and reduced utilization of glucose in the body whole, 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)" refers to a known condition that precedes the development of open type 2 diabetes. It is characterized by abnormal excursions of glucose in the blood after a meal. Current criteria for the diagnosis of IGT are based on 2-h plasma glucose levels after an oral glucose test of 75g (144-199 mg / dL). Although it is variable population to studied population, the IGT advances to completely displace NIDDM to a proportion 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 "insulin resistance" is defined clinically as the weakened capacity of a known amount of endogenous or exogenous insulin to increase the absorption and utilization of glucose in the whole body. 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 , hyperinsulinemia, a characteristic dyslipidemia (high triglycerides, low high density lipoprotein cholesterol, and low density, low density lipoprotein cholesterol), obesity, distribution of fat in the upper body, accumulation of fat in the liver ( non-alcoholic fatty liver), NASH (nonalcoholic steatohepatitis), increased production of hepatic glucose, reduced absorption of hepatic glucose and storage in glycogen, hypertension, and increased prothrombotic factors and antifibrinolytics. This group 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 ovary syndrome. The "Metabolic Syndrome" or "Metabolic Syndrome X" is characterized by a group of metabolic risk factors in a person. They include: 0 Central obesity (excessive fatty tissue in and around the abdomen) ° Atherogenic dyslipidemia (fat disorders in the blood - mainly high triglycerides and low HDL cholesterol - which stimulate the accumulations of plaque in the arterial walls) ° High blood pressure ( 130/85 mmHg or higher) 0 Insulin resistance or glucose intolerance (the body can not adequately use insulin or blood sugar) 0 Prothrombotic state (eg, high fibrinogen or plasminogen activator inhibitor [-1 ] in the blood) Proinflammatory state (for example, highly sensitive reactive protein C in the blood) According to the present invention, "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: Male: Greater than 40 inches (101.6 cm) Female: Greater than 35 inches (89 cm) ° Triglycerides in fasting blood greater than or equal to 150 mg / dL ° HDL cholesterol in the blood: Men: Less than 40 mg / dL ° Women: Less than 50 mg / dL ° Blood pressure greater than or equal to 130/85 mmHg ° Fasting blood glucose greater than or equal to 110 mg / dL The term "thyroid response element" or "TRE" refers to an element that usually consists of average sites repeated directly with the consensus sequence AGGTCA. (Harbers et al., Nucleic Acids Res. 24 (12): 2252-2259 (nineteen ninety six) ) . TREs contain two average serving sites AGGTCA which can be considered as direct repetitions, inverted repetitions, or flipped repetitions.
The term "genes with thyroid response" 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, enhance or prolong atherosclerosis and diseases related to atherosclerosis, including but not limited to coronary heart disease. Atherogenic proteins include apoAI and Lp (a). The term "thyroid hormone, or TH "includes for example natural iodinated thironins from thyroglobulin (eg, T3, T4), as well as drugs such as Levothyroxine sodium which is the sodium salt of the levorotatory isomer of T4 and a drug commonly used as therapy of replacement in hypothyroidism Other uses include the treatment of non-endemic simple goiter, chronic lymphocytic thyroiditis, and thyrotropin-dependent thyroid carcinoma.Lyothyronine sodium is the sodium salt of the levorotatory isomer of T3.Liotrix is a mixture of 4: 1 levothyroxine and lyotronin The thyroid is a preparation derived from dry and defatted thyroid glands of animals The term "thyromimetic" or "T3 mimetic" as used herein, is intended to cover any portion which is bound to a thyroid receptor and acts as an agonist, antagonist or partial agonist / T3 antagonist.The thyromimetic can also be specified as an agonist, an antagonist, a partial agonist, or a partial antagonist. The tynomimetics of the present invention are linked presumably to the T3 binding site and can inhibit the binding of T3 to a thyroid hormone receptor using a heterologous displacement reaction. Thyromimetics of the present invention that can produce one or more of the effects mediated by L-triiodothyronine that occurs naturally in a tissue or target cell would be considered an agonist or partial agonist. Thyromimetics of the present invention that can inhibit one or more of the effects mediated by L-triiodothyronine that occurs naturally in a tissue or target cell would 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 as well as disorders that are associated with abnormal levels of lipoproteins, lipids, carbohydrates and insulin such as metabolic syndrome X, diabetes , weakened glucose tolerance, atherosclerosis, coronary heart disease, cardiovascular disease. The term "biogenesis of mitochondria" or "mitochondrialgenesis" refers to the rate at which nascent mitochondria are synthesized. The biogenesis of the mitochondria that occurs during the replication of the cells provides mitochondria sufficiently new for the precursor and daughter cells. Biogenesis of the mitochondria that occurs in the absence of cellular replication, leads to an increase in the number of mitochondria within a cell.
As used herein, the term "important" or "statistically significant" means a result (that is, experimental test result) where the value of p is = 0.05 (that is, the possibility of a type I error is less than 5%) as determined by an accepted measure in the art of statistical significance suitable for experimental design.
All references cited herein are incorporated by reference in their entirety.
Detailed Description of the Invention The present invention relates to methods of preventing or treating metabolic diseases with phosphonic acid-containing compounds or phosphonic acid monoesters, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of prodrugs, wherein Phosphonic acid-containing compounds or phosphonic acid monoesters are linked to a thyroid hormone receptor. Thyroid hormones and thyroid hormone mimetics bind to the thyroid hormone receptor in the nucleus of cells and can change the expression levels of genes that code for proteins that play an important role in diseases metabolic Metabolic diseases that can be avoided or treated with thyroid hormone mimetics include obesity and lipid disorders such as hypercholesterolemia, hyperlipidemia, and hypertriglyceridemia as described in more detail below. Other metabolic diseases that can be prevented or treated with thyroid hormone mimetics include fatty liver / steatosis, NAFLD, NASH, diabetes, impaired glucose tolerance, and insulin resistance. Conditions associated with these diseases, such as atherosclerosis, coronary artery disease, and heart failure, can also be treated with these thyroid hormone receptor binding compounds. Prior to the discoveries of the present invention, phosphinic acids were thought to be poor replacement of carboxylic acids based on differences in geometry, size and charge. Phosphonic acids may also show reduced binding affinities against enzymes that use or bind the analogous carboxylic acid. Phosphonic acids may also display differences in cellular and in vivo potency, oral bioavailability, pharmacokinetics, metabolism, and safety. T3 and previously reported T3 mimetics contain a carboxylic acid that is thought to be important for the binding and activation of genes with response to T3. The acid 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, in particular negatively charged compounds, to the nucleus. Prior to the discoveries of the present invention it was not clear therefore, whether the replacement of a carboxylic acid with a phosphonic acid would produce a compound that would be effective as a T3 mimetic because of the following: 1. it was not known if a T3 mimetic with a phosphonic acid instead of the carboxylic acid it would be transported in the liver cell through the cell membrane; 2. If the T3 mimic containing phosphonic acid is transported through the cell membrane of liver cells, it is not known whether the compound would be transported through the nuclear membrane within the nucleus; 3. if the T3 mimic containing phosphonic acid is transported through both the cell membrane and the nuclear membrane of the liver cell, it was not known whether the compound would bind to the TR receptor with a sufficiently large affinity to be effective; 4. if the T3 mimic containing phosphonic acid will be transported through both the cell membrane and the nuclear membrane of the liver cell, and bind to the TR receptor with sufficient affinity for activity of the receptor, it was not known whether the compound would act as an agonist or antagonist of receptor activity; 5. if the T3 mimic containing phosphonic acid will be transported across both the cell membrane and the nuclear membrane of the liver cell, and bind to the TR receptor with sufficient affinity for receptor activation, and act as an activity agonist of the receptor, it was unknown whether the compound would have a sufficiently high tissue selectivity and would have a therapeutic index large enough to be effective in the treatment of the diseases and disorders described herein while avoiding the undesirable side effects involving the heart. 6. finally, even if the T3 mimic containing phosphonic acid will be transported across both the cell membrane and the nuclear membrane of the liver cell, and bind to the TR receptor with sufficient affinity for receptor activation, and act as an agonist of receptor activity, and had a sufficiently high tissue selectivity and had a therapeutic index large enough to be effective in the treatment of the diseases and disorders described herein while avoiding the undesirable side effects involving the heart, it was not known whether the compounds of the present invention would 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 T3 phosphonic acid mimetic compounds or phosphonic acid monoesters of the present invention could be transported effectively through the cell membrane in liver cells and through the nuclear membrane where they bind to the receptors of the thyroid and activate the genes with response to the thyroid hormone. In addition, 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. Still surprisingly, the present inventors discovered that the compounds of the present invention act as agonists rather than antagonists and thus are effective in activating the genes with response to the thyroid hormone and for the uses described herein, such as lowering cholesterol . Still further surprisingly, the present inventors discovered that the compounds of the present invention are effective in activating the genes responsive to the thyroid hormone and for the uses described herein, such as cholesterol lowering, even for the compounds of the present invention. that bind to thyroid hormone receptors with affinity reduced when compared to the corresponding carboxylic acid derivative. Still further surprisingly, the present inventors discovered that the compounds of the present invention have a 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 the undesirable side effects that they involve the heart. Still further surprisingly, the present inventors show that, while the di-lower alkyl phosphonic acid ester contains thyromimetiso are inactive, the mono-lower alkyl ester of phosphonic acid containing the compounds have similar activity to the phosphonic acids containing the compounds. It is well known that many phosphonic acids in the blood are rapidly cleared by the kidneys, which greatly diminishes 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 bloodstream as active phosphonic acids after being processed in the liver, it was not known whether the active compound would be cleared rapidly by the kidneys or if the phosphonic acid would be re-absorbed or transported in the liver. Therefore it was unexpected when the current inventors discovered that the active phosphonic acid compounds of the present invention were not rapidly cleared by the kidneys. It was also unexpected when the present inventors discovered that the active phosphonic acid compounds of the present invention were re-absorbed or transported back into the liver. In fact, it was surprisingly found that the liver was the main mode of purification of the compounds tested. In one aspect, phosphonic acid-containing compounds or phosphonic acid monoesters, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs used in these methods bind to at least one thyroid hormone receptor with a Ki of < 100 nM relative to T3, or < 90nM, < 80nM, < 70nM, < 60nM, < 50nM, < 40nM, < 30nM, < 20nM, < 10nM, < 50nM, < lnM, < 0.5nM. The binding to the thyroid hormone receptor is easily determined by using assays described in the literature. For example, nuclear extracts from animal livers can be prepared according to the methods described by Yokoyama et al. (J. Med. Chem. 38: 695 707 (1995)). Linkage assays can also be performed using purified thyroid hormone receptors. For example, when using the methods used by Chiellini et al. (Bioorg, Med. Chem. 10: 333 346 (2002)), binding affinities of the ligand in competition are determined by using 125I-T3 and the human thyroid receptors TRal and TRßl. The latter methods advantageously allow the determination of the selectivity of the thyroid receptor. The methods described in Example A were used to determine the link of the compounds of this invention. In other aspects, the compounds containing phosphonic acid or phosphonic acid monoesters, 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 Sometimes, 6 or 8 times of increase or decrease in the expression of one or more of the genes with response to the thyroid hormone. Changes in gene expression can be detected in cells or in vivo. Prodrugs of compounds containing phosphonic acid or phosphonic acid monoester may increase cell uptake but in some cases are poorly converted to phosphonic acid or monoester due to the low levels of enzymes required for conversion. Changes in gene expression in vivo require either that the phosphonic acid of the invention is taken up by the tissue after administration or that the prodrug remains intact after administration enough to be distributed to the target organ and cell. After distribution to the cell, the enzymes responsible for unfolding the prodrug must act on the prodrug and convert it to phosphonic acid or phosphonic acid monoester. The compound must then be transported to the nucleus. If a portion of the compound is excreted from the cell, it must be transported back through the cell membrane and nuclear membrane. The prodrugs of the present invention that are activated in the liver and excreted by the liver as phosphonic acid compounds are retransported again through the nuclear and cellular membrane and into the nucleus. Despite being excreted from the liver and having to be transported back into the nucleus, and despite having reduced potency in vivo, the compounds containing phosphonic acid or phosphonic acid monoester and their prodrugs, surprisingly lead to a potent biological activity. This surprisingly high biological activity is attributed to the ability of the compounds of the present invention to modulate genes known to be regulated by T3. For example, mGPDH increased by > 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 the thyroid hormone with an estimated 8% of the liver genes regulated by the thyroid hormone. Quantitative fluorescent labeled cDNA microconfiguration hybridization was used to identify genes with thyroid response in the liver as shown in Table 1 to continued (Feng et al., Mol.Endocrinol., 14: 947-955 (2000)). Liver RNA from mice treated with T3 and hypothyroid were used in the study. Thyroid hormone treatment affected the expression of 55 genes from the 2225 different mouse genes sampled with 14 that increase > 2 times and 41 decreasing > 60% Genes reported to be affected by thyroid hormone are identified by using a variety of techniques including microconfiguration analysis. Genes have been identified in the studies, which are affected by T3 and the T3 mimetics that are important in metabolic diseases. T3-responsive genes in the liver include genes that affect lipogenesis, including spot 14, fatty acid transport protein, malic enzyme, fatty acid synthase (Blennemann et al., Cell Endocrinol 110 (12)). : 1 8 (1995)) and CYP4A. HMG CoA reductase and LDL receptor genes have been identified as affecting cholesterol synthesis and having a response to T3. CPT-1 is a response gene to T3 involved in the oxidation of fatty acids. Genes that affect energy expenditure, including mitochondria genes such as sn-glycerol 3-phosphate dehydrogenase mitochondria (mGPDH), and / or enzymes associated with proton leakage such as the adenine nucleotide transporter (ANT), Na + / K + ATPase, Ca2 + -ATPase and ATP synthase they are also genes with a response to T3. Genes responsive to T3 that affect glycogenolysis and gluconeogenesis include glucose 6 phosphatase and PEPCK. Genes with a response to thyroid hormone in the heart are not as well described as in the liver, but can be determined by using similar techniques such as those described by Feng et al. Many of the genes described by being affected in the heart are the same as described above for the liver. Common genes evaluated include sn-glycerol 3-phosphate dehydrogenase mitochondria (mGPDH), and light and heavy chains of myosin (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 hepatic gene expression. Evidence for agonist activity is obtained by using standard assays described in the literature. A commonly used assay allows a reporter cell assay in which cells, e.g., HeLa cells, Hek293 cells, or Chinese hamster ovary cells, are transfected with an expression vector for human TRal or TRßl and subsequently with a reporter vector that it encodes a secreted form of alkaline phosphatase whose expression is under the control of an element of thyroid hormone response. Agonist activity is measured by exposing the cells to the compounds, especially prodrugs that contain phosphorus of the compounds that are divided for phosphonic acid, phosphonic acid, or monoester by cell homogenates, followed by the determination of alkaline phosphatase activity in the cell culture medium when using a chemiluminescent assay (Grover et al. ., Proc. Natl. Acad. Sci. USA 100 (17): 10067 72 (2003)). In one aspect, the thyromimetics containing phosphonic acid or phosphonic acid monoester and their prodrugs and salts are useful in the prevention or treatment of arteriosclerosis by modulating the levels of atherogenic proteins, for example, Lp (a), apoAI, apoAII, LDL , HDL. Clinically open hypothyroidism is associated with premature and accelerated 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 prove beneficial for patients at risk of developing atherosclerosis or patients with atherosclerosis or diseases associated with atherosclerosis. T3 and the T3 mimetics are known to lower the levels of Lp (a), for example, in the monkey, with 3,5-dichloro-4- [4-hydroxy-3- (1-methylethyl) phenoxy] benzeneacetic acid ( Grover et al., Proc. Natl. Acad. Sci. USA 100: 10067-10072 (2003)). In human hepatoma cells, the T3 mimic CGS23425 ([[4- [4-hydroxy-3- (1-methylethyl) phenoxy] -3,5-dimethylphenyl] amino] oxo acetic acid) increased the expression of apoAI by activation of the thyroid hormone receptor (Taylor et al., Mol.Pharm. 52: 542-547 (1997)). Thus in one aspect, the thyromimetics containing phosphonic acid or phosphonic acid monoester, their salts and prodrugs can be used to treat or prevent atherosclerosis, coronary heart disease and heart failure because such compounds are expected to be distributed to the liver (Examples F and H) and modulate the expression and production of atherogenic proteins. In another aspect, the thyromimetics containing phosphonic acid or phosphonic acid monoester and their prodrugs and salts are useful for preventing and / or treating metabolic diseases such as obesity, hypercholesterolemia and hyperlipidemia and conditions such as atherosclerosis, coronary heart disease, heart failure, nephrotic syndrome, and chronic renal failure without affecting the function of the thyroid, thyroid production of circulating iodine thyronines such as T3 and T4, and / or the ratio of T3 to T4. Previously reported compounds that contain a portion of a carboxylic acid, 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) acid -methylethyl) phenoxy] benzeneacetic (Grover et al., Proc. Natl. Acad. Sci. USA 100: 10067-10072 (2003)) report that these selective compounds to TRβ, decrease the cholesterol dependent dose and TSH levels . The effects on cholesterol and TSH occur at the same dose or at established doses because they are not pharmacologically different (for example, 2 times). The T3 mimetics particularly useful in these methods would minimize the effects on thyroid function, production in the thyroid of circulating iodinated thyronines such as T3 and T4, and / or the ratio of T3 to T. Unlike previous T3 mimetics, the compounds or the present invention are more easily distributed to the liver and result in pharmacological effects at doses that do not adversely affect thyroid function, thyroid production of circulating iodine thyronines such as T3 and T4, and / or the ratio 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 an important effect is observed for a use described herein, for example, to decrease cholesterol, and the dose at which a decrease important in T3 or significant decrease in T4, or significant change in the ratio of T3 to T4 is observed, and it is less than 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, 8000 times, 9000 times or at least 10,000 times. In one modality, rather than a significant amount, the amount of change in T3 or T4 is a selected decrease of at least 5%, 10%, 15%, 20%, 25% or at least 30% of the levels in circulation. In one embodiment, the thyromimetics containing phosphonic acid or phosphonic acid monoester and their prodrugs and salts are useful for significantly lowering cholesterol levels without having an important effect on TSH levels. In another embodiment, the compounds of the present invention significantly decrease cholesterol levels without decreasing TSH levels by more than 30%, 25%, 20%, 15%, 10%, or 5%. The 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) T3 is now contraindicated for patients with obesity. 3, 5-Dichloro-4- [4-hydroxy-3- (1-methylethyl) phenoxy] benzeneacetic acid and others of the T3 mimetics are reported to result in weight loss in animals, eg, rodent and monkey models . The weight loss of these compounds can result from their effects on the liver as well as peripheral tissues. It is known that TH has a multitude of effects outside 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. TH can induce WAT differentiation, proliferation and intracellular accumulation of lipids. 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 free fatty acids followed by utilization of free fatty acids in tissues, for example, liver, muscle and heart. Weight loss through administration of liver-specific T3 analogues requires that the increased consumption of oxygen in the liver resulting from T3 is sufficient to result in a net energy expenditure of the whole body. 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. Mitochondria are the fuel source for all cellular respiration. The synthesis of new mitochondria is a complex process which requires more than 1000 genes (Goffart et al., Exp. Physiol. 88 (l): 33-40 (2003)). The mechanisms which control the biogenesis of mitochondria are not well defined, but are known to include exercise (Jones et al., Am. J. Physiol. Endocrinol.
Metab. 284 (1): E96-101 (2003)), overexpression of PGC-1 (Lehman et al., J. Clin. Invest. 106 (7): 847-56 (2000)) or AMP-activated protein kinase (Bergeron et al., Am. J.
Physiol. Endocrinol Metab. 281 (6): E1340-6 (2001)). An increase in the density of the mitochondria leads to a higher ratio of energy expenditure. Thyroid hormone has been shown to play a key role in the biogenesis of the mitochondria by increasing the expression of nuclear respiratory factor-1 and PGC-1 (Weitzel et al., Exp. Physiol. 88 (1): 121 8 (2003 )). Compounds which increase the expression of NRF-1 and / or PGC-1 can lead to an increase in the density of mitochondria within a cell. Such an increase would cause the cell to have a higher energy expenditure ratio. Methods to analyze NRF-1 and PGC-1 include immunostaining with specific antibodies, or analysis of mRNA levels. The compounds that caused increases in NRF-1 or PGC-1 would therefore lead to an increased energy expenditure. Even small increases in energy expenditure over prolonged periods of 1 Time (weeks to years) could cause a decrease in weight under isocaloric circumstances. Additional methods to evaluate the biogenesis of mitochondria include the analysis of mitochondrial proteins such as cytochrome c and cytochrome c oxidase, either by immunostaining or analysis of mRNA levels. The density of mitochondria can also be measured by counting the number of mitochondria in electron micrographs. In one aspect, the thyromimetics containing phosphonic acid or phosphonic acid monoester and their prodrugs and salts can be used to cause weight loss or prevent weight gain without side effects. It may be advantageous to use compounds that result in a high specificity of the liver (Examples F and G). In one aspect, compounds that result in increasing 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 show weight loss at doses that do not affect cardiac function, e.g., cardiac pulse, systolic contraction force, duration of diastolic relaxation, vascular tone, or heart weight, may be particularly putty in Weight loss and control of weight gain. In a further aspect, compounds that cause weight loss without affecting the function of the thyroid, Thyroid production of circulating iodine thyronines such as T3 and T4, and / or the ratio of T3 to T4 are particularly useful. In addition to its use in obesity and weight control, thyromimetics containing phosphonic acid or phosphonic acid monoester 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 "T2DMs" show high levels of chronic blood glucose. Fasting high blood glucose in T2DMs is related to the overproduction of glucose by a path in the liver known as the path of gluconeogenesis. Production in this pathway is controlled in part by enzymes in the pathway such as PEPCK, fructose 1,6-bisphosphatase and glucose 6-phosphatase as well as by hormones such as insulin, which may influence the expression and activities of these enzymes. T3 is known to worsen diabetes. Although the reason why T3 worsens diabetes is not known, the effect of T3 on the increase of gene expression of PEPCK and glucose-6-phosphatase may be the cause of increasing levels of glucose. It is known that T3 increases the lipolysis of accumulated triglycerides in fat and increases the circulation of free fatty acids. (K. S. Park, et al., Metabolism 48 (10): 1318-21 (1999)). The effect of T3 on free fatty acid levels may also be responsible for the negative effect on diabetes because high levels of free fatty acids potentiate a flow through the path of gluconeogenesis. The compounds of this invention, although mimicking T3, result in the preferential activation of the T3 genes in the T3 liver, are not expected to increase lipolysis in peripheral tissues which is expected to avoid the higher circulating levels induced by T3 of T3. free fatty acids and their effects on the increase in the flow of gluconeogenesis and decrease in insulin sensitivity. Increased hepatic sensitivity to insulin will decrease the expression of genes in PEPCK and glucose 6-phosphatase thus reducing gluconeogenesis. 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 sensitivity to insulin (Shulman, 2000) and thus should improve glycemic control in type 2 diabetics through decreased glucose production and enhanced absorption of glucose. 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 skeletal muscle, which produces concomitant increases in basal glucose uptake. Studies in obese, insulin resistant Zucker rats showed that TH therapy induces GLUT-4 expression in skeletal muscle and total improvement in hyperinsulinemia, although plasma glucose levels were moderately elevated (Torrance et al. Endocrinology 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 an increased energy expenditure. Increased energy expenditure can result in increased weight loss, which in turn can result in improved glyceric control. Diet and exercise are often used initially to treat diabetics. Exercise and weight loss increase insulin sensitivity and improve glycemia. Thus, additional uses of the compounds of the present invention include increasing energy expenditure, increasing insulin sensitivity and improving glycemia. In one aspect, the compounds that contain acid The phosphonic acid or phosphonic monoester 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, compounds of the present invention result in the improvement of hyperinsulinemia and / or decreased glucose levels in diabetic animal models at doses that do not affect cardiac function, e.g., cardiac pulse, strength of systolic contraction, duration of the Diastolic relaxation, vascular tone, or heart weight. In a further aspect, compounds of the present invention result in a decrease in hyperinsulinemia and / or decreased glucose levels in diabetic animal models at 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 has been limited by the deleterious side effects on the heart. Previous attempts to overcome this limitation have focused on targeting the liver selectively over the heart by using T3 mimetics that selectively bind TRβ on TRa. Because the heart expresses mainly TRa, previous researchers have tried to increase the therapeutic index of the T3 mimetics by increasing the selectivity of the compounds for TRβ which is expressed in the liver. Previous attempts have not focused on T3 mimetics that are selectively distributed to the liver above the heart or at least have not been successful. Thus, rather than selecting a particular tissue or organ, previous work has been directed towards the discovery of T3 mimetics that selectively act at the receptor level after the drug is not selectively distributed in both heart and liver tissue. Therefore, it was unexpected when the present inventors discovered that the phosphonic acid or phosphonic acid monoester compounds of the present invention are selectively distributed to the liver above the heart. Selective distribution to the liver over the heart was also found with prodrugs, which although processed in the liver, were excreted from the liver into the blood stream as active compounds of phosphonic acid or monoester. Thus, the compounds of the present invention can be targeted selectively to the liver and thereby increase the therapeutic index compared to T3 and T3 mimetics containing a carboxylic acid. The compounds of the present invention can therefore be dosed at levels that are effective in the treatment of metabolic disorders and other disorders where the liver is 17 the target drug without negatively affecting the function of the heart. Due to the selectivity of the phosphonic acid or phosphonic acid monoester-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. In fact, surprisingly some of the compounds of the present invention selectively bind TRa on TRβ and are highly effective for the uses described herein without having the negative side effects normally associated with the TRa-selective compounds. Thus, compounds of the formula I, II, III and VIII which selectively bind to TRβ on TRa by at least 5 times, 10 times, 20 times, 30 times, 40 times, 50 times, are included as an embodiment of the present invention. 60 times, 70 times, 80 times, 90 times, 100 times, 200 times, 300 times, 400 times or at least 500 times, and compounds of the formula I, II, III and VIII that selectively bind TRa on TRβ by less 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 by using assays and methods well described in the literature. Genes in extrahepatic tissues are monitored by using methods well understood by those skilled in the art. The assays include using tissue analysis of cDNA microconfiguration isolated from treated animals. The sensitivity of the heart to T3 makes the analysis of genes with response to T3 in the heart as well as the functional consequences of these changes on cardiac properties an additional strategy to evaluate the therapeutic index of the compounds of the present invention. The measured cardiac genes include mGPDH and myosin heavy and light chain. One method to measure the effects of T3 mimetics on the heart is by the use of assays that measure the transcription of genes in the myosin heavy chain heart T3 mediated. Compounds of the present invention were tested by 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 described herein, for example, to lower cholesterol, and the dose at which an important effect on a property or function, as described herein (eg, heart rate), is observed, 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, 9000 times or at least 10,000 times. Examples of the use described herein include but are not limited to reducing lipid levels, increasing the ratio of HDL to LDL or apoAI to LDL, reducing weight or avoiding weight gain, maintaining or improving glycemic control, lowering glucose levels in the blood, increase the biogenesis of the mitochondria, increase the expression of PGC-1, protein kinase activated by AMP or nuclear respiratory factor, inhibit hepatic gluconeogenesis or for the treatment or prevention of a disease or disorder selected from the group consisting of atherosclerosis, hypercholesterolemia, hyperlipidemia, obesity, fatty liver / steatosis, NASH, NAFLD, nephrotic syndrome, chronic renal failure, insulin resistance, diabetes, metabolic syndrome X, impaired glucose tolerance, hyperlipidemia, coronary heart disease, heart disease thyroid, thyroid cancer, depression, glaucoma, cardiac arrhythmias, heart failure, and osteoporosis . Examples where the property or function is a cardiac property / function include but are not limited to cardiac hypertrophy (ratio of heart weight to body weight), cardiac pulse, and various hemodynamic parameters, including systolic and diastolic blood pressure, left ventricular pressure Systolic terminal and maximum contraction and relaxation speeds.
A variety of methods are described that provide a means to evaluate the functional consequences of the cardiac action of T3, including the measurement of cardiac hypertrophy (ratio of heart weight to body weight), cardiac pulse, and various hemodynamic parameters, including blood pressure. systolic and diastolic, left ventricular end systolic pressure and maximum contraction and relaxation velocities using methods described by Trost et al., (Endocrinology 141: 3057 64 (2000)). Compounds of the present invention were tested by using the methods described in Examples B, D, and I. Other methods are also available to evaluate the therapeutic index including effects on muscle wasting and bone density. Compounds of the present invention were tested by using the methods described in Examples C and G.
The therapeutic index is determined by administering a wide range of doses to animals and determining the minimum dose that can induce a response in the liver in relation to the dose that can induce a response in the heart. Phosphonic acids are often transported poorly in cultured cells. In this way, reporter assays in cells, while often useful for confirming agonist activity, may not provide an adequate indication of potency. Thus, the evidence of Agonist activity is most often most readily obtained in vivo for the compounds of the present invention. In vivo assays include but are not limited to treating animals with phosphonic acid-containing compounds of the invention or a prodrug thereof and monitoring the expression of genes responsive to T3 in the liver or the functional consequences of gene changes responsive to T3. 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 to test compounds useful in the methods include normal rats and mice, animals made hypothyroid using methods well described in the literature, including mice with genes inactivated to the thyroid hormone receptor (eg, TRa + ~ such such as those used in Grover et al., 2003), or animals that show high cholesterol (eg, rat or hamster fed high cholesterol), obesity and / or diabetes (eg, fa / fa rat, Zucker diabetic fat rat, ob / ob mice, db / db mice, rodent with high fat food). (Liureau et al., Biochem Pharmacol.35 (10): 1691 6 (1986), Trost et al., Endocrinology 141 (9): 3057 64 (2000), and Grover et al., 2003). The drug or prodrug is administered by a variety of routes including by bolus, oral, and continuous infusion (Examples B, D, and I). The animals are treated for 1-28 days and the liver, heart and blood are isolated. Changes in gene transcription in relation to animals treated with vehicle and animals treated with T3 are determined by using northern blot analysis, RNAse protection or reverse transcription and subsequent PCR. Although methods for monitoring changes in thousands of liver genes are available, only a small number need to be monitored to demonstrate the biological effect of compounds in this invention. Typically, genes such as spot 14, FAS, mGPDH, CPT 1, and LDL receptor are monitored. Changes of > 1.5 times in two or more genes are considered proof that the compound modulates genes with response to T3 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 genes encode enzyme activities (eg, FAS, mGPDH), direct measurements of enzyme activity in properly extracted liver tissue can be made by using standard enzymatic techniques. In cases where genes encode receptor functions (eg, the LDL receptor), ligand binding studies or antibody-based assays (eg, Western blotting) can be performed to quantify the number of receptors expressed. Depending on the gene, TR agonists increase or decrease the activity of the enzyme or increase or decrease the link or number of the recipient.
The functional consequences of changing the levels of expression of hepatic genes with response to T3 is many times and easily demonstrated when using well-described trials in the literature. The administration of phosphonic acid or phosphonic acid monoester-containing compounds that bind to a TR for animals, can result in changes in lipids, including hepatic and / or plasma cholesterol levels; changes in lipoprotein levels including LDL cholesterol, lipoprotein a (Lp (a)); changes in hepatic glycogen levels; and changes in energy expenditure when 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 mice with inactivated TRa ~ _ genes. Cholesterol is measured when using standard tests. The compounds of the present invention were tested using the methods described in Example D and I. The hepatic levels of glycogen are determined from livers isolated from treated animals. Compounds of the present invention were tested by using the methods described in Examples D and E. Changes in energy expenditure are monitored by measuring changes in oxygen consumption (MV02). A variety of methods are fine described in the literature and include measurement in the whole animal when using Oxymax cameras (U.S. Patent No. 6,441,015). Treated rat livers can also be evaluated (Fernandez et al., Toxicol Lett., 69 (2): 205-10 (1993)) as well as isolated mitochondria of the liver (Carreras et al., Am. J. Physiol. Heart Circ. Physiol. 281 (6): H2282 8 (2001)). The hepatocytes of treated rats can also be evaluated (Ismail Beigi F et al., J Gen Physiol. 73 (3): 369-83 (1979)). Compounds of the present invention were tested by using the methods described in Examples C and G. Phosphonic acid monoester phosphonic acid phosphonic compounds that bind to a TR modulate the expression of certain genes in the liver that result in lipid effects ( for example, cholesterol), glucose, lipoproteins, and triglycerides. Such compounds can lower cholesterol levels which are 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 atherosclerosis and heart disease in patients. Such compounds may elevate lipoprotein levels such as apoAI or HDL and are useful in the prevention or treatment of atherosclerosis and heart disease in patients. Such compounds can cause a reduction in weight. Such compounds can decrease glucose levels in patients with diabetes. Another aspect is the compounds that in the presence of liver cells or microsomes result in compounds of formula I, II, III, VIII and X wherein X is phosphonic acid or phosphonic acid monoester. Methods of 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, VIII and X, 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 Formula I, II, III, VIII and X or a prodrug thereof comprises a stereocenter, is enantiomerically enriched or diastereomerically enriched, or a later coated steroisomer. 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 diastereomerically enriched 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 comprises the step of administering to a In a patient, an amount of a compound of Formula I, II, III, VIII and X, 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 Formula I, II, III, VIII and X 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 in very low density lipoprotein (VLDL). In another modality, LDL is reduced to a greater degree than HDL. In another modality, VLDL is reduced to a greater degree than HDL. In another modality, VLDL is reduced to a greater degree than LDL.
In one embodiment of the lipid reduction method, the lipid is triglycerides. In one embodiment, the lipid is triglycerides of the liver. 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. Also provided are methods of increasing the ratio of HDL to LDL, HDL to VLDL, LDL to VLDL, apoAI to LDL or apoAI to VLDL in an animal, the method comprises the step of administering to a patient an amount of a compound of Formula I , II, III, VIII and X, 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 Formula I, II, III, VIII and X, 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 hyperlipidemia or 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, VIII and X, 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 Formula I, II, III, VIII and X 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 atherosclerosis 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 and X, a prodrug thereof, or a pharmaceutically salt acceptable or co-crystal of it. In one embodiment, the compound is an active form. In another embodiment, the compound is a prodrug. In another embodiment, the compound of Formula I, II, III, VIII and X 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 mixture diastereomeric In yet another embodiment the compound is administered as an individual stereoisomer. Methods of reducing the fat content in the liver or preventing or treating fatty liver / 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 and X, 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 Formula I, II, III, VIII and X 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 nephrotic syndrome or chronic renal failure 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 and X, a prodrug thereof , or a pharmaceutically acceptable salt or co-crystal thereof. In one embodiment, the compound is an active form. In other modality the compound is a prodrug. In another embodiment, the compound of Formula I, II, III, VIII and X 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 reducing weight or preventing weight gain in an animal, the method comprises the step of administering to a patient an amount of a compound of Formula I, II, III, VIII and X, 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 Formula I, II, III, VIII and X 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. Prevention methods are also provided or obesity treatment in an animal, the method comprises the step of administering to a patient an amount of a compound of Formula I, II, III, VIII and X, 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 Formula I, II, III, VIII and X 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, VIII and X, 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 Formula I, II, III, VIII and X or a prodrug thereof comprises a stereocenter. In another embodiment, the compound is administered as a racemic mixture. In another embodiment, the compound 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 in an animal that is treated with a T3 mimetic are also provided, the method comprising the step of administering to a patient an amount of a compound of Formula I, II, III, VIII and X, 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 Formula I, II, III, VIII and X 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 glycemic control is maintained after the animal is treated for at least 14 days with the compound. In another embodiment, the glycemic control is improved 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 step of administering to a patient an amount of a compound of Formula I, II, III, VIII and X, 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 Formula I, II, III, VIII and X 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 diabetes, insulin resistance, metabolic syndrome X or weakened glucose tolerance 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 and X, 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 Formula I, II, III, VIII and X or a prodrug thereof comprises a stereocenter. In another embodiment, the compound is administered as a racemic mixture. In other 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, VIII and X, 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 Formula I, II, III, VIII and X 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 liver disease responsive to modulation of genes responsive to T3 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 and X, 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 Formula I, II, III, VIII and X 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, heart failure, or osteoporosis 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 and X 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 Formula I, II, III, VIII and X 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 modality the The compound is administered as a diastereomeric mixture. In yet another embodiment the compound is administered as an individual stereoisomer. Methods of increasing the biogenesis of mitochondria 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 and X, a prodrug thereof, or a salt pharmaceutically acceptable 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 Formula I, II, III, VIII and X 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, protein kinase activated by AMP or nuclear respiratory factor in an animal, the method comprises the step of administering to a patient an amount of a compound of Formula I, II, III, VIII and X, 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 Formula I, II, III, VIII and X 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 inhibiting hepatic gluconeogenesis in an animal, the method comprising the step of administering to a patient an amount of a compound of Formula I, II, III, VIII and X, a prodrug thereof, or a pharmaceutically acceptable salt. or co-crystal of it. In one embodiment, the compound is an active form. In another embodiment, the compound is a prodrug. In another embodiment, the compound of Formula I, II, III, VIII and X 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. Kits are also provided to reduce levels of lipids, increase the ratio of HDL to LDL or apoAI to LDL, reduce weight or prevent weight gain, maintain or improve glycemic control, decrease blood glucose levels, increase the biogenesis of the mitochondria, increase the expression of PGC-1, protein kinase activated by AMP or nuclear respiratory factor, inhibit hepatic gluconeogenesis, or for the prevention or treatment of a disease or disorder for which a compound of the present invention is effective in the prevention or treatment of, kits comprising: a) a pharmaceutical composition comprising a compound of Formula I, II, III, VIII or X 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, II, III, VIII or X or a prodrug thereof and a second pharmaceutical compound of the same Formula but wherein the first and second pharmaceutical compounds are not same molecules. Pharmaceutical compositions comprising a first pharmaceutical compound are also provided selected from Formula I, II, III, VIII or X or a prodrug thereof and a second pharmaceutical compound selected from Formula I, II, III, VIII, X or a prodrug thereof, but wherein the first and second pharmaceutical compounds are not they are both of the same Formula. Also provided are pharmaceutical compositions comprising a first pharmaceutical compound selected from Formula I, II, III, VIII or X or a prodrug thereof and a second pharmaceutical compound that is not a compound selected from Formula I, II, III, VIII or X 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, maintaining or improving glycemic control, decrease blood glucose levels, increase the biogenesis of the mitochondria, increase the expression of PGC-1, protein kinase activated by AMP or nuclear respiratory factor, inhibit hepatic gluconeogenesis or for the treatment or prevention of atherosclerosis , hyperlipidemia, hypercholesterolemia, obesity, fatty liver / steatosis, NASH, NAFLD, nephrotic syndrome, chronic renal failure, insulin resistance, diabetes, metabolic syndrome X, impaired glucose tolerance, hyperlipidemia, coronary heart disease cardiac, thyroid disease, thyroid cancer, depression, glaucoma, cardiac arrhythmias, heart failure, or osteoporosis. In one embodiment, a composition comprising the first and second compound is a single unit dose. In another embodiment, the unit is not in the form of a tablet, hard capsule or soft gel capsule. Also provided are pharmaceutical compositions of the present invention having 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 the prevention or treatment of, the kits comprise: a) a first pharmaceutical composition comprising a compound of Formula I, II, III, VIII or X or a prodrug thereof; 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 the prevention or treatment of; and c) at least one container for containing the first or second or both of the first and second pharmaceutical composition.
Kits are also provided to reduce lipid levels, increase the ratio of HDL to LDL or apoAI to LDL, reduce weight or prevent weight gain, maintain or improve glycemic control, decrease blood glucose levels, increase biogenesis of the mitochondria, increase the expression of PGC-1, protein kinase activated by AMP or nuclear respiratory factor, inhibit hepatic gluconeogenesis or for the treatment or prevention of a disease or disorder selected from the group consisting of atherosclerosis, hyperlipidemia, hypercholesterolemia, obesity, fatty liver / steatosis, NASH, NAFLD, nephrotic syndrome, chronic renal failure, insulin resistance, diabetes, metabolic syndrome X, impaired glucose tolerance, hyperlipidemia, coronary heart disease, thyroid disease, thyroid cancer , depression, glaucoma, cardiac arrhythmias, heart failure, and osteoporosis, the kits that comprise : a) a first pharmaceutical composition comprising a compound of Formula I, II, III, VIII or X or a prodrug thereof; 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 avoiding weight gain, maintaining or improving glycemic control, decrease blood glucose levels, increase the biogenesis of the mitochondria, increase the expression of PGC-1, protein kinase activated by AMP or nuclear respiratory factor, inhibit hepatic gluconeogenesis or for the treatment or prevention of atherosclerosis , hyperlipidemia, hypercholesterolemia, obesity, fatty liver / steatosis, NASH, NAFLD, nephrotic syndrome, chronic renal failure, insulin resistance, diabetes, metabolic syndrome X, impaired glucose tolerance, hyperlipidemia, coronary heart disease, thyroid disease , thyroid cancer, depression, glaucoma, cardiac arrhythmias, heart failure, or osteoporosis; and c) at least one container for containing the first or second or both of the first and second pharmaceutical composition. Methods are also provided to reduce lipid levels, increase the ratio of HDL to LDL or apoAI to LDL, reduce weight or prevent weight gain, maintain or improve glycemic control, decrease blood glucose levels, increase biogenesis of the mitochondria, increase the expression of PGC-1, protein kinase activated by AMP or nuclear respiratory factor, inhibit hepatic gluconeogenesis or for the treatment or prevention of atherosclerosis, hyperlipidemia, hypercholesterolemia, obesity, fatty liver / steatosis, NASH, NAFLD, nephrotic syndrome, chronic renal failure, insulin resistance, diabetes, metabolic syndrome X, impaired glucose tolerance, hyperlipidemia, coronary heart disease, thyroid disease, cancer thyroid, depression, glaucoma, cardiac arrhythmias, heart failure, or osteoporosis, the methods comprising 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, VIII or X or a prodrug thereof, and 2) a second pharmaceutical composition, wherein the second pharmaceutical composition is either another compound of Formula I, II, III, VIII or X or a prodrug thereof, or is not another compound of Formula I, II, III, VIII or X or a prodrug thereof. Methods are also provided to reduce lipid levels, increase the ratio of HDL to LDL or apoAI to LDL, reduce weight or prevent weight gain, maintain or improve glycemic control, decrease blood glucose levels, increase biogenesis of the mitochondria, increase the expression of PGC-1, protein kinase activated by AMP or nuclear respiratory factor, inhibit hepatic gluconeogenesis or for the treatment or prevention of atherosclerosis, hyperlipidemia, hypercholesterolemia, obesity, fatty liver / steatosis, NASH, NAFLD, nephrotic syndrome, chronic renal failure, insulin resistance, diabetes, metabolic syndrome X, impaired glucose tolerance, hyperlipidemia, coronary heart disease, thyroid disease, cancer thyroid, depression, glaucoma, cardiac arrhythmias, heart failure, or osteoporosis, the methods comprising 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, VIII or X or a prodrug thereof and 2) a second pharmaceutical composition that is effective alone to reduce lipid levels, increase the ratio of HDL to LDL or apoAI to LDL, reduce weight or prevent weight gain, maintain or improve glycemic control, decrease blood glucose levels, increase the biogenesis of the mitochondria, increase the expression of e PGC-1, protein kinase activated by AMP or nuclear respiratory factor, inhibit hepatic gluconeogenesis or for the treatment or prevention of atherosclerosis, hyperlipidemia, hypercholesterolemia, obesity, fatty liver / steatosis, NASH, NAFLD, nephrotic syndrome, chronic renal failure, insulin resistance, diabetes, metabolic syndrome X, impaired glucose tolerance, hyperlipidemia, coronary heart disease, thyroid disease, thyroid cancer, depression, glaucoma, cardiac arrhythmias, heart failure, or osteoporosis. Also provided is the use of a compound of the present invention for the manufacture of a medicament for reducing lipid levels, increasing the ratio of HDL to LDL or apoAI to LDL, reducing weight or preventing weight gain, maintaining or improving the glycemic control, decrease blood glucose levels, increase the biogenesis of the mitochondria, increase the expression of PGC-1, protein kinase activated by AMP or nuclear respiratory factor, inhibit hepatic gluconeogenesis or for the treatment or prevention of atherosclerosis, hypercholesterolemia, obesity, NASH, NAFLD, nephrotic syndrome, chronic renal failure, insulin resistance, diabetes, metabolic syndrome X, impaired glucose tolerance, hyperlipidemia, coronary heart disease, thyroid disease, thyroid cancer, depression, glaucoma, cardiac arrhythmias, heart failure, 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 , 2000 times, 3000 times, 4000 times, 5000 times 6000 times, 7000 times, 8000 times, 9000 times, 10,000 times, 20,000 times, 30,000 times, 40,000 times or 50,000 times greater selectivity. In one embodiment, the selectivity for the liver is compared to that of the heart. In another embodiment, selectivity for the liver is compared to the pituitary. In another embodiment, the selectivity for the liver is compared with that of the kidney. T3 mimetics are also provided which contain phosphonic acids or phosphonic acid monoester or prodrugs thereof which have improved selectivity for the liver as compared to a corresponding compound where the phosphorus-containing group is replaced with a carboxylic acid, but wherein the compound corresponding is otherwise identical. In one embodiment, the compound containing phosphonic acid or phosphonic acid monoester (or prodrug thereof) is 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 corresponding carboxylic acid compound. In one modality the selectivity of the liver is related to that of the heart. In another modality the selectivity of the liver is related to that of the kidney. In another modality the selectivity of the liver is related to the of the pituitary. T3 mimetics are also provided which contain phosphonic acids or phosphonic acid monoester or prodrugs thereof which have a decreased Ki as compared to a corresponding compound where the phosphorus-containing group is replaced with a carboxylic acid, but wherein the corresponding compound is another identical form. In one embodiment, the compound containing phosphonic acid or phosphonic acid monoester having at least 2 times, 5 times, 7 times, 10 times, 25 times, or 50 times less Ki than the corresponding carboxylic acid derivative compound (wherein Ki is measured in relation to T3). In another embodiment, the Ki of the phosphonic acid-containing compound or phosphonic acid monoester is < 150 nM, < 100 nM, < 90 nM, < 80 nM, < 70 nM, < 60 nM, < 50 nM, < 40 nM, < 30 nM, in relation to T3. For purposes of clarity, it is observed that the binding affinity increases as the numerical value of Ki decreases, that is, that is, there is an inverse relationship between Ki and the binding affinity. In another embodiment, the phosphonic acid or phosphonic acid monoester-containing compound has the same Ki as the corresponding carboxylic acid derivative. In another embodiment, the compound containing the phosphonic acid or phosphonic acid monoester has a higher Ki 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, < 90 nM, < 80 nM, < 70 nM, < 60 nM, < 50 nM, < 40 nM, < 30 nM, < 20 nM, < 10 nM, < 50 nM, < 1 nM, or < 0.5nM in relation to T3. In one modality, the thyroid hormone receptor is TRa. In one embodiment, the thyroid hormone receptor is TRβ. Compounds that bind at least one thyroid hormone receptor with a Ki of > 100 nM, = 90 nM, = 80 nM, > 70 nM, > 60 nM, > 50 nM, > 40 nM, = 30 nM, > 20 nM, > 10 nM, = 50 nM, = l nM, or = O .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 TRβ. 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 compounds containing phosphonic acid or phosphonic acid monoester that bind to the TRs. In one aspect, the novel compounds described below include compounds of formula I, II, III, VIII and X. 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 or phosphonic acid monoester that bind to and activate thyroid receptors in the liver. The present invention relates to compounds of formula I, II, III, VIII and X, including stereoisomers and mixtures of stereoisomers thereof, pharmaceutically acceptable salts thereof, co-crystals thereof, and prodrugs (including stereoisomers and mixtures of stereoisomers thereof) thereof, and pharmaceutically acceptable salts and co-crystals of the prodrugs. Importantly, the lower alkyl esters of phosphonic acid are not pro-drug prod- ucts when the phosphoester linkage is not split in vivo. Thus, the compounds containing phosphonic acid monoester of the invention are not themselves prodrugs. The compounds can be made in prodrugs as described above. The compounds of the present invention can 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 polymorphs different from 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 co-crystal forms and one or more polymorphs of one or more salt forms. The pharmaceutically acceptable base addition salts of the compounds herein are included in the present invention. The pharmaceutically acceptable base addition salts refer to those salts which retain their 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 of 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 ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including substituted amines that occur naturally, 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, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. The pharmaceutically acceptable acid addition salts of the compounds herein having a base functional group (eg, a prodrug whereby the phosphorus-containing group is protected with a group comprising a base functional group) are also included in the present invention. The pharmaceutically acceptable acid addition salts refer to those salts which retain their effectiveness and biological properties of the free base, which are not biologically or otherwise undesirable. These salts are 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, salts of acistrate, bromohydrate, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, besylate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, lauryl sulphonate, bromide, fumarate, pamoate, glucuronate, iodohydrate, iodide, sulfate, xinofoate and chloride. 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 a pharmaceutically acceptable composition. The compounds can also be part of a biological material or sample. 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 (sham or current), intestinal fluid (sham or current), and urine. In one aspect the invention relates to a phosphonic acid or phosphonic acid monoester containing a thyromimetic compound 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 bind Ar1 and Ar2 through a single C, S, Se, O or N atom or through two C atoms or through a C atom and an S atom or through of a C atom and an 0 atom, where C and N are substituted; T is an atom or group of atoms linked to Ar2 up to X through 1-4 contiguous atoms or is absent; X is a phosphonic acid, monoester of phosphonic acid, or a 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 - (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, 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) (OH) 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 fluoro, and R5 is -OH, then X is not P (0) (0H) 2, P (0) (OH) (0CH3) or P (0) (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 -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-Ce alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aryloxy, substituted amide, sulfone, sulfonamide and C3-C 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 C? -C4 alkyl or not substituted, and substituted or unsubstituted C3-C5 cycloalkyl; R7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, -0- C C-C4 alkyl, -SH and -S-C C-C alkyl; and R5 is selected from the group consisting of hydroxyl, -0 optionally substituted C6-C6 alkyl, and -0C (0) Re; then X is not -P (0) (0H) 2. In another aspect the invention relates to a method for improving the selectivity of the liver against the heart or for increasing the therapeutic index of a thyromimetic compound of the formula Y: (Ar1) -G- (Ar2) -TE where: Ar1 and Ar2 are aryl groups; G is an atom or group of atoms that are linked to Ar1 and Ar2 through an atom of C, S, Se, 0 or N single or through two C atoms or through a C atom and an S atom or through a C atom and a 0 atom, where C and N are substituted; T is an atom or group of atoms linked to Ar2 up to E through 1-4 contiguous atoms or is absent; E is a moiety or functional group with a pKa = 7.4, is carboxylic acid (COOH) or esters thereof, sulfonic acid, tetrazole, hydroxamic acid, 6-azauracil, thiazolidinedione, acisulphonamide, or other carboxylic acid substitutes known in the art or a prodrug thereof, or an atom or group of atoms containing a 0 or N which binds to the thyroid hormone binding cage 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 phosphonic acid, phosphonic acid monoester, or a 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 another aspect the invention relates to a method for designing a thyromimetic compound with improvement in the selectivity of the liver against the heart or improving the therapeutic index comprising the steps of: obtaining a formula by a thyromimetic of the formula Y: (Ar1) -G- (Ar2) -T-E wherein: Ar1 and Ar2 are aryl groups; G is an atom or group of atoms that are linked to Ar1 and Ar2 through a single C, S, Se, O or N atom or through two C atoms or through a C atom and an S atom or through a C atom and an O atom, where C and N are substituted; T is an atom or group of atoms linked to Ar2 up to E a through 1-4 contiguous atoms or is absent; E is a portion or functional group with a pKa = 7.4, is carboxylic acid (COOH) or esters thereof, sulfonic acid, tetrazole, hydroxamic acid, 6-azauracil, thiazolidinedione, aciisulfonamida, or other substitutes carboxylic acid known in the art or a prodrug thereof, or an atom or group of atoms containing a 0 or N that binds to the thyroid hormone binding cavity 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 phosphonic acid, phosphonic acid monoester, or a prodrug thereof; and synthesizing a compound of the formula X wherein X is phosphonic acid, phosphonic acid monoester, or a 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 aspect, the invention relates to a compound of the formula I: wherein: G is selected from the group consisting of -0-, -S-, -Se-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF -, -C (0) -, -CH (OH) -, -NH-, and -N (CX-C4 alkyl) -, or CH2 linked to any of the preceding groups; or G is R50-R51 wherein; R50-R51 together are -C (R52) = C (R52) - or alternatively R50 and R51 are independently selected from 0, S and -CH (R53) -, with the provisos that at least one R50 and R51 is -CH (R53) -, and when one of R50 and R51 is 0 or S, then R53 is R54; R54 is hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl; R53 is selected from hydrogen, halogen, hydroxyl, mercapto, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 6 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; and R52 is selected from hydrogen, halogen, C? ~ C4 alkyl, C2-C4 alkenyl, C2-C4, alkoxy C? -C4, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; T is selected from the group consisting of - (CR a 2) k- ^ -CRb = CRb- (CR a 2) n - (CR a 2) n-CRb = CRb-, - (CR a 2) -CRb = CRb- (CR a 2) - , -0 (CRb2) (CRa2) n-, -S (CRb2) (CRa2) n-, -N (Rc) (CRb2) (CRa2) n-, -N (Rb) C (0) (CRa2) n- , - (CR a 2) mC (Rb) (NRbRc) -, -C (O) (CR a 2) m-, - (CR a 2) mC (0) -, - (Crb2) -O- (Crb2) - (CR a 2) p -, - (CRb2) -S- (CRb2) - (CRa2) p-, - (CR2) -N (Rc) - (CRb2) - (CRa2) p-, - (CRa2) p- (CRb2) -O - (CRb2) -, - (CRa2) p- (CRb2) -S- (CRb2) -, - (CRa2) p- (CRb2) -N (Rc) - (CRb2) -and- (CH2) pC (0) N (Rb) C (Ra2) -; 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, optionally substituted -O-C1-C4 alkyl, -OCF3, -OCHF2, -OCH2F, -S-C1 alkyl- C4 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 that binds to the same C 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 that consists of hydrogen, optionally substituted C 1 -C 4 -alkyl, -C (O) -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 -C alkyl, optionally substituted -S-C-C3 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl , -CF 3, -CHF 2, -CH 2 F, -0CF 3, -OCHF 2, -OCH 2 F, -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, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, cyano, optionally substituted -C1 -C2 alkyl, alkenyl- C2-C2 optionally substituted, optionally substituted C2-C2-C2 alkynyl, optionally substituted - (CRa2) maryl, - (CRa2) optionally substituted cycloalkyl, (CRa2) optionally substituted mheterocycloalkyl, -C (Rb) = C (Rb) ) -aryl, -C (Rb) = C (Rb) -cycloalkyl, -C (Rb) = C (Rb) -heterocycloalkyl, -C = C (aryl), -C = C (cycloalkyl), -C = C (heterocycloalkyl), - (CRa2) n (CRb2) NRfRg, -ORd, -SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRfRg, -C (0) NRfRg, -C (0) ORh, -C (0) Re, -N (Rb) C (O) 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 20 alkenyl, C 2 -C 2 alkynyl optionally substituted, - (CRb2) optionally substituted naril, - (CRb2) optionally substituted cycloalkyl, - (CRb) optionally substituted n-heterocycloalkyl, and -C (0) NRfRg; Each Re is optionally substituted C 1 -C 2 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl, optionally substituted (C 1 -C) aryl, optionally substituted - (CR a 2) n cycloalkyl, and - (CRa2) optionally substituted n-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 2, - (CR 2) optionally substituted, optionally substituted - (CRb2) n-cycloalkyl, and optionally substituted - (CRb2) nheterocycloalkyl, or Rf and Rg can together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, which may contain a second heterogroup 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 1 -C 4 -alkyl, -ORb, oxo, cyano, -CF3, -CHF2, -CH2F, optionally substituted phenyl, and -C (0) ORh; Each Rh is selected from the group consisting of alkyl Optionally substituted -C 2 -C 2, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 1 -C 2 alkynyl, optionally substituted - (CR 2) naryl, - (CR b 2) n Optionally substituted cycloalkyl, and - (CR 2) nheterocycloalkyl optionally substituted; R5 is selected from the group consisting of -OH, -0-C-C6 alkyl optionally substituted, -0C (0) Re, -0C (0) 0Rh ', -NHC (0) 0Rh, -0C (0) NH (Rh), -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh ); or R3 and R5 are taken together with the carbons to which they join to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, they do not include the unsaturation on the ring to which R3 and R5 are linked, including 0 to 2 heteroatoms independently selected from -NR-, -0-, and -S-, with the proviso that when these are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms have to be separated by at least a carbon atom; X is P (0) (YR11) (Y'R11); Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are both -0-, R11 is 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 (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 when Y and Y 'are both -NRV-, then R11 is linked to -NRV- it is independently selected from the group consisting of -H, - [C (Rz) 2] qC (0) 0Ry, -C (Rx) 2C (0) 0Ry, - [C (Rz) 2] qC (0) SRy, and -cycloalkylene-C (0) 0Ry; and when Y is -0- and Y 'is NRV, then R11 is 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-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; and R11 is 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; but if both R11 are alkyl, at least one is alkyl higher; and both R11 are not -H; or when Y and Y 'are independently selected from -0- and -NRV-, then R11 and R11 together form a cyclic group comprising -alkyl-S-S-alkyl-, or R11 and R11 together 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 carbon atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydrogen, hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy are bonded to a carbon atom which are three atoms of both groups Y attached to phosphorus; or or together V and Z are connected by means of 3-5 additional carbon atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon 0 carbon substituted by hydrogen, and the cyclic group is fused to an aryl group in the beta position and gamma in 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 or carbon substituted by hydrogen and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, is bonded to one of the carbon atoms which are three atoms of a Y bonded 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 or carbon substituted by hydrogen, and V can be aryl, aryl substituted, 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 or carbon replaced by hydrogen, and V can 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 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 cycloalkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the conditions 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. In another aspect, the invention relates to a compound of the formula I: where: G, T, k, m, n, p, Ra, Rb, Rc, R1, R2, R3, R4, Rd, Re, Rf, Rg, Rh, R5, X, V, W, W ', Z, q, Rz, Ry, Rx, and Rv are as defined above; Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are both -O-, R11 is linked to -O- it 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-S-C (0) Ry, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; when Y and Y 'are both -NRV-, then R11 is linked to -NRV- it is independently selected from the group consisting of -H, - [C (Rz) 2] qC (0) 0Ry, -C (Rx) 2C (0) 0Ry, - [C (Rz) 2] qC (0) SRy, and -cycloalkylene-C (0) 0Ry; when Y is -0- and Y 'is NRV, then R11 is linked to -0- it 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 (O) NRZ2, -NRz-C ( 0) -Ry, -C (Rz) 2-OC (0) Ry, -C (Rz) 2-0-C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-S-C (0) Ry, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; and R11 is 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 form a cyclic group comprising -alkyl-S-S-alkyl-, or together R11 and R11 are the group: with the conditions that: a) when G is -0-, T is -CH2-, R1 and R2 are each chlorine, R3 is phenyl, R4 is hydrogen, and R5 is -OH, then X is not P (0) ) (OH) (OCH2CH3); b) 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 (O) (OH) 2 or P (O) (OCH2CH3) 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. In another aspect, the invention relates to a compound of the formula I: where: G, T, k, m, n, p, Ra, Rb Rc, R1, R2, R3, R4, Rd, Re, Rf, Rg, Rh, R5 X, V, W, W, Z, q , Rz, Ry, Rx, and Rv are defined as above; Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are both -O-, R11 is linked to -O- it 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, -alkylaryl optionally substituted, -C (Rz) 2OC (O) NRZ2, -NRz-C (O) -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 both -NRV-, then R11 is linked to -NRV- it is independently selected from the group consisting of -H, - [C (Rz) 2] qC (0) ORy, -C (Rx) 2C (O) ORy, - [C (Rz) 2] qC (O) SRy, and -cycloalkylene-C (O) ORy; when Y is -O- and Y 'is NRV, then R11 is linked to -0-is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, CH -heterocycloalkyl optionally substituted wherein the cyclic contains a carbonate or thiocarbonate, -alkylaryl optionally substituted, -C (Rz) 20C (0) NRZ2, -NR2-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) ) 2-0-C (0) 0Ry, -C (R2) 20C (0) SRy, -alkyl-S-C (0) Ry, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; and R11 is 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 -NRV-, then R11 and R11 together form a cyclic group comprising -alkyl-S-S-alkyl-, or together R11 and R11 are the group: with the conditions that: a) when G is -0-, -S-, -Se-, -S (= 0) -, -S (= 0) 2-, -CH2-, -C (0) - , -NH- and, T is - (CH2) 0-4- or -C (0) NH (CRb2) -, R1 and R2 is independently selected from the group consisting of hydrogen, halogen, C-C4 alkyl, R3 is -C (0) NR25R26, -CH2-NR25R26, -NR25-C (0) R26, -OR27, R28, or RYX, R4 is hydrogen, halogen, cyano or alkyl, and R5 is -OH, R25 and R26 are each independently selected from the group consisting of hydrogen, aryl, heteroaryl, alkyl, cycloalkyl, aralkyl or heteroaralkyl, R27 is aryl, heteroaryl , alkyl, aralkyl, or heteroaralkyl, R28 is aryl, heteroaryl, or cycloalkyl, R29 is hydrogen, aryl, heteroaryl, alkyl, aralkyl, heteroaralkyl, then X is not -P (0) (0H) 2, or -P (0 ) (0-lower alkyl) 2; b) when G is -0-, -S-, -Se-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -C (0) -, - NH- and, T is -C (0) NH (CRb2) -, R1 and R2 are independently halogen, cyano, C-C4-alkyl, R3 is halogen, Ci-Ce alkyl, C2-C6 alkynyl, cycloalkenyl -C4-C7, cycloalkoxy-C3-C7, -S (= 0) 2 (NR14R15), -N (R16) S (= 0) 2R17, -SR17, -S (= 0) R17, -S (= 0) 2R17, -C (0) R16, or -CR18 (OR16) R19, R4 is halogen, cyano or alkyl, and R5 is -OH, -0-optionally substituted Ci-Cß alkyl, aroyl or alkanoyl, R14, R15, R16, R18 and R19 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroalkyl , arylalkyl, and heteroarylalkyl, or R 14 and R 15 can together comprise a chain of 3 to 6 methylene groups to form a ring of 4 to 7 members in size, R 17 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroalkyl, arylalkyl , and heteroarylalkyl, then X is not -P (0) (0H) 2 or -P (0) (O-lower alkyl) 2; c) when G is 0 and T is - (CH2) k-, R1 and R2 are independently halogen, alkyl of 1 to 3 carbons, R3 is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 7 carbons, R4 is hydrogen, R5 is OH, then X is not phosphonic acid or lower alkyl ester thereof; d) when G is 0, T is - (CH2)? _ 3- or - (CH2)? -2-CH (Raa), Raa is -OH, -NH2, -NH (C? _4 alkyl), -NH ( C2_4 alkenyl), or -NH (C2_4 alkynyl), R4 is hydrogen, R1 and R2 are independently selected from halogen, Ci alkyl substituted with 1, 2, or 3 hydrogen, fluoride, or a bioisostomeric equivalent, C? -4 alkyl and CF3, and R3 and R5 are taken together with the carbon atoms to which they are bound to form a five-membered heterocyclic ring of the formula -A- C (Rbb) = B- where A, where the group R5 is linked, is selected from -0-, -S-, and -NRh-, B is selected from -CH-, and -N-, Rbb is selected from C C-io aryl / C 5-9 heteroaryl, or C 1-4 alkyl, then X is not phosphonic acid, phosphamic acid, or a lower alkyl ester or acyloxyalkyl ester thereof; e) when G is 0, R4 is hydrogen, R3 is selected from hydrogen, halogen, cyano, C6-? aryl, C5_? 0 heteroaryl, C? _? 0 alkyl, C3-3 cycloalkyl, C2_? 0 alkenyl, alkynyl C2_? O, and R5 is -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2Re, -NHC (= S) NH (Rh) or -NHC (0) NH (Rh) , T is - (CH2)? _ 2-, -CH = CH-, -0 (CH2)? -2-, O -NH (CH2)? -2-, then X is not phosphonic acid or phosphamic acid or ester of lower alkyl thereof; f) when G is -CH2-0-, where the oxygen atom is linked to the ring leading to the group T, T is - (CH2)? - 2CH (RCC), Rcc is -OH, -SH, -NH2 , or -NH (C? _4), R1 and 2 are each independently selected from chlorine, bromine, C? _4 alkyl, C2_4 alkenyl, and C2_4 alkynyl, then X is not phosphonic acid or phosphamic acid or lower alkyl ester of the same; g) V, Z, W, W 'are not all -H; and h) 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. In one aspect, the invention relates to a compound of formula II: wherein: A is selected from the group consisting of -NR1-, -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, and C 1 -C 4 alkyl; 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-, -Se-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF-, - C (0) -, -CH (OH) -, -NH-, and -N (C1-C4 alkyl) -, or CH2 linked to any of the preceding groups; or G is R50-R51 wherein; R50-R51 together are -C (R52) = C (R52) - or alternatively R50 and R51 are independently selected from 0, S and -CH (R53) -, with the provisos that at least one R50 and R51 is -CH (R53) -, and when one of R50 and R51 is 0 or S, then R53 is R54; R54 is hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C alkenyl, C 2 -C 4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl; R53 is selected from hydrogen, halogen, hydroxyl, mercapto, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; and R52 is selected from hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; 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 alkyl, halogen, -OH, -O-C 1 -C 4 alkyl optionally substituted, -OCF 3, -OCHF 2, -OCH 2 F, -S-C alkyl Optionally substituted -C4, -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 is linked to the same C is a hydrogen, or is linked by means of a carbon atom; R1 and R2 are each independently selected from the group consisting of halogen, C-C4 alkyl optionally substituted, -S-C-C3 alkyl optionally substituted, C2-C4 alkenyl optionally substituted, C2-C4 alkynyl optionally substituted, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, -O- C1-C3 alkyl, and cyano; R 8 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 20 alkenyl, optionally substituted C 2 -C 4 alkynyl, -CF 3 , -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, -O-C-C3 alkyl optionally substituted, hydroxy, - (CRa2) aryl, (CRa2) cycloalkyl, - (CRa2) heterocycloalkyl, -C (O) aryl, C (O) cycloalkyl, -C (O) heterocycloalkyl, -C (O) alkyl and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -0CH2F, cyano, optionally substituted -C? -C? 2 alkyl, alkenyl- C2-Ci2 optionally substituted, C2-Ci2 alkynyl optionally substituted, - (CRa2) optionally substituted maryl, - (CRa2) optionally substituted cycloalkyl, - (CRa2) mheterocycloalkyl optionally substituted, -C (Rb) = C (Rb) -aryl , -C (Rb) = C (Rb) -cycloalkyl, -C (Rb) = C (Rb) -heterocycloalkyl, -C = C (aryl), -C = C (cycloalkyl), -C = C (heterocycloalkyl), - (CRa2) n (CRb2) NRfRg, -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 1 -C 2 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl 2, optionally substituted (CR 2) naryl, - (CR 2) n Optionally substituted cycloalkyl, - (CRb2) n-heterocycloalkyl optionally substituted, 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 2 alkynyl 2, optionally substituted (CRa 2), - ( CRa2) n Optionally substituted cycloalkyl, and - (CRa2) n -heterocycloalkyl optionally substituted; R f and R g are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 2 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl, optionally substituted (C 2 -C 2) substituted, - (CRb2) nCycloalkyl optionally substituted, and - (CRb2) nheterocycloalkyl optionally substituted, or Rf and Rg can together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, which may contain a second heterogroup 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, -ORb, oxo, cyano, -CF 3, -CHF 2, CH 2 F, optionally substituted phenyl, and -C (0) ORh; Each Rh 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 2, optionally substituted - (CR 2) naryl, - ( CRb2) optionally substituted cycloalkyl, and - (CRb2) n -heterocycloalkyl optionally substituted; or R3 and R8 are taken together with the carbon atoms to which they are bound to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, they do not include the unsaturation on the ring to which R3 and R8 are linked , including 0 to 2 heteroatoms independently selected from -NRh-, -O-, and -S-, with the proviso that when these are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms have to be separated by at least one carbon atom; or R8 and G are taken together with the carbon atoms to which they join to form an optionally substituted ring comprising -CH = CH-CH =, -N = CH-CH =, -CH = N-CH = or -CH = CH-N =; R5 is selected from the group consisting of -OH, optionally substituted -0 Ci-Ce alkyl, -0C (0) Re, 0C (0) 0Rh, -NHC (0) 0Rh, -OC (0) NH (Rh), -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2 Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); or R3 and R5 are taken together with the carbons to which they join to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, they do not include the unsaturation on the ring to which R3 and R5 are linked, including 0 to 2 heteroatoms independently selected from -NRh-, -0-, and -S-, with the proviso that when these are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms have to be separated by at least a carbon atom; X is P (0) YRuY'Rn; Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are both -0-, R11 is 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-S-C (O) Ry, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; when Y and Y 'are both -NRV-, then R11 is linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] qC (0) ORy, -C (Rx) 2C (O) ORy, - [C (Rz) 2] qC (O ) SRy, and -cycloalkylene-C (O) ORy; when Y is -O- and Y 'is NRV, then R11 is 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 portion cyclic contains a carbonate or thiocarbonate, optionally substituted alkylaryl, -C (R2) 2OC (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-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; and R11 is linked to -NRV- is independently selected from the group consisting of -H, - [C (R2) 2] q-C00Ry, -C (Rx) 2C00Ry, - [C (Rz) 2] q-C (0) SRy, and -cycloalkylene-C00Ry; but if both R11 are alkyl, at least one is higher alkyl; and both R11 are not -H; or when Y and Y 'are independently selected from -0- and -NRV-, then R11 and R11 together form a cyclic group comprising -alkyl-S-S-alkyl-, 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 carbon atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydrogen, hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy is bonded to a carbon atom which are three atoms of both groups Y attached to phosphorus; or together V and Z 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 or carbon substituted by hydrogen, and the cyclic group is fused to an aryl group in the beta position and gamma in 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 or carbon substituted by hydrogen and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, is bonded to one of the carbon atoms which are three atoms of a Y bonded to phosphorus; or together Z and W are connected by means of 3-5 additional carbon atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon or carbon replaced by hydrogen, and V can be aryl, aryl substituted, 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 or carbon replaced by hydrogen, and V can be aryl, substituted aryl , heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHRzOH, -CHRzOC (0) Ry, -CHRzOC (S) Ry, -CHR20C (S) ORy, -CHRz0C (O) SRy, -CHR2OC02Ry, -OR2, -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-SR2; q is an integer 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 cycloalkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the conditions that: a) V, Z, W, W 'are not all -H; and b) when Z is -R2, 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. In another aspect, the invention relates to a compound of the formula II: R3 R8 R2 B "D-X R3 R8 R2 A -X 4 R1 R4 R1 where: A, B, R1, Rb, G, D, Ra, R1, R2, R8, R3, R4, Rd, Re, Rf, Rg, Rh, R5, X, V, W, W ', Z, q, Rz, Ry, Rx, and Rv are defined as above; Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are both -0-, R11 is 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 both -NRV-, then R11 is linked to -NRV- it is independently selected from the group consisting of -H, - [C (R2) 2] qC (0) 0Ry, -C (Rx) 2C (0) 0Ry, - [C (Rz) 2] qC (0) SRy, and -cycloalkylene-C (0) 0Ry; when Y is -0- and Y 'is NRV, then R11 is 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 portion cyclic contains a carbonate or thiocarbonate, -alkylaryl optionally substituted, -C (Rz) 20C (0) NR22, -NRz-C (0) -Ry, -C (Rz) 2-0C (0) Ry, -C (Rz) ) 2-0-C (0) 0Ry, -C (Rz) 20C (O) SRy, -alkyl-S-C (0) Ry, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; and R11 is 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 form a cyclic group comprising -alkyl-SS-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 carbon atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydrogen, hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy is bonded to a carbon atom which are three atoms of both groups Y attached to phosphorus; or together V and Z 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 or carbon replaced by hydrogen, and the cyclic group is fused to an aryl group in the beta position and gamma in Y linked to the phosphorous together V and W are connected by means of 3 additional carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms or carbon replaced by hydrogen and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, is bonded to one of the carbon atoms which are three atoms of an Y bonded to phosphorus; or together Z and W are connected by means of 3-5 additional carbon atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon or carbon replaced by hydrogen, and V can be aryl, aryl substituted, heteroaryl, or substituted heteroaryl; or together W and W 'are connected by means of 2-5 additional atoms to form a cyclic group, where 0-2 atoms are heteroatoms and the remaining atoms are carbon or carbon substituted by hydrogen, and V can be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHRzOH, -CHRzOC (0) Ry, -CHR20C (S) Ry, -CHRzOC (S) 0Ry, -CHR20C (0) SRy, -CHRz0C02Ry, -0RZ, -SRZ, -CHRZN3 , -CH2aryl, -CH (aryl) OH, -CH (CH = CR22) 0H, -CH (C = CRz) 0H, -Rz, -NRZ2, -0C0Ry, -0C02Ry, -SC0Ry, -SC02Ry, -NHC0Rz, -NHC02Ry, -CH2NHaril, - (CH2) q-0Rz, and - (CH2) q-SR2; q is an integer 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 and Rx form a cycloalkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the conditions that: a) V, Z, W, W 'are not all -H; and b) when Z is -R2, 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.
In another aspect, the invention relates to a compound of the formula III: wherein: G is selected from the group consisting of -0-, -S-, -Se-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF -, -C (0) -, -CH (OH) -, -NH-, and -N (C 1 -C 4 alkyl) -, or CH 2 linked to any of the preceding groups; or G is R50-R51 wherein; R50-R51 together are -C (R52) = C (R52) - or alternatively R50 and R51 are independently selected from 0, S and -CH (R53) -, with the provisos that at least one R50 and R51 is -CH (R53) -, and when one of R50 and R51 is 0 or S, then R53 is R54; R54 is hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl; R53 is selected from hydrogen, halogen, hydroxyl, mercapto, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; and R52 is selected from hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C?-C4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; T is selected from the group consisting of - (CRa2) k-, CRb = CRb- (CRa2) n-, "(Ra2) 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) mC (Rb) (NRbRc) -, -C (0) (CRa2) m-, - (CRa2) mC (0) -, - (CRb2) -0- (CRb2) - (CRa2) p-, - (CRb2) -S- (CRb2) - (CRa2) p-, - (CRb2) -N (Rc) - (CRb2) - (CRa2) p-, - (CRa2) p- (CRb2) -0- (CRb2) -, - (CRa2) p- (CRb2) -S- (CRb2) -, - ( CRa2) p- (CRb2) -N (Rc) - (CRb2) - and - (CH2) pC (0) N (Rb) C (Ra2) -; 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, -0- optionally substituted C 1 -C 4 alkyl, -0CF 3, -OCHF 2, -OCH 2 F, -S- alkyl Optionally substituted C 1 -C 4, -NRbRc, optionally substituted C 2 -C 4 alkenyl, and optionally substituted C 2 -C 4 alkynyl; with the proviso that when one Ra is linked to C through an atom 0, S or N, then the other Ra is linked to the same C 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 and optionally substituted C 1 -C 4 -alkyl, -C (O) -alkyl optionally substituted C 1 -C 4, and -C (0) H; R 1 and R 2 are each independently selected from the group consisting of halogen, optionally substituted C 1 -C 4 alkyl, optionally substituted -S-C? -C 3 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl , -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -0CH2F, -O- C C-C3 alkyl optionally substituted, and cyano; R 8 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 4 alkyl, -S- optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, -CF 3 , -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, -O- optionally substituted C1-C3 alkyl, hydroxy, - (CRa2) aryl, (CRa2) cycloalkyl, - (CRa2) heterocycloalkyl, -C (O) aril, C (O) cycloalkyl, -C (O) heterocycloalkyl, -C (O) alkyl and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -CHF2, -CH2F, -0CF3, -OCHF2, -OCH2F, cyano, C-C2alkyl optionally substituted, optionally substituted C2-Ci2 alkenyl, optionally substituted alkynyl-C2-Ci2, optionally substituted - (CRa2) maryl, - (CRa2) optionally substituted cycloalkyl, - (CRa2) optionally substituted mheterocycloalkyl, -C (Rb) = C ( Rb) -aryl, -C (Rb) = C (Rb) -cycloalkyl, -C (Rb) = C (Rb) -heterocycloalkyl, -C = C (aryl), -C = C (cycloalkyl), -C = C (heterocycloalkyl), - (CRa2) n (CRb2) NRfRg, -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 12 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl 2, optionally substituted (CR 2) naryl, - ( CRb) n Optionally substituted cycloalkyl, - (CRb2) n-heterocycloalkyl optionally substituted, 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 2 alkynyl 2, optionally substituted (CRa 2), - ( CRa2) n Optionally substituted cycloalkyl, and - (CRa2) n -heterocycloalkyl optionally substituted; Rf and Rg are each independently selected from the group consisting of hydrogen, C 1 -C 2 alkyl optionally replacedoptionally substituted C2-C2-C2-alkenyl, optionally substituted C2-C2 alkynyl, optionally substituted - (CRb2) naril, optionally substituted - (CRb2) n-cycloalkyl, and optionally substituted - (CRb2) nheterocycloalkyl, or Rf and Rg they may together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, which may contain a second hetero group selected from the group consisting 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 alquilo ~C4 alkyl, -ORb, oxo, cyano, -CF, -CHF2, CH2F, optionally substituted phenyl, and -C (0) 0Rh; 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) naril, - (CRb2) nCycloalkyl optionally substituted, and - (CRb2) n-heterocycloalkyl optionally substituted; or R3 and R8 are taken together with the carbon atoms to which they are bound to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, they do not include the unsaturation on the ring to which R3 and R8 are linked , including 0 to 2 heteroatoms independently selected from -NRh-, -O-, and -S-, with the condition that when these are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms have to be separated by at least one carbon atom; or R8 and G are taken together with the carbon atoms to which they join to form an optionally substituted ring comprising -CH = CH-CH =, -N = CH-CH =, -CH = N-CH = or -CH = CH-N =; R5 is selected from the group consisting of -OH, -0 optionally substituted C6-C6 alkyl, -0C (0) Re, -0C (0) 0R ', -NHC (0) OR, -0C (0) NH ( Rh), -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); or R3 and R5 are taken together with the carbons to which they join to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, they do not include the unsaturation on the ring to which R3 and R5 are linked, including 0 to 2 heteroatoms independently selected from -NRh-, -0-, and -S-, with the proviso that when these are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms have to be separated by at least a carbon atom; R7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, -O- C? -C alkyl, -0CF3, -OCHF2, -0CH2F, -CF3, -CHF2, -CH2F, cyano, -SH and -SC C4 alkyl; X is P (0) (YR11) (Y'R11); Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are both -0-, R11 is linked to -0- it 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, -NR2-C (0) -Ry, -C (Rz) 2.-OC (O) Ry, -C (R2) 2-0-C (O) 0Ry, -C (R2) 20C (0) SRy, -alkyl-S-C (0) Ry, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; when Y and Y 'are both -NRV-, then R11 is linked to -NRV- it is independently selected from the group consisting of -H, - [C (R2) 2] qC (0) 0Ry, -C (Rx) 2C (0) 0Ry, - [C (Rz) 2] qC (0) SRy, and -cycloalkylene-C (0) 0Ry; when Y is -0- and Y 'is NRV, then R11 is 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 portion cyclic contains a carbonate or thiocarbonate, -alkylaryl optionally substituted, -C (Rz) 20C (0) NRz2, -NRz-C (0) -Ry, -C (Rz) 2-OC (0) Ry, -C (Rz) 2"0-C (O) 0Ry, -C (Rz) 20C (O) SRy, -alkyl-S-C (0) Ry, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; and R11 is 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; but if both R11 are alkyl, at least one is higher alkyl; and both R11 are not -H; or when Y and Y 'are independently selected from -0- and -NRV-, then R11 and R11 together form a cyclic group comprising -alkyl-S-S-alkyl-, 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 carbon atoms to form a cyclic group containing 5-7 atoms, wherein 0 - 1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydrogen, hydroxy, acyloxy , alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy is bonded to a carbon atom which are three atoms of both groups Y attached to phosphorus; or together V and Z are connected by means of 3-5 additional carbon atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon 0 carbon substituted by hydrogen, and the cyclic group is fused to an aryl group in the beta position and gamma in 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 or carbon substituted by hydrogen and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, is bonded to one of the carbon atoms which are three atoms of a Y bonded 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 or carbon substituted by hydrogen, and V can 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 or carbon replaced by hydrogen, and V can be aryl, substituted aryl , heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHRzOH, -CHRzOC (0) Ry, -CHRzOC (S) Ry, -CHR20C (S) ORy, -CHR20C (O) SRy, -CHRz0C02Ry, -ORz, -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 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 cycloalkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the conditions 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. In another aspect, the invention relates to a compound of the formula III: where: G, T, k, m, n, p, Ra, Rb, Rc, R1, R2, R8, R3, R4, Rd, Re, Rf, Rg, R, R5, R7, X, V, W , W, Z, q, Rz, Ry, Rx, and Rv are defined as above; Y and Y 'are each independently selected from the group consisting of -O-, and -NRV-; when Y and Y 'are both -O-, R11 is linked to -O- it 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 (O) -Ry, -C (Rz) 2-OC (0) Ry, -C (R2) 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 both -NRV-, then R is linked to -NRV- it is independently selected from the group consisting of -H, - [C (Rz) 2] qC (0) ORy, -C (Rx) 2C (0) ORy, - [C (Rz) 2] qC (0) SRy, and -cycloalkylene-C (0) 0Ry; when Y is -0- and Y 'is NRV, then R11 is 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 portion cyclic contains an optionally substituted carbonate or thiocarbonate, -alkylaryl, -C (R2) 20C (0) NR22, -NR2-C (0) -Ry, -C (R2) 2-0C (0) Ry, -C (R2) ) 2-0-C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-S-C (0) Ry, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; and R11 is 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 form a cyclic group comprising -alkyl-S-S-alkyl-, or together R11 and R11 are the group: with the conditions 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 fluoro, and R5 is -OH , then X is not P (O) (OH) 2, P (O) (OH) (OCH3) or P (O) (OCH3) 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 'is not -H, alkyl, aralkyl, or heterocycloalkyl; and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs. In a further aspect, the invention relates to a compound of formula III: where: G, T, k, m, n, p, Ra, Rb, Rc, R1, R2, R8, R3, R4, Rd, Re, Rf, Rg, Rh, R5, R7, X, V, W , W ', Z, q, Rz, Ry, Rx, and Rv are defined as above; Y and Y 'are each independently selected from the group consisting of -O-, and -NRV-; when Y and Y 'are both -O-, R11 is linked to -O- it 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 (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; when Y and Y 'are both -NRV-, then R11 is linked to -NRV- it is independently selected from the group consisting of -H, - [C (R2) 2] qC (0) 0Ry, -C (Rx) 2C (0) 0Ry, - [C (Rz) 2] qC (0) SRy, and -cycloalkylene-C (0) 0Ry; when Y is -0- and Y 'is NRV, then R11 is 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 portion cyclic contains a carbonate or thiocarbonate, -alkylaryl optionally substituted, -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-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; and R11 is 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 selected independently of -0- and -NRV-, then R11 and R11 together form a cyclic group comprising -alkyl-S-S-alkyl-, or together R11 and R11 are the group: with the conditions that: a) when G is selected from the group consisting of -O-, -S-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CH (OH ) -, -C (O) - and -NRb-; T is -AB- where A is selected from the group consisting of -NR-, -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-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; R1 and R2 are each independently selected from the group consists of halogen, and substituted or unsubstituted C1-C4 alkyl; R7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, C 1 -C 4 alkyl, C 0 -C 4 alkyl, -SH and -SC C 4 -C 4 alkyl; and R5 is selected from the group consisting of hydroxyl, -0 optionally substituted C6-C6 alkyl, and -0C (0) Re; then X is not -P (0) (0H) 2 or lower alkyl ester or acyloxyalkyl ester thereof; b) V, Z, W, 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; and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs. In one aspect, the invention relates to a compound of formula VIII: wherein: G is selected from the group consisting of -0-, -S-, -Se-, -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 (C 1 -C 4 alkyl) -, or CH 2 linked to any of the preceding groups; or G is R50-R51 wherein; R50-R51 together are -C (R52) = C (R52) - or alternatively R50 and R51 are independently selected from 0, S and -CH (R53) -, with the provisos that at least one R50 and R51 is ~ CH (R53) -, and when one of R50 and R51 is 0 or S, then R53 is R54; R54 is hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl; R53 is selected from hydrogen, halogen, hydroxyl, mercapto, C?-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C?-C4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; and R52 is selected from hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; 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) mC (Rb) (NRbRc) -, -C (0) (CRa2) m-, - (CRa2) mC (0) -, - (CRb2) -0- (CRb2) - (CRa2) p-, - (CRb2) -S- (CRb2) - (CRa2) p-, - (CRb2) -N (Rc) - (CRb2) - (CRa2) p-, - (CRa2) p- (CRb2) - 0- (CRb2) -, - (CRa2) p- (CRb2) -S- (CRb2) -, - (CRa2) p- (CRb2) -N (Rc) - (CRb2) - and - (CH2) pC (0) N (Rb) C (Ra2) -; 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, -OCHF 2, -OCH 2 F, -S- alkyl C 1 C4 optionally substituted, -NRbRc, optionally substituted C2-C4 alkenyl, and optionally substituted C2-C4 alkynyl; with the proviso that when one Ra is linked to C through an atom O, S or N, then the other Ra is linked to the same C 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 and optionally substituted C 1 -C 4 -alkyl, -C (O) -alternatively substituted C 1 -C 4 alkyl, and -C (0) H; R1, R2, R6, and R7 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted C -C4 alkyl, -S- alkyl optionally substituted, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, optionally substituted C1-C3 alkyl, and cyano; with the proviso that at least one of R1 and R2 is not hydrogen; R8 and R9 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted -C?-C4 alkyl, -S-optionally substituted C1-C3 alkyl, optionally substituted C2-C4 alkenyl, C2-C4 alkynyl optionally substituted, -CF3, -CHF2, -CH2F, -0CF3, -OCHF2, -0CH2F, -O-C-C3 alkyl optionally substituted, hydroxy, - (CRa2) aryl, - (CRa2) cycloalkyl, (CRa2) heterocycloalkyl, -C (0) aryl, -C (0) cycloalkyl, C (0) heterocycloalkyl, -C (0) alkyl and cyano; or R6 and T are taken together with the carbons to which they join to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, they do not include the unsaturation on the ring to which R3 and R5 are linked, including 0 to 2 heteroatoms independently selected from -NR1-, -0-, and -S-, with the proviso that when these are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms have to be separated by at least a carbon atom; and X is linked to this ring by a direct bond to a carbon in the ring, or by - (CRa2) - or -C (0) - linked to a carbon in the ring or a nitrogen in the ring; R1 is selected from the group consisting of hydrogen, -C (0) C? -C4 alkyl, C? -C4 alkyl, and C? -C4 aryl; or R1 and R7 are taken together with the carbons to which they are bound to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, they do not include the unsaturation on the ring to which R1 and R7 are linked, including 0 to 2 heteroatoms independently selected from -NRh-, -O-, and -S-, with the proviso that when these are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms have to be separated by at least a carbon atom; t is an integer from 3-6; r and s are integers from 0-5; 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-C2-alkenyl, C2-alkynyl Optionally substituted C 2, optionally substituted - (CRa) maryl, - (CRa 2) optionally substituted cycloalkyl, - (CRa 2) optionally substituted metheterocycloalkyl, C (Rb) = C (Rb) -aryl, -C (Rb) = C ( Rb) -cycloalkyl, -C (Rb) = C (Rb) -heterocycloalkyl, -C = C (aryl), -C = C (cycloalkyl), -C = C (heterocycloalkyl), -ORd, -SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRfRg, -C (0) NRfRg, -C (0) ORh, -C (0) Re, -N (Rb) C (O) 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 2, optionally substituted (CR 2) naryl, - ( CRb2) optionally substituted cycloalkyl, - (CRb2) n-heterocycloalkyl 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, C 2 -C 8 alkynyl? optionally substituted, - (CRa2) optionally substituted naril, - (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 12 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl 2, optionally substituted substituted, - (CRb2) nCycloalkyl optionally substituted, and - (CRb2) nheterocycloalkyl optionally substituted, or Rf and Rg can together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, the heterocyclic ring may contain a second heterogroup 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 alkyl, -0Rb, oxo, cyano, -CF3, -CHF2, -CHF, optionally substituted phenyl, and -C (0) 0Rh; Each Rh 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 2, optionally substituted (CR 2) naryl, - ( CRb2) n Optionally substituted cycloalkyl, and - (CRb2) n -heterocycloalkyl optionally substituted; or R3 and R8 are taken together with the carbon atoms to which they are bound to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, they do not include the unsaturation on the ring to which R3 and R8 are linked , including 0 to 2 heteroatoms independently selected from -NRh-, -0-, and -S-, with the proviso that when these are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms must be separated by at least one carbon atom; or R8 and G are taken together with the carbon atoms to which they join to form an optionally substituted ring comprising -CH = CH-CH =, -N = CH- CH =, -CH = N-CH = or -CH = CH-N =; R5 is selected from the group consisting of -OH, -O optionally substituted C-C6 alkyl, -OC (0) Re, -OC (0) ORh, -NHC (0) ORh, -OC (0) NH (Rh) , -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2 Re, -NHC (= S) NH (Rh), and -NHC (O) NH (Rh); or R3 and R5 are taken together with the carbons to which they join to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, they do not include the unsaturation on the ring to which R3 and R5 are linked, including 0 to 2 heteroatoms independently selected from -NRh-, -O-, and -S-, with the proviso that when these are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms have to be separated by at least a carbon atom; X is P (0) (YR11) (Y'R11); Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are both -0-, R11 is linked to -O- it 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-OC (0) Ry, -C (Rz) 2-0-C (0) ORy, -C (Rz) 20C (O) SRy, -alkyl-SC (O) Ry, -alkyl -SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; when Y and Y 'are both -NRV-, then R11 is linked to -NRV- it is independently selected from the group consisting of -H, - [C (Rz) 2] qC (0) ORy, -C (Rx) 2C (0) 0Ry, - [C (R2) 2] qC (0) SRy, and -cycloalkylene-C (0) 0Ry; when Y is -0- and Y 'is NRV, then R11 is 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 portion cyclic 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-S-C (0) Ry, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; and R11 is 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; but if both R11 are alkyl, at least one is higher alkyl; and both R11 are not -H; or when Y and Y 'are independently selected from -0- and -NRV-, then R11 and R11 together form a cyclic group that it comprises -alkyl-S-S-alkyl-, 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 carbon atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydrogen, hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy is bonded to a carbon atom which are three atoms of both groups Y attached to phosphorus; or together V and Z 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 or carbon substituted by hydrogen, and the cyclic group is fused to an aryl group in the beta position and gamma in Y linked 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 or carbon substituted by hydrogen and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, is bonded to one of the carbon atoms that are three atoms of a Y bonded to phosphorus; or together Z and W are connected by means of 3-5 additional carbon atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon or carbon replaced by hydrogen, and V can be aryl, aryl substituted, 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 or carbon substituted by hydrogen, and V can 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 = CR2) 0H, -R2, -NRZ2, -OCORy, -OC02Ry, -SCORy, -SC02Ry, -NHCORz, -NHC02Ry, -CH2NHaril, - (CH2) q-ORz, and - (CH2) q-SR2; q is an integer 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 cycloalkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the conditions 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. In another aspect, the invention relates to a compound of the formula VIII: where: G, T, k, m, n, p, Ra, Rb, Rc, R1, R2, R6, R7, R \ R3 R4, R5, R8, R9, Rd, Re, Rf, Rg, Rh, X, V, W, W, Z, q, Rz, Ry, Rx, and Rv are defined as above; Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are both -0-, R11 is 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 (R2) 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 both -NRV-, then R11 is linked to -NRV- it is independently selected from the group consisting of -H, - [C (Rz) 2] qC (0) 0Ry, -C (Rx) 2C (0) 0Ry, - [C (Rz) 2] qC (0) SRy, and -cycloalkylene-C (0) 0Ry; when Y is -0- and Y 'is NRV, then R11 is 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 portion cyclic contains a carbonate or thiocarbonate, -alkylaryl optionally substituted, -C (Rz) 20C (0) NRz2, -NRz-C (0) -Ry, -C (Rz) 2-OC (0) Ry, -C (Rz) 2-0-C (O) 0Ry, -C (Rz) 20C (O) SRy, -alkyl-S-C (0) Ry, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; and R11 is 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-COORy; or when Y and Y 'are independently selected from -0- and -NRV-, then R11 and R11 together form a cyclic group comprising -alkyl-S-S-alkyl-, or together R11 and R11 are the group: with the conditions that: a) when G is -0-, T is -CH2-, R1 and R2 are each chlorine, R3 is phenyl, R4 is hydrogen, and R5 is -OH, then X is not P (0) ) (OH) (OCH2CH3); b) 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) (OCH2CH3) 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. In a further aspect, the invention relates to a compound of the formula VIII: where: G, T, k, m, n, p, Ra, Rb, Rc, R1, R2, R6, R7, R1, R3, R4, R5, R8 R9, Rd, Re, Rf, Rg, Rh, X, V, W, W ', Z, q, Rz, Ry, Rx, and Rv are defined as above; Y and Y 'are each independently selected from the group consisting of -O-, and -NRV-; when Y and Y 'are both -O-, R11 is linked to -O- it 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 (O) -Ry, -C (Rz) 2-OC (0) Ry, -C (Rz) 2 -0-C (0) ORy, -C (Rz) 2OC (0) SRy, -alkyl-SC (0) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; when Y and Y 'both are -NRV-, then R11 is linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] qC (0) ORy, -C (Rx) 2C (0) ORy, - [C (Rz) 2] qC (0) ) SRy, and -cycloalkylene-C00Ry; when Y is -0- and Y 'is NRV, then R11 is 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 portion cyclic contains an optionally substituted carbonate or thiocarbonate, -alkylaryl, -C (Rz) 20C (0) NRZ2, -NRz-C (0) -Ry, -C (R2) 2-0C (0) Ry, -C (R2) ) 2-0-C (0) 0Ry, -C (R2) 20C (0) SRy, -alkyl-S-C (0) Ry, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; and R11 is 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 form a cyclic group comprising -alkyl-S-S-alkyl-, or together R11 and R11 are the group: with the conditions that: a) when G is -0-, -S-, -Se-, -S (= 0) -, -S (= 0) 2-, -CH2-, -C (0) - , -NH- and, T is - (CH2) o -4- or -C (0) NH (CRb2) -, R1 and R2 is independently selected from the group consisting of hydrogen, halogen, C-C4 alkyl, R8 and R9 are each independently selected from hydrogen, halogen and C? - alkyl, R6 and R7 are each independently selected from hydrogen, halogen O-C? -3 alkyl, hydroxy, cyano and C4 alkyl, R3 is -C ( 0) NR25R26, -CH2-NR25R26, -NR25-C (0) R26, -OR27, R28, or R29 / -or R4 is hydrogen, halogen, cyano or alkyl, and R "is -OH, R25 and R26 are each independently selected from the group consisting of hydrogen, aryl, heteroaryl, alkyl, cycloalkyl, aralkyl or heteroaralkyl, R27 is aryl, heteroaryl, alkyl, aralkyl, or heteroaralkyl, R28 is aryl, heteroaryl, or cycloalkyl, R29 is hydrogen, aryl, heteroaryl, alkyl, aralkyl, heteroaralkyl, then X is not -P (0) (0H) 2, or - P (0) (O-lower alkyl) 2; b) when G is -0-, -S-, -Se-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -C (0) -, -NH- and, T is -C (0) NH (CRb2) -, R1 and R2 are independently halogen, cyano, C-C4-alkyl, R8 and R9 are selected each independently of hydrogen, halogen and C C _4 alkyl, R6 and R7 are each independently selected from hydrogen, halogen 0-C C -3 alkyl, hydroxy, cyano and C C4 alkyl, R3 is halogen, Ci-Cd alkyl, C2-C6 alkynyl, C4-cycloalkenyl, C3-C7 cycloalkoxy, S (= 0) 2 (NR1R15), -N ( R16) S (= 0) 2R17, -SR17, -S (= 0) R17, -S (= 0) 2R17, -C (0) R16, or -CR18 (OR16) R19, R4 is halogen, cyano or alkyl , and R 5 is -OH, -0 optionally substituted C 1 -C 6 alkyl, aroyl or alkanoyl, R 14, R 15, R 16, R 18 and R 19 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroalkyl, arylalkyl, and heteroarylalkyl, R17 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroalkyl, arylalkyl, and heteroarylalkyl, or R14 and R15 can together comprise a chain of 3 to 6 methylene groups to form a ring of 4 to 7 members in size, then X it is not -P (0) (OH) 2 or -P (O) (O-lower alkyl) 2; c) when G is O and T is - (CH2) k-, R1 and R2 are independently halogen, alkyl of 1 to 3 carbons, R3 is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 7 carbons, R4 is hydrogen, R5 is OH, R6, R7, R8 and R9 are hydrogen, then X is not phosphonic acid or lower alkyl ester thereof; d) when G is 0, T is - (CH2)? _ 3- or - (CH2) -2-CH (Raa), Ra is -OH, -NH2, -NH (C? _4alkyl), -NH (C2- 4-alkenyl), or -NH (C2-alkynyl), R4, R6, R7, R8 and R9 are hydrogen, R1 and R2 are independently selected from halogen, C-alkyl substituted with 1, 2, or 3 hydrogen, fluoride, or a bioisostomeric equivalent, alkyl C? _4 and CF3, and R3 and R5 are taken together with the carbon atoms to which they join to form a five-membered heterocyclic ring of the formula -AC (Rbb) = B- where A, they are linked where group R5 is linked, selected from -0-, -S-, and -NRh-, B is selected from -CH-, and -N-, Rbb is selected from C6-aryl, C5_9 heteroaryl, or C? _4 alkyl, then X is not phosphonic acid, phosphamic acid, or lower alkyl ester or acyloxyalkyl ester thereof; e) when G is 0, R4, R6, R7, R8 and R9 are hydrogen, R3 is selected from hydrogen, halogen, cyano, C6_? aryl, C5-10 heteroaryl, C1-10 alkyl, C3-8 cycloalkyl, alkenyl C2_? O, C2-10 alkynyl, and R5 is -NHC (0) Re, NHS (= 0) Re, NHS (= 0) 2Re, -NHC (= S) NH (Rh) or -NHC (0) NH (Rh), then X is not phosphonic acid or phosphamic acid or lower alkyl ester thereof; f) when G is -CH2-0-, where the oxygen atom is bound to the ring leading to group T, R6 and R7 are hydrogen, T is - (CH2)? -2CH (Rcc), Rcc is -OH , -SH, -NH2, or -NH (C? -4), R1 and R2 are each independently selected from chlorine, bromine, C? _4 alkyl, C2-4 alkenyl, and C2_4 alkynyl, then X is not phosphonic acid or phosphamic acid or lower alkyl ester thereof; g) when G is 0, T is - (CRa2) 0-4-, R4, R6, R7 and R8 are hydrogen, R5 is hydroxy, methoxy, or -NHC (0) Re, R3 is hydrogen, halogen, C? _4 alkyl, C3-6 cycloalkyl, or C5_8 cycloalkylalkyl, R1 and R2 are each independently selected from hydrogen, halogen, C? - alkyl, or C3-6 cycloalkyl, and R9 is C? alkyl? _4, CH2aryl, C (0) aryl, or C (0) alkyl, then X is not phosphonic acid or lower alkyl ester thereof; h) V, Z, W, W 'are not all -H; and i) 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. For compounds of formula I, II, III, and VIII, 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 -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 (C 1 -C 4 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 one aspect G is R50-R51 wherein; R50-R51 together are -C (R52) = C (R52) -, wherein R52 is selected from hydrogen, halogen, Ci, C2, C3, or C4 alkyl, C2, C3 or C alkenyl, C2, C3 or C4 alkynyl, Ci, C2, C3, or C4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio. In another aspect one of R50 and R51 is oxygen and the other is -CH (R54) -, wherein R54 is hydrogen, halogen, Ci, C2, C3, or C4 alkyl, C2, C3 or C4 alkenyl, C, C3 alkynyl or C4, fluoromethyl, difluoromethyl, or trifluoromethyl. In another aspect one of R50 and R51 is sulfur and the other is -CH (R54) -, wherein R54 is hydrogen, halogen, Ci, C2, C3, or C4 alkyl, C2, C3 or C4 alkenyl, C2, C3 alkynyl or C4, fluoromethyl, difluoromethyl, or trifluoromethyl. In another aspect both R50 and R51 are -CH (R53) -, wherein R53 is selected from hydrogen, halogen, hydroxyl, mercapto, Ci, C2, C3, or C4 alkyl, C2, C3 or C4 alkenyl, C2, C3 alkynyl or C4, Ci, C2, C3, or C4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio. For compounds of the formula I, in one aspect, T is -CH2-. In another aspect, T is - (CH2) 0-4-. In another aspect, T is selected from the group consisting of - (CH2) m-, -CH = CH-, -0 (CH2)? -2-, and -NH (CH2)? -2-. In still 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-, -N (Rb) C (0) -, 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 another aspect, T is - (CRa2) 1-2-0- (CRa2)? _2-. In a further aspect, T is - (CRa2) k "- In another aspect, T is -CRb = CRb- (CRa2) n- • In a further aspect, T is - (CRa2) m-CRb = CRb-. another aspect, T is - (CRa2) -CRb = CRb- (CRa2) - In a further aspect, T is -0 (CRb2) (CRa2) n- or -NH (CRb2) (CRa2) p-. 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) (CRa2) m-- In a further aspect, T is - ( CRa) mC (0) - In another aspect, T is - (CRa2) C (0) (CRa2) n- In an additional aspect, T is - (CRa2) nC (0) (CRa2) -. Another aspect, T is -C (0) NH (CRb2) (CRa2) p- For compounds of formula III and VIII, 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, -N (Rb) C (0) -, and -CH2CH (NRcRb) - In a further aspect, T is - (CRa) k-- In another aspect, T is -CRb = CRb- (CRa2) n-. an additional aspect, T is - (CRa2) m-CRb = CRb-. In another aspect, T is - (CRa2) -CRb = CRb- (CR2) -. In a further aspect, T is -0 (CRb2) (CRa2) n- or -NH (CRb2) (CRa2) p-. 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) (CRa2) 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 another aspect, T is - (CRa2)? -2-0- (CRa2)? -2-. For the compounds of formula II, 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) -.
For compounds of formula II, 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-. For compounds of formula II, in a further aspect, B is selected from -CH-, CMe-, and -N-. In another aspect, B is -CRb-. In a further aspect, B is -N-. For compounds of formula I, III, and VIII, 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. For compounds of formula I, II, III, and VIII, in a aspect, each Ra is hydrogen with the proviso that when one Ra is linked to C through an atom 0, S or N, then the other Ra is linked to the same C is a hydrogen, or is linked by means of an atom of carbon. 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 a 0 atom, S or N, then the other Ra binds to the same C 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 one Ra is linked to C through a 0 atom, S or N, then the other Ra binds to the same C is a hydrogen, or is bonded via of a carbon atom. In another aspect, each Ra is -OH with the proviso that when one Ra is linked to C through an atom 0, S or N, then the other Ra is linked to the same C is a hydrogen, or is bonded through of a carbon atom. In a further aspect, each Ra is optionally substituted -0- C-C4 alkyl with the proviso that when one Ra is linked to C through a 0, S or N atom, then the other Ra is linked to the same C It is a hydrogen, or it is bonded by means of a carbon atom. In another aspect, each Ra is -0CF3, -0CHF2, or -0CH2F, with the proviso that when a Ra is linked to C through an atom 0, S or N, then the another Ra is linked to the same C is a hydrogen, or is linked by means of a carbon atom. In a further aspect, each Ra is optionally substituted -S-C-C4 alkyl with the proviso that when one Ra is linked to C through a 0, S or N atom, then the other Ra is linked to the same C 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 an atom 0, S or N, then the other Ra is linked to the same C is a hydrogen, or is bound by means of a carbon atom. In a further aspect, each Ra is optionally substituted C2-C4 alkenyl 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 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 one Ra is linked to C through a 0, S or N atom, then the other Ra binds to the same C is a hydrogen, or it is bonded by means of a carbon atom. For compounds of formula I, II, III, and VIII, in one aspect, Rb is hydrogen. In a further aspect, R b is optionally substituted C 1 -C 4 alkyl. For compounds of formula I, III, and VIII, in one aspect, Rc is hydrogen. In another aspect, Rc is optionally substituted C 1 -C 4 alkyl. In one aspect further, R is -C (0) -alkyl C? -C4 optionally substituted. In still another aspect, Rc is -C (0) H. For compounds of the formula I, 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, C-alkyl ? -C4, -CF3, -CHF2, -CH2F, and cyano. In a further aspect, R 1 and R 2 are different and are selected from the group consisting of halogen, C 1 -C 4 alkyl, -CF 3, -CHF 2, -CH 2 F, and cyano. In one aspect, R 1 and R 2 are each independently selected from the group consisting of halogen, C 1 -C 4 -CF 3, -CHF 2, -CH 2 F, 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 both alkyl. 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 not both halogen.
In another aspect, R 1 and R 2 are each optionally substituted C 1 -C 4 alkyl. In a further aspect, R1 and R2 are each optionally substituted -S-C [beta] -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, -CHF2, or -CH2F. In a further aspect, R1 and R2 are each -OCF3, -OCHF2, or -OCH2F. In another aspect, R 1 and R 2 are each optionally substituted C 1 -C 3 alkyl. In a further aspect, R1 and R2 are each cyano. For compounds of formula II and III, in one aspect, R1 and R2 are the same and are selected from the group consisting of halogen, C 1 -C 4 alkyl, -CF 3, -CHF 2, -CH 2 F, and cyano. In another aspect, R 1 and R 2 are different and are selected from the group consisting of halogen, C 1 -C 4 alkyl, -CF 3, -CHF 2, -CH 2 F, and cyano. In a further aspect, R1 and R2 are each halogen. In another aspect, R1 and R2 are both not halogen. In another aspect, R 1 and R 2 are each optionally substituted C 1 -C 4 alkyl. In a further aspect, R1 and R2 are each optionally substituted -S-C [beta] -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, -CHF2, or -CH2F. In a further aspect, R1 and R2 are each one -OCF3, -OCHF2, or -OCH2F. In another aspect, R1 and R2 are each optionally substituted-C- C3 alkyl optionally substituted. In a further aspect, R1 and R2 are each cyano. For compounds of formula VIII, 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, -CHF 2, -CH 2 F, and cyano. In yet another aspect, R 1 and R 2 are different and are selected from the group consisting of halogen, C 1 -C 4 alkyl, -CF 3, -CHF 2, -CH 2 F, and cyano. In a further aspect, R1 and R2 are each halogen. In a further aspect, R1 and R2 are both not halogen. In another aspect, R 1, R 2, R 6, R 7, R 8, and R 9 are each optionally substituted C 1 -C 4 alkyl. In a further aspect, R1, R2, R6, R7, R8, and R9 are each optionally substituted -S-C-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-C4 alkynyl. In another aspect, R1, R2, R6, R7, R8, and R9 are each -CF3, -CHF2, or -CH2F. In a further aspect, R1, R2, R6, R7, R8, and R9 are each -OCF3, -OCHF2, or -OCH2F. In another aspect, R1, R2, R6, R7, R8, and R9 are each optionally substituted-C-C3-O-alkyl. In a further aspect, R1, R2, R6, R7, R8, and R9 are each cyano. In a further aspect, R 6 and R 7 are independently hydrogen, halogen, C 1 -C 4 alkyl, cyano or CF 3. In a further aspect, R6 and R7 are independently hydrogen, halogen, or methyl. In another aspect, R and R are independently hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkylaryl, C (O) aryl, cyano, CF 3, -CHF 2, or -CH 2 F. In another aspect, R 8 and R 9 are independently hydrogen, halogen, C 1 -C 4 alkyl, alkylaryl -C?-C 4 or C (O) aryl. In another aspect, R8 and R9 are independently hydrogen, halogen, methyl, benzyl or benzoate. For compounds of formula VIII, in one aspect, R6 and T are taken together with the carbons to which they are bound to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations including 0 to 2 heteroatoms independently selected from -NR1-, -O-, and -S-, with the proviso that when these are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms must be separated by at least one carbon atom; and X binds to this ring to either a carbon or a 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 with the carbons to which they join to form a ring of 5 to 6 atoms containing 0 unsaturations. In another aspect, R6 and T are taken together with the carbons to which they join to form a ring of 5 to 6 atoms containing 1 unsaturation. R6 and T are taken together with the carbons to which they join 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-. For the compounds of formula II and VIII, in one aspect, R1 is hydrogen. In another aspect, R 1 is -C (O) C 1 -C 4 alkyl. In another aspect, R 1 is C 1 -C 4 -alkyl. In a further aspect, R1 is aryl-C? ~ C4. For the compounds of formula I, II, III, and VIII, still in 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, R 3 and R 4 are each optionally substituted C 1 -C 2 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-C2. In a further aspect, R3 and R4 are each - (CRa2) optionally substituted maryl. In another aspect, R3 and R4 are each - (CRa2) mCycloalkyl optionally substituted. In a further aspect, R3 and R4 are each - (CRa2) optionally substituted m-heterocycloalkyl. In a further aspect, R3 and R4 are each -CH (Rb) = CH (Rb) -aryl. In a further aspect, R3 and R4 are each -CH (Rb) = CH (Rb) -cycloalkyl. In a further aspect, R3 and R4 are each -CH (Rb) = CH (Rb) -heterocycloalkyl. In a further aspect, R3 and R4 are each -C_aryl). In a further aspect, R3 and R4 are each -C_cycloalkyl). In a further aspect, R3 and R4 are each -C_heterocycloalkyl). In a further aspect, R3 and R4 are each - (CRa2) n (CRb2) NRfRg. 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) 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. For compounds of the formula I, in one aspect, R 4 is selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, cyano and CF 3. 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.
For the compounds of formula III and VIII, in another aspect, R 4 is selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, cyano and CF 3. In another aspect, R4 is hydrogen. 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 a further aspect, R3 is isopropyl or 4-fluorobenzyl. For the compounds of the formula I, II, III, and VIII, in another aspect, each Rd is optionally substituted alkyl -C? -C? 2. In a further aspect, each Rd is optionally substituted C2-C2-alkenyl. In another aspect, each Rd is optionally substituted C2-C2 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. For the compounds of formula I, II, III, and VIII, in a further aspect, Re is optionally substituted C 1 -C 2 alkyl. In another aspect, Re is optionally substituted C2-C2-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) n-cycloalkyl optionally replaced. In another aspect, Re is - (CRa2) n -heterocycloalkyl optionally substituted. For the compounds of formula I, II, III, and VIII, in one aspect, Rf and Rg are each hydrogen. In a further aspect, Rf and Rg are each optionally substituted C 1 -C 2 alkyl. In another aspect, Rf and Rg are each optionally substituted C2-C2-alkenyl. In a further aspect, Rf and Rg are each optionally substituted C2-C2 alkynyl-C2. 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. For compounds of formula I, II, III, and VIII, in a further aspect, Rf and Rg can together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, which may contain a second heterogroup which is 0. In another aspect, Rf and Rg can together form an optionally substituted heterocyclic ring, which may contain a second heterogroup which is NRC. In another aspect, Rf and Rg can together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, which may contain a second heterogroup which is S. In one aspect, Rf and Rg can together form a unsubstituted heterocyclic ring 3-8 atoms containing 0-4 unsaturations, 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, -CHF 2, -CH 2 F, optionally substituted phenyl, and -C (0) 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, -CHF 2, -CH 2 F, 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 alkyl, -OR b, oxo, cyano, -CF 3, -CHF 2, -CH 2 F, optionally substituted phenyl, and -C (0) ORh. 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 alkyl, -OR b, oxo, cyano, -CF3, -CHF2, -CH2F, optionally substituted phenyl, and -C (0) ORh.
For the compounds of formula I, II, III, and VIII, in a further aspect, Rh is optionally substituted C 1 -C 12 alkyl. In another aspect, Rh is optionally substituted C2-C2-C2-alkenyl. In a further aspect, Rh is C2-C2 alkynyl optionally substituted. 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. For compounds of formula I, II, III, and VIII, in one aspect, R5 is selected from the group consisting of -OH, -OC (0) Re, -OC (0) ORh, -F, and -NHC (0) Re. In another aspect, R5 is -OH. In a further aspect, R5 is optionally substituted -OC? -C6 alkyl. In another aspect, R5 is -OC (0) Re. In a further aspect, R5 is -OC (0) ORh. In another aspect, R5 is -NHC (0) ORh. In another aspect, R5 is -OC (O) NH (Rh). 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). For the compounds of formula I, in one aspect, R3 is selected from the group consisting of halogen, optionally substituted C 1 -C 7 alkyl, -CF 3, -CHF 2, -CH 2 F, cyano, -C (0) NRfRg, (CR a 2 ) optionally substituted naril, -S02NRfRg, and -S02Re. In another aspect, R3 is iso-propyl or 4-fluorobenzyl. In a further aspect, R3 is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 7 carbons. In yet another aspect, R 3 is selected from the group consisting of halogen, optionally substituted C 1 -C 6 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- methylopiperizinyl, 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 another aspect, R3 is iodine. In yet another aspect, R3 is selected from the group consisting of iodine, bromine, 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-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). For the compounds of formula III, in another aspect, R7 is selected from the group consisting of hydrogen, fluoro, chloro, amino, hydroxyl, and -0-CH3. For compounds of formula I, II, III, and VIII, in one aspect, X is -P (0) YRnY 'R11. For compounds of formula I, II, III, and VIII, in one aspect, X is selected from the group consisting of -P03H2, -P (O) [-OCRz2OC (0) Ry] 2, -P (O) [-OCRz2OC (0) 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 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 (O) [-0CRz20C (0) Ry] 2, -P (O) [-OCRz2OC (O) ORy] 2, -P (0) [-OCH2CH2SC (0) Me] 2, -P (O) [-N (H) CRZ2C (O) OR]] 2, -P (O) [-N (H) CR22C (O) 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, X is selected from the group consisting of -P03H2, -P (O) [-OCRz2OC (0) Ry] 2, -P (O) [-OCR22OC (O) ORy] 2, -P (0) [-Oalk-SC (0) Ry] 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 one aspect, X is selected from the group consisting of -P (O) [-OCR22OC (0) Ry] 2, -P (O) [-OCRz2OC (O) 0Ry] 2, -P (O) [-N (H) CRz2C (0) ORy] 2, -P (0) [-N (H) CRZ2C (O) ORy] [-OR11], -P (O) [-OCH ( V) CH2CH20-], -P (O) (OH) (OR11), -P (O) (ORe) (ORe), -P (O) [-OCRz2OC (0) Ry] (ORe), -P ( 0) [-OCRz2OC (0) ORy] (0Re), and -P (0) [-N (H) CRz2C (0) 0Ry] (ORe), wherein V is selected from the group consisting of optionally substituted aryl, aril, heteroaryl, and optionally substituted heteroaryl. In another aspect, 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], -P (O) [-OCH (V) CH2CH20-] , -P (O) (OH) (ORe), -P (O) (ORe) (ORe), -P (O) [-OCRz2OC (0) Ry] (ORe), -P (O) [-OCRz2OC (O) ORy] (ORe), -P (O) [-N (H) CRz2C (0) ORy] (ORe), and -P (O) (OH) (NH2), wherein V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl. For compounds of formula I, II, III, and VIII, in one aspect, X is selected from the group consisting of -P03H2, -P (O) [-OCH2OC (O) -t-butyl] 2, -P (O) [-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 (0) OCH2CH3] [3, 4-methylenedioxyphenyl], -P (O) [-0-CH2CH2S-C (0) CH3] 2, and -P (O) [-OCH (3- chlorophenyl) CH2CH20-]. In a further aspect, X is selected from the group consisting of -P03H2, -P (O) [-OCH2OC (0) -t-butyl] 2, -P (O) [-0CH20C (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-methylenedioxy-phenyl], -P (O ) [-N (H) C (CH3) 2C (0) OCH2CH3] [3,4-methylenedioxyphenyl], and -P (O) [-OCH (3-chlorophenyl) CH2CH20-]. In another aspect, X is -P03H2. In still another aspect, X is selected from the group consisting of -P (0) [-OCH2OC (0) -t-butyl] 2 and -P (0) [-0CH20C (0) -i-propyl] 2. In 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 (0) OCH2CH3] [3,4-methylenedioxyphenyl], -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] [3, 4-methylenedioxyphenyl], -P (0) [-OCH (3-chlorophenyl) CH2CH20-], -P (0) [-0CH (pyrid-4-yl) CH2CH20-], -P (0) (OH) ( 0CH3), -P (0) (OH) (OCH2CH3), -P (O) [-OCH2OC (0) -t-butyl] (OCH3), -P (0) [-0CH20C (0) 0-i- propyl] (0CH3), -P (0) [-0CH (CH3) 0C (0) -t-butyl] (0CH3), -P (0) [-0CH (CH3) 0C (0) 0-i-propyl ] (0CH3), -P (0) [-N (H) CH (CH3) C (0) OCH2CH3] (0CH3), -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3 ] (0CH3), and -P (0) (OH) (NH2). For compounds of formula I, II, III, and VIII, 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) [-OCRz2OC (0) Ry] 2, -P (0) [-OCRz2OC (0) 0Ry] 2, -P (0 ) [-N (H) CR22C (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. In another 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 (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 a further aspect, this invention relates to formulas I, II, III, or VIII wherein X is P (0) YRX1Y 'R11. For compounds of formula I, II, III, and VIII, 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 both -0-, R11 is 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 both -0-, R11 is linked to -0- is optionally substituted aryl. In other aspect, Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are both -0-, R11 is 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 both -0-, R11 is linked to -0- is optionally substituted CH2-heterocycloalkyl. In one aspect, the cyclic portion contains a carbonate or thiocarbonate. In another aspect, the cyclic portion contains optionally substituted -alkylaryl. In another aspect, the cyclic portion contains a -C (R2) 20C (0) NR22. In another aspect, the cyclic portion contains a -NRZ-C (0) -Ry. In another aspect, the cyclic portion contains a -C (Rz) 2-0C (0) Ry. In another aspect, the cyclic portion contains a -C (Rz) 2-0-C (0) 0Ry. In a further aspect, the cyclic portion contains a -C (Rz) 20C (0) SRy. In another aspect, the cyclic portion contains an -alkyl-S-C (0) Ry. In another aspect, the cyclic portion contains an -alkyl-S-S-alkylhydroxy. In a further aspect, the cyclic portion contains an -alkyl-S-S-S-alkylhydroxy. For compounds of formula I, II, III, and VIII, still in another aspect, Y and Y 'are both -NRV-. In another aspect, when Y and Y 'are both -NRV-, then R11 is linked to -NRV- is -H. In a further aspect, when Y and Y 'are both -NRV-, then R11 is linked to -NRV- it is - [C (Rz) 2] q-C (0) 0Ry. In another aspect, when Y and Y 'are both -NRV-, then R11 is linked to -NRV- is -C (Rx) 2C (0) 0Ry. In a further aspect, when Y and Y 'are both -NRV-, then R11 is linked to -NRV- is - [C (Rz) 2] q-C (0) SRy. In another aspect, when Y and Y 'both are -NRv-, then R11 is linked to -NRV-is -cycloalkylene-C (0) 0Ry. For compounds of formula I, II, III, and VIII, in one aspect, Y is -0- and Y 'is NRV. In another aspect, when Y is -0- and Y 'is NRV, then R11 is linked to -0- is -H. In a further aspect, when Y is -0- and Y 'is NRV, then R11 is linked to -0- is alkyl. In another aspect, when Y is -0- and Y 'is NRV, then R11 is linked to -0- is optionally substituted aryl. In a further aspect, when Y is -0- and Y 'is NRV, then R11 is linked to -0- is optionally substituted heterocycloalkyl. In another aspect, when Y is -0- and Y 'is NRV, then R11 is 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 a -NRZ-C (0) -Ry. In another aspect, the cyclic portion contains a -C (RZ) 2- 0C (0) Ry. In another aspect, the cyclic portion contains a -C (Rz) 2-0-C (0) 0Ry. In an additional aspect, the portion cyclic contains a -C (R2) 20C (0) SRy. In another aspect, the cyclic portion contains an -alkyl-S-C (0) Ry. In another aspect, the cyclic portion contains an -alkyl-S-S-alkylhydroxy. In a further aspect, the cyclic portion contains an -alkyl-S-S-S-alkylhydroxy. For compounds of formula I, II, III, and VIII, in another aspect, when Y is -0- and Y 'is NRV, and R11 is linked to -NRV- it is -H. In a further aspect, when Y is -0- and Y 'is NRV, and R11 is linked to -NRV- it is - [C (Rz) 2] q-C00Ry. In another aspect, when Y is -0- and Y 'is NRV, and R11 is linked to -NRV-is -C (Rx) 2C00Ry. In a further aspect, when Y is -0- and Y 'is NRV, and R11 is linked to -NRV- it is - [C (Rz) 2] q-C (0) SRy. In another aspect, when Y is -0- and Y 'is NRV, and R11 is linked to -NRV- it is -cycloalkylene-C00Ry. For compounds of formula I, II, III, and VIII, in another aspect, Y and Y 'are independently selected from -0- and -NRV-, then R11 and R11 together form a cyclic group comprising -alkyl-SS -I rent- . For the compounds of formula I, II, III, and VIII, in one aspect, Y and Y 'are independently selected from -0- and -NRV- and together R11 and R11 are the group: For the compounds of formula I, II, III, and VIII, 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. For the compounds of formula I, II, III, and VIII, 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. For the compounds of formula I, II, III, and VIII, 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 ' It is aril. 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. For the compounds of the formula I, II, III, and VIII, in one aspect, together V and Z are connected by means of 3-5 additional carbon atoms to form a cyclic group containing 5-7 atoms, wherein -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 three atoms of both Y groups attached to the phosphorus. In another aspect, the ring is substituted with acyloxy is bonded to a carbon atom which are three atoms of both groups Y attached to the phosphorus. In a further aspect, the ring is substituted with alkylthiocarbonyloxy bonded to a carbon atom which are three atoms of both Y groups attached to the phosphorus. In another aspect, the ring is substituted with alkoxycarbonyloxy is bonded to a carbon atom which are three atoms of both groups Y attached to the phosphorus. In a further aspect, the ring is substituted with aryloxycarbonyloxy is bonded to a carbon atom which are three atoms of both groups Y attached to the phosphorus. For the compounds of the formula I, II, III, and VIII, still in another aspect, together V and Z are connected by means of of 3-5 additional carbon atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which is fused to an aryl group in the beta position and gamma in Y bonded to phosphorus. For the compounds of formula I, II, III, and VIII, 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 three atoms of a Y bonded to phosphorus. In another aspect, the substituent is acyloxy which is bonded to one of the carbon atoms which are three atoms of an Y bonded to the phosphorus. In another aspect, the substituent is alkoxycarbonyloxy which is bonded to one of the carbon atoms which are three atoms of an Y bonded to phosphorus. In another aspect, the substituent is alkylthiocarbonyloxy which is bonded to one of the carbon atoms which are three atoms of an Y bonded to phosphorus. In another aspect, the substituent is aryloxycarbonyloxy which is bonded to one of the carbon atoms which are three atoms of a Y bonded to phosphorus. For the compounds of formula I, II, III, and VIII, in another aspect, 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 can be aryl, substituted aryl, heteroaryl, or substituted heteroaryl. For compounds of formula I, II, III, and VIII, still in 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 can be aryl, substituted aryl, heteroaryl, or substituted heteroaryl. For compounds of formula I, II, III, and VIII, in one aspect, Z is -CHRz0H. In another aspect, Z is -CHRzOC (O) Ry. In a further aspect, Z is-CHRzOC (S) Ry. In another aspect, Z is -CHRzOC (S) ORy. In a further aspect, Z is -CHRzOC (0) SRy. In another aspect, Z is -CHRz0C02Ry. In a further aspect, Z is -0RZ. In another aspect, Z is -SR2. In a further aspect, Z is -CHR2N3. In another aspect, Z is -CH2aryl. In a further aspect, Z is -CH (aryl) OH. In another aspect, Z is -CH (CH = CR22) OH. In another aspect, Z is -CH (C = CR2) 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 -OC02Ry. In a further aspect, Z is -SC0Ry. 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-0Rz. In a further aspect, Z is - (CH2) q-SRz.
For the compounds of formula I, II, III, and VIII, in one aspect R11 is not hydrogen. In one aspect, q is 2. In a further aspect, q is 3. For the compounds of formula I, II, III, and VIII, 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. For compounds of formula I, II, III, and VIII, in one aspect, Rx is -H. In another aspect, Rx is alkyl. In still another aspect, together Rx and Rx form a cycloalkyl group. For compounds of formula I, II, III, and VIII, 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. For the compounds of the formula I, II, III, and VIII, in one aspect, the present invention excludes the completely unsubstituted lower alkyl diesters of X when X is P03H2, for example, where X is -P (0) (OCH2CH3 )2. For compounds of formula I, II, III, and VIII, in another aspect, X is -P (O) YRnY 'R11 wherein Y and Y' are each independently selected from -O- 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 carbon 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 is bonded to a carbon atom which are three atoms of both groups Y attached to phosphorus; or together V and Z are connected by means of 3-5 additional carbon atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which is fused to an aryl group in the beta position and gamma in Y linked to phosphorus; or together V and W are connected by means of 3 atoms of additional carbon 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, is bonded to one of the carbon atoms which are three atoms of a Y linked to the match; 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 can 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 can be aryl, substituted aryl, heteroaryl, or heteroaryl replaced; Z is selected from the group consisting of -CHRzOH, -CHRz0C (0) Ry, -CHR20C (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, -SCORy, -SC02Ry, -NHCOR2, -NHC02Ry, -CH2NHaril, - (CH2) q-OR2, and - (CH2) q-SR2; q is an integer 2 or 3; with the conditions 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; 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; and Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl. For compounds of formula I, II, III, and VIII, 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. For compounds of formula I, II, III, and VIII, in one aspect, the relative stereochemistry between substituent group V and T in the dioxaphosphonan ring is cis. In another aspect, the cis-dioxaphosphonane ring has stereochemistry R on the carbon where V binds. In another aspect, the cis-dioxaphosphonan ring has S-stereochemistry at the carbon where V binds. For the compounds of formula I, II, III, and VIII, in one aspect R11 is not hydrogen. For the compounds of formula I, II, III, and VIII, in one aspect, X is -P (O) YRUY ", wherein Y" is C -C6 alkyl.
In one aspect, Y "is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. In another aspect, X is P02H2, P (0) (OH) (Rz), -P (0) [-0CRz20C (0) Ry] (R2), -P (0) [-0CRz20C (0) 0Ry] ( Rz), -P (0) [-N (H) CRz2C (0) 0Ry] (Rz), -P (0) [-N (H) CRZ2C (0) 0Ry] [-0R11], or -P ( 0) (OH) [-N (H) CRz2C (0) 0Ry]. In a further aspect, X is -P (0) (OH) (CH3), -P (0) (OH) (CH2CH3), -P (0) (OH) (isopropyl), or -P (0) ( OH) (t-butyl). For the compounds of formula I, in a further aspect 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 . In another aspect, when G is -0-, T is - (CH2) or -4, 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)? _ 2-, and -NH (CH2) 1-2-, then R4 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 (CR2) (CRa2) p-, -N (Rb) C (0) -, and -CH2CH (NRcRb) -; R1 R¿ e each independently selected from the group consisting of halogen, C 1 -C 4 alkyl, -CF 3, and cyano; R 4 is selected from the group consisting of hydrogen, halogen, -C ?C 4 alkyl, cyano and CF 3; 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, 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) [-OCR22OC (0) Ry] 2, -P (O) [-0CR220C (O) ORy] 2, -P (O) [-Oalk -SC (0) Ry] 2, -P (O) [-N (H) CR22C (0) 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. For compounds of formula I, in another aspect, 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-, -N (Rb) C (0) -, 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 (O) Re, -OC (0) ORh, -F and -NHC (0) Re; R3 is selected from the group that consists of halogen, optionally substituted C 1 -C 7 alkyl, -CF 3, cyano, -C (0) NRfRg, - (CR a 2) optionally substituted naril, -S02NRfRg, and -S02Re; 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] [-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. For the compounds of formula I, 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; 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 wherein the amido group is selected from the group consists 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-metipiperizinyl, 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 -PO3H2, -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] [0Re] and -P (0) [ -0CRz (aryl) CH2CH20-]. For the compounds of the formula I, 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 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) CR22C (0) 0Ry] [0Re] and -P (0) [-0CR2 (aryl) CH2CH20-], then R4 is not hydrogen. For the compounds of the formula I, in one aspect for the compounds of the formula I, G is -0-; T is -CH2CH (NH) -; 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 -PO3H2, -P (0) [-0CR220C (0) Ry] 2, -P (0) [-OCRz2OC (0) ORy] 2, P (0) [-N ( H) CR22C (0) 0Ry] 2, -P (0) [-N (H) CRz2C (0) 0Ry] [0Re] and -P (0) [-0CRz (aryl) CH2CH20-]. For the compounds of formula I, 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) [-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 (O) OCH2CH3] 2, -P (O) [-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) [-OCH (3-chlorophenyl) CH2CH20-]. For the compounds of the formula I, in a further aspect for the compounds of the 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; R5 is selected from the group consisting of -OH and -0C (0) Re; R 3 is selected from the group consisting of hydrogen, iodine, bromine, optionally substituted C 1 -C 7 alkyl, optionally substituted -CH 2 aryl, optionally substituted -CH (OH) aryl, -C (0) -amido wherein the amido group is selected of 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-metipiperizinyl , 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 select from the group consisting of -P03H2, -P (0) [-0CRz2OC (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) [-0CR2 (aryl) CH2CH20-]. For the compounds of the formula I, an additional aspect is when G is -0-; T is -N (H) C (0) -; R1 and R2 are methyl; R4 is hydrogen; R5 is -OH; R3 is -CH (OH) (4-f luorofenil); and X is selected from the group consisting of -P03H2, -P (0) [-0CR220C (0) Ry] 2, -P (0) [-OCRz2OC (0) ORy] 2, -P (0) [-N (H) CRz2C (0) ORy] 2, -P (0) [-N (H) CRz2C (0) 0Ry] [ORe] and -P (0) [-0CRz (aryl) CH2CH2O-]. For the compounds of formula I, an additional 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-f luorophenyl); 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) OCH2CH3] 2, -P (0) [-N (H) C (CH3) 2C (0) 0CH2CH3] 2, -P (0) [-N (H) CH (CH3) C (0) OCH2CH3] [3,4-methylenedioxy] enyl], -P (0) [-N (H) C (CH3) 2C (0) OCH2CH3] [3, 4-methylenedioxyphenyl], and -P (0) [-OCH (3-chlorophenyl) CH2CH20-]. For the compounds of formula I, in a further aspect G is selected from the group consisting of -0- and -CH2-; T is -0CH2-; R1 and R2 are each selected independently of 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 (O) -amido wherein the amido group is selected from the group it consists 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-metipiperizinyl, 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) [-OCRz2OC (0) ORy] 2, P (0) [-N (H) CRz2C (0) ORy] 2, -P (O) [-N (H) CRZ2C (0) 0Ry] [0Re] and -P (0) [-0CRz (aryl) CH2CH20-]. For the compounds of formula I, in another aspect G is -CH-; 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 (O) Ry] 2, -P (0) [-OCRz2OC (0) ORy] 2, -P (0) [-N (H) CRZ2C (O) 0Ry] 2, -P (0) [-N (H) CR22C (0) ORy] [0Re] and -P (O) [-0CR2 (aryl) CH2CH20-]. For the compounds of the formula I, in another aspect, G is -CH 2 -; 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 -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) [-OCH (3-chlorophenyl) CH2CH20-]. For the compounds of formula I, in a further aspect, G is selected from the group consisting of -0- and -CH2-; 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, -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-metipiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, -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 -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) [-OCRz2OC (0) ORy] 2, P (0) [-N ( H) CRz2C (0) ORy] 2, -P (0) [-N (H) CRZ2C (0) 0Ry] [0Re] and -P (0) [-0CRz (aryl) CH2CH20-]. For compounds of formula I, in a further aspect, 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) [-0CR220C (0) Ry] 2, -P (0) [-0CR220C (0) 0Ry] 2, -P (0) [-N (H) CR22C (0) 0Ry] 2, -P (0) [-N (H) CR22C (0) 0Ry] [0Re] and -P (0) [-0CR2 (aryl) CH2CH20-], then R4 is not hydrogen. For the compounds of the formula I, 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) [-0CRz20C (0) Ry] 2, -P (0) [-OCRz2OC (0) ORy], -P (0) [-N ( H) CRZ2C (0) 0Ry] 2, -P (0) [-N (H) CRz2C (0) 0Ry] [0Re] and -P (0) [-0CRz (aryl) CH2CH20-]. For the compounds of the formula I, in another aspect, G is -0-; T is -CH-; 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) OCH2CH3] 2, -P (O) [-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 for the compounds of 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 -0C (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 it consists 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-metipiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -S0R 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, P (0) [-N (H) CRz2C (0) ORy] 2, -P (O) [-N (H) CRZ2C (O) 0Ry] [0Re] and -P (0) [-OCRz (aryl) CH2CH20-]. For the compounds of formula I, in a further 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) [-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] [0Re] and -P (0) [-0CRz (aryl) CH2CH2O-]. For the compounds of the formula I, 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 (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) OCH2CH3] 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 -methylene dioxide), and -P (0) [-OCH (3-chlorophenyl) CH2CH20-]. For the compounds of formula I, 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) t-OCH2OC (0) -t-butyl] 2 and -P (0) [-OCH2OC (0) -i-propyl] 2. In another 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) [-0CH20C (0) 0-ethyl] 2 and -P (0) [-0CH20C (0) 0-i-propyl] 2. 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) [-N (H) CH (CH3) C (0) OCHCH3] 2 and -P (0) [-N (H) C (CH3) 2C (0 ) OCH2CH3] 2. In a further aspect, 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) [-OCH2CH2SC (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]. For the compounds of formula I, 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 not It is hydrogen. For the compounds of the formula I, in one aspect additional, 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 -P (0) YR11Y'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 1-alkynyl optionally substituted; or together V and Z are connected by means of 3-5 additional carbon 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 is bonded to a carbon atom which are three atoms of both Y groups attached to the phosphorus; or together V and Z are connected by means of 3-5 atoms of additional carbon to form a cyclic group, where 0 1 atoms are heteroatoms and the remaining atoms are carbon, which is fused to an aryl group in the beta position and gamma in Y bonded 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, it binds to one of the carbon atoms that are three atoms of a Y bonded 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 can be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or together W and W 'are connected by means of an additional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V can be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHRzOH, -CHRz0C (0) Ry, -CHRzOC (S) Ry, -CHRzOC (S) ORy, -CHRzOC (O) SRy, -CHRzOC02Ry, -0RZ, -SRZ, -CHRZN3, -CH2aryl, -CH (aryl) OH, -CH (CH = CRz2) OH, -CH (C = CR2) 0H, -Rz, -NRZ2, -OCORy, -OC02Ry, -SCORy, -SC02Ry, -NHCOR2, -NHC02Ry, -CH2NHaril, - (CH2) q -ORz, and - (CH2) q-SRz; q is an integer 2 or 3; with the conditions 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; 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 cycloalkyl 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-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 3-fluorophenyl, pyrid-4-yl, pyrid-3-yl or 3,5-dichlorophenyl. In a further aspect the relative stereochemistry between the substituents on the dioxaphosphonan ring is cis. For compounds of formula I, in another aspect, each Ra is independently selected from the group that consists of hydrogen, optionally substituted -C alquilo -C-C alquilo alkyl, halogen, -OH, -0-C opcional ~C opcional optionally substituted alkyl, -OCF 3, -S- optionally substituted C?-C alquilo alkyl, -NRbRc, C 2 -alkenyl optionally substituted, 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 C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted - (CRb 2) nphenyl, - (CR 2) nmonocyclic-heteroaryl optionally substituted, - (CRb2) n-C3-C6-cycloalkyl optionally substituted, - (CRb2) n_ C4-C5-optionally substituted heterocycloalkyl, and -C (0) NRfRg; Each Re is selected from the group consisting of optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted - (CRb 2) nphenyl, - (CR 2) nmonocyclic-heteroaryl optionally replaced, - (CRb2) optionally substituted C3-C6-cycloalkyl, optionally substituted C4-C5- (CR2) n -heterocycloalkyl; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 7 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, - (CR b 2) nphenyl optionally substituted, - (CR b 2 ) optionally substituted monocyclic-heteroaryl, - optionally substituted - (C3-C3-C3-C6-cycloalkyl, - optionally substituted C4-C5- (CRb2) n-heterocycloalkyl, or Rf and Rg can together form an optionally substituted heterocyclic ring, which can be containing a second heterogroup selected from the group of O, NR, and S, wherein the optionally substituted heterocyclic ring can be substituted with 0-2 substituents selected from the group consisting of optionally substituted C 1 -C 2 -alkyl, -ORb, oxo, cyano, -CF3, optionally substituted phenyl, and -C (0) ORh; Each Rh is optionally substituted Ci-Ciß alkyl, optionally substituted C2-Ci6 alkenyl, optionally substituted C2-Ci6 alkynyl, optionally substituted - (CRb2) nphenyl, - (CRb2) nmonocyclic-heteroaryl optionally substituted, - (CRb2) n optionally substituted C3-C6 cycloalkyl, optionally substituted C4-C5-cycloalkyl (CRb2) n-heterocycle. For the compounds of the formula I, in one aspect Further, each Ra is independently selected from the group consisting of hydrogen, methyl, fluoro, chloro, -OH, -O-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 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted - (CH 2) nphenyl, - (CH 2) nmonocyclic-heteroaryl optionally substituted, - (CH2) n-C3-C6-cycloalkyl optionally substituted, - (CH2) n-C4-C5-optionally substituted 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, optionally substituted - (CH 2) nphenyl, - (CH 2) nmonocyclic-heteroaryl optionally substituted, - (CH2) n-C3-C6-cycloalkyl optionally substituted, - (CH2) n-C4-C5-optionally substituted heterocycloalkyl; Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C2-C4 alkynyl, - (CH2) optionally substituted n-phenyl, - (CH2) nmonocyclic-heteroaryl optionally substituted, - (CH2) n-C3-C6 cyclyl optionally substituted, - (CH2) n-C4-C5 heterocyclyl optionally substituted, or Rf and Rg may together forming an optionally substituted heterocyclic ring, which may contain a second hetero group selected from the group of 0, NRb, and S, wherein the optionally substituted heterocyclic ring may be substituted with 0-2 substituents selected from the group consisting of optionally substituted methyl , -0Rb, oxo, cyano, -CF3, optionally substituted phenyl, and -C (0) ORh; Each Rh is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted - (CH 2) nphenyl, - (CH 2) nmonocyclic heteroaryl optionally substituted, - (CH 2) n-C3-C6-optionally substituted cycloalkyl, - (CH2) n-C4-C5-optionally substituted heterocycloalkyl. For compounds of formula II, 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-, -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 halogen, C 1 -C 4 alkyl, -CF 3, 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) 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 (0) [-OCRz2OC (0) Ry] 2, -P (0) [-OCRz2OC (0) ORy] 2, P (O) [-N ( H) CRz2C (0) ORy] 2, -P (O) [-N (H) CRZ2C (O) ORy] [-OR11] and -P (O) [-OCH (V) CH2CH20-], where 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 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 (O) -amido, -S (= 0) 2 amido, where the group amido is selected from the group consisting of phenethylamino, piperidinyl, 4-methylopiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -S02Re wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, and -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. For compounds of formula II, 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) [-0CH20C (O) -t-butyl] 2, -P (0) [-OCH2OC (0) 0-i-propyl ] 2, -P (O) [-N (H) CH (CH3) C (O) OCH2CH3] 2, -P (O) [-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-]. For the compounds of formula II, 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 one 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 (0) [-OCH2OC (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) [-OCH (3-chlorophenyl) CH2CH20-]. For compounds of formula III, in another aspect, when G is -0-, 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. In a further aspect, when G is selected from the group consisting of oxygen, sulfur, sulfoxide, sulfonyl, -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 C1-C3 alkyl; R3 is selected from the group consisting of halogen, trifluoromethyl, substituted or unsubstituted Cx-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; 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 or unsubstituted C 3 -C 5 cycloalkyl; and R7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, -O-C?-C4 alkyl, -SH and -S-C CC 4 alkyl; then R5 is not hydroxyl, -O optionally substituted Ci-C alquilo alkyl, or -OC (0) Re. For compounds of formula III, in one 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) (CRa2) p-, -S (CRb2) (CRa2) p- , -N (RbC (0) -, and -CH 2 CH (NRcRb) -; R 1 and R 2 are each independently selected from the group consisting of halogen, C 1 -C 4 alkyl, -CF 3, and cyano; R 4 is selected from a group consisting of hydrogen, halogen, C-C 4 alkyl, and CF 3, R 5 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 C -C6 alkyl, -CF3, cyano, -C (0) NRfRg, - (CRa2) optionally substituted naril, -S02NRfRg, and -S02Re; R7 is selected from the group which consists of hydrogen, fluoro, chloro, amino, hydroxyl, and -O-CH3 ,. and X is selected from the group consisting of -PU3H2, -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) [-0CH (V) CH2CH20-], where V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl. For compounds of formula III, in a further aspect, when G is -0-, T is -CH2-, R1 and R2 are chlorine, R3 is iso-propyl, R7 is fluoro, and R5 is -OH, then R4 It is not hydrogen. In another aspect, when G is selected from the group consisting of -0- and -CH2-; 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; 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; R 1 and R 2 are each independently selected from the group consisting of halogen and substituted C 1 -C 4 -alkyl or not replaced; 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 Ci-C alquilo alkyl, or -0C (0) Re. For compounds of formula III, 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 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-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; and R7 is selected from the group consisting of hydrogen and fluoro. For compounds of formula III, 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. For compounds of formula III, in one aspect additional, 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 (0) [-0CH20C (0) -t-butyl] 2, -P (0) [-0CH20C (0) Oi-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) [-OCH (3-chlorophenyl) CH2CH20-]. For compounds of formula III, 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-methylopiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -SÜ2Re 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.
For compounds of formula III, in another aspect, T is -OCH-; G is -0-; R1 and R2 are each chlorine; R4 is hydrogen; R5 is -OH; R3 is iso-propyl; and R7 is fluoro. For compounds of formula III, 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 -PO3H2, -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 (0) OCH2CH3] 2, -P (O) [-N (H) CH (CH3) C (0) OCH2CH3] [3,4-methylenedioxyphenyl], -P (O) [-N (H) C (CH3) 2C (0) OCH2CH3] [3, 4- methylenedioxyphenyl], and -P (O) [-OCH (3-chlorophenyl) CH2CH20-]. For compounds of formula III, 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; R3 is selected from the group consisting of iodine, bromine, optionally substituted C? -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-methylopiperizinyl, 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. For compounds of formula III, 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. For compounds of formula III, 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 (O) [-0CH20C (0) -t-butyl] 2, -P (O) [-OCH2OC (O) Oi-propyl] 2, P (O ) [-N (H) CH (CH3) C (0) OCH2CH3] 2, -P (O) [-N (H) C (CH3) 2C (0) OCH2CH3] 2, -P (O) [-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) [-OCH (3-chlorophenyl) CH2CH20-]. For the compounds of the formula III, in a further aspect, 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 -0C (0) Re; R3 is selected from the group consisting of iodine, bromine, optionally substituted Cx-Cß 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-methylopiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -S02Re wherein Re is selected from the group it consists of phenyl, 4-chlorophenyl, 4-fluorophenyl, and 4-pyridyl; and R7 is selected from the group consisting of hydrogen and fluoro. For compounds of formula III, 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. For compounds of formula III, in another aspect, T is -CHCH2-; 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 -PO3H2, -P (O) [-0CH20C (0) -t-butyl] 2, -P (0) [-0CH20C (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 (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-]. For compounds of formula III, 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; R3 is selected from the group that consists 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 group amido is selected from the group consisting of phenethylamino, piperidinyl, 4-methylopiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, and -S02R6 wherein Re is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, and -pyridyl; and R7 is selected from the group consisting of hydrogen and fluoro. For compounds of formula III, still in another aspect, T is -NHCH-; 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.
For the compounds of formula III, 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 (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) [-OCH (3-chlorophenyl) CH2CH20-]. For compounds of formula III, in one aspect, G is -0-; T is -CH2CH (NH2) -; R1 and R2 are each chlorine; R4 and R8 are selected from the group consisting of hydrogen and iodine; R5 is -OH; and R3 is iodine. In another aspect, G is -0-; T is -N (H) C (0) -; R1 and R2 are each chlorine; R4 and R8 are hydrogen; R5 is -OH; and R3 is -CH2 (4-fluorophenyl). In a further aspect, G is -0-; T is -OCH2-; R1 and R2 are each methyl; R4 and R8 are hydrogen; R5 is -OH; and R3 is iso-propyl. In a further aspect, G is -0-; T is -CH2-; R1 and R2 are each chlorine; R4 and R8 are hydrogen; R5 is -OH; and R3 is iso-propyl. In another aspect, G is -0-; T is -CH2CH2-; R1 and R2 are each chlorine; R4 and R8 are hydrogen; R5 is -OH; and R3 is iso-propyl. For compounds of formula VIII, 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) (OH) 2 or P (O) (OCH 2 CH 3) 2. In another aspect, when G is -O-, T is - (CH) 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 (0) (0H) 2 or -P (0) (0 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) ra-, - CH = CH-, -0 (CH2) 1-2-, or -NH (CH2)? -2-, then X is not P (0) (0H) 2 or -P (0) (OH) NH2. For the compounds of formula VIII, in one 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; R6, R7, R8 and R9 are hydrogen; R5 is -OH; and R3 is iodine. In another aspect, G is -0-; T is -N (H) C (0) -; R1 and R2 are each methyl; R4, R6, R7, R8 and R9 are hydrogen; R5 is -OH; and R3 is -CH (OH) (4-fluorophenyl). In a further aspect, G is -CH2-; T is -0CH2-; R1 and R2 are each methyl; R4, R6, R7, R8 and R9 are hydrogen; R5 is -OH; and R3 is iso-propyl. In a further aspect, G is -0-; T is -CH2-; R1 and R2 are each chlorine; R4, R6, R7, R8 and R9 are hydrogen; R5 is -OH; and R3 is iss-propyl. In a further aspect, G is -0-; T is -CH2CH2-; R1 and R2 are each chlorine; R4, R6, R7, R8 and R9 are hydrogen; R5 is -OH; and R3 is iso-propyl. Each of the individual species of the compounds of formula I, II, III, and VIII which can be generated by making all the above changes can be specifically established by inclusion or can specifically be excluded from the present invention.
Specific compounds In one aspect the following compounds are included in the invention but the compounds are not limited to these illustrative compounds. The compounds are shown without representation of the 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 the numbers assigned to the variables of formulas V-VII using the following convention: V1, V2, V3, V4.
Formula VI Formula VII Variable V1 1) -P (O) (OH) 2 2) -P (O) [0-CH2OC (0) C (CH3) 3] 2 3) -P (0) [0-CH2OC (0) CHO (CH3) 2] 2 4) -P (0) [0-CH2? C (0) OCH2CH3] 2 5) -P (0) [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) -OCH2-3) -CH2-CH2-4) -NHCH2-5) -NH ( CO) - 6) -CH2-CH (NH2) - (i-configuration) 7) -CH2-CH (NH2) - (S-configuration) 8) -CH = CH- (trans) 9) - null Variable V3: 1) -Omethyl 2) iodine 3) bromo 4) chloro 5) fluoro 6) methyl 7) trifluoromethyl cyano -OCF ^ Variable V4 1) iodine 2) CH (CH3) 2 3) C6H ?? 4) C6H5 5) -C (0) NHC6Hn 6) -CH (OH) (4-fluorophenyl) 7) -S02 (4-fluorophenyl) 8) -S02 (N-piperazinyl) 9) bromine In another aspect the additional compounds they 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 -S02 (4-fluorophenyl).
Table 2 1.1.1.1 1.1.1.2 1.1.1.3 1.1.1.4 1.1.1.5 1.1.1.6 1.1.1.7 1.1.1.8 1.1.1.9 1.1.2.1 1.1.2.1 1.1.2.2 1.1.2.3 1.1.2.4 1.1.2.5 1.1.2.6 1.1.2.7 1.1.2.8 1.1.2.9 1.1.3.1 1.1.3.2 1. 1.3.3 1.1.3.4 1.1.3.5 1.1.3.6 1.1.3.7 1.1.3, 1.1.3.9 1.1.4.1 1.1.4.2 1.1.4.3 1.1.4.4 1.1.4.5 1.1.4.6 1.1.4.7 1.1.4 1.1.4.9 1.1 .5.1 1.1.5.2 1.1.5.3 1.1.5.4 1.1.5.5 1.1.5.6 1.1.5.7 1.1.5.8 1.1.5.9 1.1.6.1 1.1.6.2 1.1.6.3 1.1.6.3 1.1.6.4 1.1.6.5 1.1.6.6 1.1.6.7 1.1.6.8 1.1.6.9 1.1.7.1 1.1.7.2 1.1.7.3 1.1.7.4 1.1.7.5 1.1.7.6 1.1.7.7 1.1.7.8 1.1.7.9 1.1.8.1 1.1.8.1 1.1.8.2 1.1.8.3 1.1.8.4 1.1.8.5 1.1.8.6 1.1. 8.7 1.1.8.8 1.1.8.9 1.1.9.1 1.1.9.2 1.1.9.3 1.1.9.4 1.1.9.5 1.1.9.6 1.1.9.7 1.1.9.8 1.1.9.9 1.2.1.1 1.2.1.2 1.2.1.3 1.2.1.4 1.2.1.5 1.2 .1.6 1.2.1.7 1.2.1.8 1.2.1.9 1.2.2.1 1.2.2.2 1.2.2.3 1.2.2.4 1.2.2.5 1.2.2.6 1.2.2.7 1.2.2.8 1.2.2.9 1.2.3.1 1.2.3.2 1.2.3.3 1.2.3.4 1.2.3.5 1.2.3.6 1.2.3.7 1.2.3.8 1.2.3.9 1.2.4.1 1.2.4.2 1.2.4.3 1.2.4.4 1.2.4.5 1.2.4.6 1.2.4.7 1.2.4.8 1.2.4.9 1.2.5.1 1.2.5.2 1.2. 5.3 1.2.5.4 1.2.5.5 1.2.5.6 1.2.5.7 1.2.5.8 1.2.5.9 1.2.6.1 1.2.6.2 1.2.6.3 1.2.6.4 1.2.6.5 1.2.6.6 1.2.6.7 1.2.6.8 1.2.6.9 1.2.7.1 1.2 .7.2 1.2.7.3 1.2.7.4 1.2.7.5 1.2.7.6 1.2.7.7 1.2.7.8 1.2.7.9 1.2.8.1 1.2.8 .2 1. 2.8.3 1.2.8.4 1.2.8.5 1.2.8.6 1.2.8.7 1.2.8.8 1.2.8.9 1.2.9.1 1.2.9.2 1.2.9.3 1. 2.9.4 1.2.9.5 1.2.9.6 1.2.9.7 1.2.9.8 1.2.9.9 1.3.1.1 1.3.1.2 1.3.1.3 1.3.1.4 1.3.1.5 1.3.1.6 1.3.1.7 1.3.1.8 1.3.1.9 1.3.2.1 1.3. 2.2 1.3.2.3 1.3.2.4 1.3.2.5 1. 3.2.6 1.3.2.7 1.3.2.8 1.3.2.9 1.3.3.1 1.3.3.2 1.3.3.3 1.3.3.4 1.3.3.5 1.3.3. 1. 3.3.7 1.3.3.8 1.3.3.9 1.3.4.1 1.3.4.2 1.3.4.3 1.3.4.4 1.3.4.5 1.3.4.6 1.3.4.7 1. 3.4.8 1.3.4.9 1.3.5.1 1.3.5.2 1.3.5.3 1.3.5.4 1.3.5.5 1.3.5.6 1.3.5.7 1.3.5. 1. 3.5.9 1.3.6.1 1.3.6.2 1.3.6.3 1.3.6.4 1.3.6.5 1.3.6.6 1.3.6.7 1.3.6.8 1.3.6.9 1.3.7.1 1.3.7.2 1.3.7.3 1.3.7.4 1.3.7.5 1.3.7.6 1.3. 7.7 1.3.7.8 1.3.7.9 1.3.8.1 1. 3.8.2 1.3.8.3 1.3.8.4 1.3.8.5 1.3.8.6 1.3.8.7 1.3.8.8 1.3.8.9 1.3.9.1 1.3.9.2 1. 3.9.3 1.3.9.4 1.3.9.5 1.3.9.6 1.3.9.7 1.3.9.8 1.3.9.9 1.4.1.1 1.4.1.2 1.4.1.3 1. 4.1.4 1.4.1.5 1.4.1.6 1.4.1.7 1.4.1.8 1.4.1.9 1.4.2.1 1.4.2.2 1.4.2.3 1.4.2.4 1. 4.2.5 1.4.2.6 1.4.2.7 1.4.2.8 1.4.2.9 1.4.3.1 1.4.3.2 1.4.3.3 1.4.3.4 1.4.3.5 1.4.3.6 1.4.3.7 1.4.3.8 1.4.3.9 1. 4.4.1 1.4.4.2 1.4.4.3 1.4.4.4 1.4.4.5 1.4.4.6 1.4.4.7 1.4.4.8 1.4.4.9 1.4.5.1 1.4.5.2 1.4.5.3 1.4.5.4 1.4.5.5 1.4.5.6 1.4.5.7 1.4. 5.8 1.4.5.9 1.4.6.1 1.4.6.2 1.4.6.3 1.4.6.4 1.4.6.5 1.4.6.6 1.4.6.7 1.4.6, 1.4.6.9 1.4.7.1 1.4.7.2 1.4.7.3 1.4.7.4 1.4.7.5 1.4.7.6 1.4.7.7 1.4.7. 1.4.7.9 1.4.8.1 1.4.8.2 1.4.8.3 1.4.8.4 1.4.8.5 1.4.8.6 1.4.8.7 1.4.8.8 1.4.8.9 1.4.9.1 1.4.9.2 1.4.9.3 1.4.9.4 1.4.9.5 1.4.9.6 1.4. 9.7 1.4.9.8 1.4.9.9 1.5.1.1 1.5.1.2 1.5.1.3 1.5.1.4 1.5.1.5 1.5.1.6 1.5.1.7 1.5.1.8 1.5.1.9 1.5.2.1 1.5.2.2 1.5.2.3 1.5.2.4 1.5.2.5 1.5 .2.6 1.5.2.7 1.5.2.8 1.5.2.9 1.5.3.1 1.5.3.2 1.5.3.3 1.5.3.4 1.5.3.5 1.5.3.6 1.5.3.7 1.5.3.8 1.5.3.9 1.5.4.1 1.5.4.2 1.5.4.3 1.5.4.4 1.5.4.5 1.5.4.6 1.5.4.7 1.5.4.8 1.5.4.9 1.5.5.1 1.5.5.2 1.5.5.3 1.5.5.4 1.5.5.5 1.5.5.6 1.5.5.7 1.5.5.8 1.5.5.9 1.5.6.1 1.5.6.2 1.5. 6.3 1.5.6.4 1.5.6.5 1.5.6.6 1.5.6.7 1.5.6.8 1.5.6.9 1.5.7.1 1.5.7.2 1.5.7.3 1.5.7.4 1.5.7.5 1.5.7.6 1.5.7.7 1.5.7. 1.5.7.9 1.5.8.1 1.5.8.2 1.5.8.3 1.5.8.4 1.5.8.5 1.5.8.6 1.5.8.7 1.5, 1.5.8.9 1. 5.9.1 1.5.9.2 1.5.9.3 1.5.9.4 1.5.9.5 1.5.9.6 1.5.9.7 1.5.9.8 1.5.9.9 1.6.1.1 1. 6.1.2 1.6.1.3 1.6.1.4 1.6.1.5 1.6.1.6 1.6.1.7 1.6.1.8 1.6.1.9 1.6.2.1 1.6.2.2 1. 6.2.3 1.6.2.4 1.6.2.5 1.6.2.6 1.6.2.7 1.6.2.8 1.6.2.9 1.6.3.1 1.6.3.2 1.6.3.3 1. 6.3.4 1.6.3.5 1.6.3.6 1.6.3.7 1.6.3.8 1.6.3.9 1.6.4.1 1.6.4.2 1.6.4.3 1.6.4.4 1. 6.4.5 1.6.4.6 1.6.4.7 1.6.4.8 1.6.4.9 1.6.5.1 1.6.5.2 1.6.5.3 1.6.5.4 1.6.5.5 1. 6.5.6 1.6.5.7 1.6.5.8 1.6.5.9 1.6.6.1 1.6.6.2 1.6.6.3 1.6.6.4 1.6.6.5 1.6.6. 1. 6.6.7 1.6.6.8 1.6.6.9 1.6.7.1 1.6.7.2 1.6.7.3 1.6.7.4 1.6.7.5 1.6.7.6 1.6.7.7 1. 1. 8.8.7 1.8.8.8 1.8.8.9 1.8.9.1 1.8.9.2 1.8.9.3 1.8.9.4 1.8.9.5 1.8.9.6 1.8.9.7 1.8.9.8 1.8.9.9 1.9.1.1 1.9.1.2 1.9.1.3 1.9.1.4 1.9. 1.5 1.9.1.6 1.9.1.7 1.9.1.8 1. 9.1.9 1.9.2.1 1.9.2.2 1.9.2.3 1.9.2.4 1.9.2.5 1.9.2.6 1.9.2.7 1.9.2.8 1.9.2.9 1. 9.3.1 1.9.3.2 1.9.3.3 1.9.3.4 1.9.3.5 1.9.3.6 1.9.3.7 1.9.3.8 1.9.3.9 1.9.4.1 1. 9.4.2 1.9.4.3 1.9.4.4 1.9.4.5 1.9.4.6 1.9.4.7 1.9.4.8 1.9.4.9 1.9.5.1 1.9.5.2 1. 9.5.3 1.9.5.4 1.9.5.5 1.9.5.6 1.9.5.7 1.9.5.8 1.9.5.9 1.9.6.1 1.9.6.2 1.9.6.3 1.9.6.4 1.9.6.5 1.9.6.6 1.9.6.7 1.9.6.8 1.9.6.9 1.9. 7.1 1.9.7.2 1.9.7.3 1.9.7.4 1. 9.7.5 1.9.7.6 1.9.7.7 1.9.7.8 1.9.7.9 1.9.8.1 1.9.8.2 1.9.8.3 1.9.8.4 1.9.8.5 1. 9.8.6 1.9.8.7 1.9.8.8 1.9.8.9 1.9.9.1 1.9.9.2 1.9.9.3 1.9.9.4 1.9.9.5 1.9.9.6 1. 9.9.7 1.9.9.8 1.9.9.9 2.1.1.1 2.1.1.2 2.1.1.3 2.1.1.4 2.1.1.5 2.1.1.6 2.1.1.7 2.1.1.8 2.1.1.9 2.1.2.1 2.1.2.2 2.1.2.3 2.1.2.4 2.1. 2.5 2.1.2.6 2.1.2.7 2.1.2.8 2.1.2.9 2.1.3.1 2.1.3.2 2.1.3.3 2.1.3.4 2.1.3.5 2.1.3.6 2.1.3.7 2.1.3.7. 2.1.3.9 2.1.4.1 2.1.4.2 2.1.4.3 2.1.4.4 2.1.4.5 2.1.4.6 2.1.4.7 2.1.4.8 2.1.4.9 2.1.5.1 2.1.5.2 2.1.5.3 2.1.5.4 2.1.5.5 2.1.5.6 2.1. 5.7 2.1.5.8 2.1.5.9 2.1.6.1 2.1.6.2 2.1.6.3 2.1.6.4 2.1.6.5 2.1.6.6 2.1.6.7 2.1.6.8 2.1.6.9 2.1.7.1 2.1.7.2 2.1.7.3 2.1.7.4 2.1.7.5 2.1 .7.6 2.1.7.7 2.1.7.8 2.1.7.9 2.1.8.1 2.1.8.2 2.1.8.3 2.1.8.4 2.1.8.5 2.1.8.6 2.1.8.7 2.1.8.8 2.1.8.9 2.1.9.1 2.1.9.2 2.1.9.3 2.1.9.4 2.1.9.5 2.1.9.6 2.1.9.7 2.1.9.8 2.1.9.9 2.2.1.1 2.2.1.2 2.2.1.3 2.2.1.4 2.2.1.5 2.2.1.6 2.2.1.7 2.2.1.8 2.2.1.9 2.2.2.1 2.2.2.2 2.2. 2.3 2.2.2.4 2.2.2.5 2.2.2.6 2.2.2.7 2.2.2.8 2.2.2.9 2.2.3.1 2.2.3.2 2.2.3.2 2.2.3.3 2.2.3.4 2.2.3.5 2.2.3.6 2.2.3.7 2.2.3.7. 2.2.3.9 2.2.4.1 2.2.4.2 2.2.4.3 2.2.4.4 2.2.4.5 2.2.4.6 2.2.4.7 2.2.4.8 2.2.4.9 2.2.5.1 2.2.5.2 2.2.5.3 2.2.5.4 2. 2.5.5 2.2.5.6 2.2.5.7 2.2.5.8 2.2.5.9 2.2.6.1 2. 2.6.2 2.2.6.3 2.2.6.4 2.2.6.5 2.2.6.6 2.2.6.7 2.2.6.8 2.2.6.9 2.2.7.1 2.2.7.2 2. 2.7.3 2.2.7.4 2.2.7.5 2.2.7.6 2.2.7.7 2.2.7.8 2.2.7.9 2.2.8.1 2.2.8.2 2.2.8.3 2. 2.8.4 2.2.8.5 2.2.8.6 2.2.8.7 2.2.8.8 2.2.8.9 2.2.9.1 2.2.9.2 2.2.9.3 2.2.9.4 2. 2.9.5 2.2.9.6 2.2.9.7 2.2.9.8 2.2.9.9 2.3.1.2 2.3.1.2 2.3.1.3 2.3.1.4 2.3.1.5 2.3.1.6 2.3.1.7 2.3.1.8 2.3.1.9 2.3.2.1 2.3.2.2 2.3. 2.3 2.3.2.4 2.3.2.5 2.3.2.6 2. 3.2.7 2.3.2.8 2.3.2.9 2.3.3.1 2.3.3.2 2.3.3.3 2.3.3.4 2.3.3.5 2.3.3.6 2.3.3.7 2. 3.3.8 2.3.3.9 2.3.4.1 2.3.4.2 2.3.4.3 2.3.4.4 2.3.4.5 2.3.4.6 2.3.4.7 2.3.4.8 2. 3.4.9 2.3.5.1 2.3.5.2 2.3.5.3 2.3.5.4 2.3.5.5 2.3.5.6 2.3.5.7 2.3.5.8 2.3.5.9 2.3.6.1 2.3.6.2 2.3.6.3 2.3.6.4 2.3.6.5 2.3.6.6 2.3. 6.7 2.3.6.8 2.3.6.9 2.3.7.1 2.3.7.2 2.3.7.3 2.3.7.4 2.3.7.5 2.3.7.6 2.3.7.7 2.3.7.8 2.3.7.9 2.3.8.1 2.3.8.2 2. 3.8.3 2.3.8.4 2.3.8.5 2.3.8.6 Table 2 - continued 2.3.8.7 2.3.8.8 2.3.8.9 2.3.9.1 2.3.9.2 2.3.9.3 2.3.9.4 2.3.9.5 2.3.9.6 2.3.9.7 2.3.9.8 2.3.9.9 2.4.1.1 2.4.1.2 2.4.1.3 2.4 .1.4 2.4.1.5 2.4.1.6 2.4.1.7 2.4.1.8 2.4.1.9 2.4.2.1 2.4.2.2 2.4.2.3 2.4.2.4 2.4.2.5 2. 4.2.6 2.4.2.7 2.4.2.8 2.4.2.9 2.4.3.1 2.4.3.2 2.4.3.3 2.4.3.4 2.4.3.5 2.4.3.6 2. 4.3.7 2.4.3.8 2.4.3.9 2.4.4.1 2.4.4.2 2.4.4.3 2.4.4.4 2.4.4.5 2.4.4.6 2.4.4.7 2. 4.4.8 2.4.4.9 2.4.5.1 2.4.5.2 2.4.5.3 2.4.5.4 2.4.5.5 2.4.5.6 2.4.5.7 2.4.5.8 2. 4.5.9 2.4.6.1 2.4.6.2 2.4.6.3 2.4.6.4 2.4.6.5 2.4.6.6 2.4.6.7 2.4.6.8 2.4.6.9 2.4.7.1 2.4.7.2 2.4.7.3 2.4.7.4 2.4.7.5 2.4.7.6 2.4. 7.7 2.4.7.8 2.4.7.9 2.4.8.1 2. 4.8.2 2.4.8.3 2.4.8.4 2.4.8.5 2.4.8.6 2.4.8.7 2.4.8.8 2.4.8.9 2.4.9.1 2.4.9.2 2. 4.9.3 2.4.9.4 2.4.9.5 2.4.9.6 2.4.9.7 2.4.9.8 2.4.9.9 2.5.1.1 2.5.1.2 2.5.1.3 2. 5.1.4 2.5.1.5 2.5.1.6 2.5.1.7 2.5.1.8 2.5.1.9 2.5.2.1 2.5.2.2 2.5.2.3 2.5.2.4 2. 2.5.8.9 2.5.9.1 2.5.9.2 2.5.9.3 2.5.9.4 2.5.9.5 2.5.9.6 2.5.9.7 2.5.9.8 2.5.9.9 2.6.1.1 2.6.1.2 2.6.1.3 2.6.1.4 2.6.1.5 2.6.1.6 2.6. 1.7 2.6.1.8 2.6.1.9 2.6.2.1 2.6.2.2 2.6.2.3 2.6.2.4 2.6.2.5 2.6.2.6 2.6.2.7 2.6.2.8 2.6.2.9 2.6.3.1 2.6.3.2 2.6.3.3 2.6.3.4 2.6.3.5 2.6 .3.6 2.6.3.7 2.6.3.8 2.6.3.9 2.6.4.1 2.6.4.2 2.6.4.3 2.6.4.4 2.6.4.5 2.6.4.6 2.6.4.7 2.6.4.8 2.6.4.9 2.6.-5.1 2.6.5.2 2.6.5.3 2.6. 5.4 2.6.5.5 2.6.5.6 2.6.5.7 2.6.5.8 2.6.5.9 2.6.6.1 2.6.6.2 2.6.6.3 2.6.6.4 2.6.6.5 2.6.6.6 2.6.6.7 2.6.6.8 2.6.6.9 2.6.7.1 2.6.7.2 2.6 .7.3 2.6.7.4 2.6.7.5 2.6.7.6 2.6.7.7 2.6.7. 2.6.7.9 2.6.8.1 2.6.8.2 2.6.8.3 2.6.8.4 2.6.8.5 2.6.8.6 2.6.8.7 2.6.8.8 2.6.8.9 2. 6.9.1 2.6.9.2 2.6.9.3 2.6.9.4 2.6.9.5 2.6.9.6 2.6.9.7 2.6.9.8 2.6.9.9 2.7.1.1 2. 7.1.2 2.7.1.3 2.7.1.4 2.7.1.5 2.7.1.6 2.7.1.7 2.7.1.8 2.7.1.9 2.7.2.1 2.7.2.2 2.7.2.3 2.7.2.4 2.7.2.5 2.7.2.6 2.7.2.7 2.7.2.8 2.7. 2.9 2.7.3.1 2.7.3.2 2.7.3.3 2. 7.3.4 2.7.3.5 2.7.3.6 2.7.3.7 2.7.3.8 2.7.3.9 2.7.4.1 2.7.4.2 2.7.4.3 2.7.4.4 2. 7.4.5 2.7.4.6 2.7.4.7 2.7.4.8 2.7.4.9 2.7.5.1 2.7.5.2 2.7.5.3 2.7.5.4 2.7.5.5 2. 7.5.6 2.7.5.7 2.7.5.8 2.7.5.9 2.7.6.1 2.7.6.2 2.7.6.3 2.7.6.4 2.7.6.5 2.7.6.6 2. 7.6.7 2.7.6.8 2.7.6.9 2.7.7.1 2.7.7.2 2.7.7.3 2.7.7.4 2.7.7.5 2.7.7.6 2.7.7.7 2.7.7.8 2.7.7.9 2.7.8.1 2.7.8.2 2.7.8.3 2.7.8.4 2.7. 8.5 2.7.8.6 2.7.8.7 2.7.8. 2. 7.8.9 2.7.9.1 2.7.9.2 2.7.9.3 2.7.9.4 2.7.9.5 2.7.9.6 2.7.9.7 2.7.9.8 2.7.9.9 2. 8.1.1 2.8.1.2 2.8.1.3 2.8.1.4 2.8.1.5 2.8.1.6 2.8.1.7 2.8.1.8 2.8.1.9 2.8.2.1 2. 8.2.2 2.8.2.3 2.8.2.4 2.8.2.5 2.8.2.6 2.8.2.7 2.8.2.8 2.8.2.9 2.8.3.1 2.8.3.2 2. 8.3.3 2.8.3.4 2.8.3.5 2.8.3.6 2.8.3.7 2.8.3.8 2.8.3.9 2.8.4.1 2.8.4.2 2.8.4.3 2.8.4.4 2.8.4.5 2.8.4.6 2.8.4.7 2. 8.4.8 2.8.4.9 2.8.5.1 2.8.5.2 2.8.5.3 2.8.5.4 2. 8.5.5 2.8.5.6 2.8.5.7 2.8.5.8 2.8.5.9 2.8.6.1 2.8.6.2 2.8.6.3 2.8.6.4 2.8.6.5 2. 8.6.6 2.8.6.7 2.8.6.8 2.8.6.9 2.8.7.1 2.8.7.2 2.8.7.3 2.8.7.4 2.8.7.5 2.8.7.6 2. 8.7.7 2.8.7.8 2.8.7.9 2.8.8.1 2.8.8.2 2.8.8.3 2.8.8.4 2.8.8.5 2.8.8.6 2.8.8.7 2. 8.8.8 2.8.8.9 2.8.9.1 2.8.9.2 2.8.9.3 2.8.9.4 2.8.9.5 2.8.9.6 2.8.9.7 2.8.9.8 2.8.9.9 2.9.1.1 2.9.1.2 2.9.1.3 2.9.1.4 2.9.1.5 2.9. 1.6 2.9.1.7 2.9.1 2.9.1.9 2. 9.2.1 2.9.2.2 2.9.2.3 2.9.2.4 2.9.2.5 2.9.2.6 2.9.2.7 2.9.2.8 2.9.2.9 2.9.3.1 2. 9.3.2 2.9.3.3 2.9.3.4 2.9.3.5 2.9.3.6 2.9.3.7 2.9.3.8 2.9.3.9 2.9.4.1 2.9.4.2 2. 9.4.3 2.9.4.4 2.9.4.5 2.9.4.6 2.9.4.7 2.9.4.8 2.9.4.9 2.9.5.1 2.9.5.2 2.9.5.3 2. 9.5.4 2.9.5.5 2.9.5.6 2.9.5.7 2.9.5.8 2.9.5.9 2.9.6.1 2.9.6.2 2.9.6.3 2.9.6.4 2.9.6.5 2.9.6.6 2.9.6.7 2.9.6.8 2.9.6.9 2.9.7.1 2.9. 7.2 2.9.7.3 2.9.7.4 2.9.7.5 2. 9.7.6 2.9.7.7 2.9.7.8 2.9.7.9 Table 2 - continued 2.9.8.1 2.9.8.2 2.9.8.3 2.9.8.4 2.9.8.5 2.9.8.6 2.9.8.7 2.9.8.8 2.9.8.9 2.9.9.1 2.9.9.2 2.9.9.3 2.9.9.4 2.9.9.5 2.9.9.6 2.9 .9.7 2.9.9.8 2.9.9.9 3.1.1.1 3.1.1.2 3.1.1.3 3.1.1.4 3.1.1.5 3.1.1.6 3.1.1.7 3.1.1.8 3.1.1.9 3.1.2.1 3.1.2.2 3.1.2.3 3.1.2.4 3.1.2.5 3.1.2.6 3.1.2.7 3.1.2.8 3.1.2.9 3. 1.3.1 3.1.3.2 3.1.3.3 3.1.3.4 3.1.3.5 3.1.3.6 3.1.3.7 3.1.3.8 3.1.3.9 3.1.4.1 3. 1.4.2 3.1.4.3 3.1.4.4 3.1.4.5 3.1.4.6 3.1.4.7 3.1.4.8 3.1.4.9 3.1.5.1 3.1.5.2 3. 1.5.3 3.1.5.4 3.1.5.5 3.1.5.6 3.1.5.7 3.1.5.8 3.1.5.9 3.1.6.1 3.1.6.2 3.1.6.3 3.1.6.4 3.1.6.5 3.1.6.6 3.1.6.7 3.1.6.8 3.1.6.9 3.1. 7.1 3.1.7.2 3.1.7.3 3.1.7.4 3. 1.7.5 3.1.7.6 3.1.7.7 3.1.7.8 3.1.7.9 3.1.8.1 3.1.8.2 3.1.8.3 3.1.8.4 3.1.8.5 3. 1.8.6 3.1.8.7 3.1.8.8 3.1.8.9 3.1.9.1 3.1.9.2 3.1.9.3 3.1.9.4 3.1.9.5 3.1.9.6 3. 1.9.7 3.1.9.8 3.1.9.9 3.2.1.1 3.2.1.2 3.2.1.3 3.2.1.4 3.2.1.5 3.2.1.6 3.2.1.7 3. 2.1.8 3.2.1.9 3.2.2.1 3.2.2.2 3.2.2.3 3.2.2.4 3.2.2.5 3.2.2.6 3.2.2.7 3.2.2.8 3.2.2.9 3.2.3.1 3.2.3.2 3.2.3.3 3. 2.3.4 3.2.3.5 3.2.3.6 3.2.3.7 3.2.3 3.2.3.9 3.2.4.1 3.2.4.2 3.2.4.3 3.2.4.4 3.2.4.5 3.2.4.6 3.2.4.7 3.2.4.8 3.2.4.9 3.2.5.1 3.2. 5.2 3.2.5.3 3.2.5.4 3.2.5.5 3.2.5.6 3.2.5.7 3.2.5.8 3.2.5.9 3.2.6. 3.3.9.2 3.3.9.3 3.3.9.4 3.3.9.5 3.3.9.6 3.3.9.7 3.3.9.8 3.3.9.9 3.4.1.1 3.4.1.2 3.4.1.3 3.4.1.4 3.4.1.5 3.4.1.6 3.4.1.7 3.4.1.8 3.4. 1.9 3.4.2.1 3.4.2.2 3.4.2.3 3.4.2.4 3.4.2.5 3.4.2.6 3.4.2.7 3.4.2.8 3.4.2.9 3.4.3.1 3.4.3.2 3.4.3.3 3.4.3.4 3.4.3.5 3.4.3.6 3.4.3.7 3.4 .3.8 3.4.3.9 3.4.4.1 3.4.4.2 3.4.4.3 3.4.4.4 3.4.4.5 3.4.4.6 3.4.4.7 3.4.4.3. 3.4.4.9 3.4.5.1 3.4.5.2 3.4.5.3 3.4.5.4 3.4.5.5 3.4.5.6 3.4.5.7 3.4.5.7. 3.4.5.9 3.4.6.1 3.4.6.2 3.4.6.3 3.4.6.4 3.4.6.5 3.4.6.6 3.4.6.7 3.4.6.8 3.4.6.9 3.4.7.1 3.4.7.2 3.4.7.3 3.4.7.4 3.4.7.5 3.4.7.6 3.4. 7.7 3.4.7.8 3.4.7.9 3.4.8.1 3.4.8.2 3.4.8.3 3.4.8.4 3.4.8.5 3.4.8.6 3.4.8.7 3.4.8.8 3.4.8.9 3.4.9.1 3.4.9.2 3.4.9.3 3.4.9.4 3.4.9.5 3.4 .9.6 3.4.9.7 3.4.9.8 3.4.9.9 3.5.1.1 3.5.1.2 3.5.1.3 3.5.1.4 3.5.1.5 3.5.1.6 3.5.1.7 3.5.1.8 3.5.1.9 3.5.2.1 3.5.2.2 3.5.2.3 3.5.2.4 3.5.2.5 3.5.2.6 3.5.2.7 3.5.2.8 3.5.2.9 3.5.3.1 3.5.3.2 3.5.3.3 3.5.3.4 3.5.3.5 3.5.3.6 3.5.3.7 3.5.3.8 3.5.3.9 3.5.4.1 3. 5.4.2 3.5.4.3 3.5.4.4 3.5.4.5 3.5.4.6 3.5.4.7 3.5.4.8 3.5.4.9 3.5.5.1 3.5.5.2 3.5.5.4 3.5.5.5 3.5.5.6 3.5.5.7 3.5.5. 3. 5.5.9 3.5.6.1 3.5.6.2 3.5.6.3 3.5.6.4 3.5.6.5 3.5.6.6 3.5.6.7 3.5.6. 3.5.6.9 3.5.7.1 3.5.7.2 3.5.7.3 3.5.7.4 3.5.7.5 3.5.7.6 3.5.7.7 3.5.7.8 3.5.7.9 3.5.8.1 3.5.8.2 3.5.8.3 3.5.8.4 3.5.8.5 3.5.8.6 3.5. 8.7 3.5.8.8 3.5.8.9 3.5.9.1 3.5.9.2 3.5.9.3 3.5.9.4 3.5.9.5 3.5.9.6 3.5.9.7 3.5.9.8 3.5.9.9 3.6.1.1 3.6.1.2 3.6.1.3 3.6.1.4 3.6.1.5 3.6 .1.6 3.6.1.7 3.6.1.8 3.6.1.9 3.6.2.1 3.6.2.3 3.6.2.3 3.6.2.4 3.6.2.5 3.6.2.6 3.6.2.7 3.6.2.8 3.6.2.9 3.6.3.1 3.6.3.2 3.6.3.3 3.6.3.4 3.6.3.5 3.6.3.6 3.6.3.7 3.6.3.8 3.6.3.9 3.6.4.1 3.6.4.2 3.6.4.3 3.6.4.6 3.6.4.5 3.6.4.6 3.6.4.7 3.6.4.8 3.6.4.9 3.6.5.1 3.6.5.2 3.6. 5.3 3.6.5.4 3.6.5.5 3.6.5.6 3.6.5.7 3.6.5.8 3.6.5.9 3.6.6.1 3.6.6.2 3.6.6.3 3.6.6.4 3.6.6.5 3.6.6.6 3.6.6.7 3.6.6.6. 3.6.6.9 3.6.7.1 3.6.7.2 3.6.7.3 Table 2 - continued 3.6.7.4 3.6.7.5 3.6.7.6 3.6.7.7 3.6.7.8 3.6.7.9 3.6.8.1 3.6.8.2 3.6.8.3 3.6.8.4 3.6.8.5 3.6.8.6 3.6.8.7 3.6.8.8 3.6.8.9 3.6 .9.1 3.6.9.2 3.6.9.3 3.6.9.4 3.6.9.5 3.6.9.6 3.6.9.7 3.6.9.8 3.6.9.9 3.7.1.1 3.7.1.2 3. 7.1.3 3.7.1.4 3.7.1.5 3.7.1.6 3.7.1.7 3.7.1.8 3.7.1.9 3.7.2.1 3.7.2.2 3.7.2.3 3. 7.2.4 3.7.2.5 3.7.2.6 3.7.2.7 3.7.2.8 3.7.2.9 3.7.3.1 3.7.3.2 3.7.3.3 3.7.3.4 3. 7.3.5 3.7.3.6 3.7.3.7 3.7.3.8 3.7.3.9 3.7.4.1 3.7.4.2 3.7.4.3 3.7.4.4 3.7.4.5 3. 7.4.6 3.7.4.7 3.7.4.8 3.7.4.9 3.7.5.1 3.7.5.2 3.7.5.3 3.7.5.4 3.7.5.5 3.7.5.6 3.7.5.7 3.7.5.8 3.7.5.9 3.7.6.1 3.7.6.2 3.7.6.3 3.7. 6.4 3.7.6.5 3.7.6.6 3.7.6.7 3. 7.6.8 3.7.6.9 3.7.7.1 3.7.7.2 3.7.7.3 3.7.7.4 3.7.7.5 3.7.7.6 3.7.7.7 3.7.7.8 3. 7.7.9 3.7.8.1 3.7.8.2 3.7.8.3 3.7.8.4 3.7.8.5 3.7.8.6 3.7.8.7 3.7.8.8 3.7.8.9 3. 7.9.1 3.7.9.2 3.7.9.3 3.7.9.4 3.7.9.5 3.7.9.6 3.7.9.7 3.7.9.8 3.7.9.9 3.8.1.1 3. 8.1.2 3.8.1.3 3.8.1.4 3.8.1.5 3.8.1.6 3.8.1.7 3.8.1.8 3.8.1.9 3.8.2.1 3.8.2.2 3.8.2.3 3.8.2.4 3.8.2.5 3.8.2.6 3. 8.2.7 3.8.2.8 3.8.2.9 3.8.3.1 3.8.3.2 3.8.3.3 3. 8.3.4 3.8.3.5 3.8.3.6 3.8.3.7 3.8.3.8 3.8.3.9 3.8.4.1 3.8.4.2 3.8.4.3 3.8.4.4 3. 8.4.5 3.8.4.6 3.8.4.7 3.8.4.8 3.8.4.9 3.8.5.1 3.8.5.2 3.8.5.3 3.8.5.4 3.8.5.5 3. 8.5.6 3.8.5.7 3.8.5.8 3.8.5.9 3.8.6.1 3.8.6.2 3.8.6.3 3.8.6.4 3.8.6.5 3.8.6.6 3. 8.6.7 3.8.6.8 3.8.6.9 3.8.7.1 3.8.7.2 3.8.7.3 3.8.7.4 3.8.7.5 3.8.7.6 3.8.7.7 3.8.7.8 3.8.7.9 3.8.8.1 3.8.8.2 3.8.8.3 3.8.8.4 3.8. 8.5 3.8.8.6 3.8.8.7 3.8.8 3. 8.8.9 3.8.9.1 3.8.9.2 3.8.9.3 3.8.9.4 3.8.9.5 3.8.9.6 3.8.9.7 3.8.9 3.8.9.9 3. 9.1.1 3.9.1.2 3.9.1.3 3.9.1.4 3.9.1.5 3.9.1.6 3.9.1.7 3.9.1.8 3.9.1.9 3.9.2.1 3. 9.2.2 3.9.2.3 3.9.2.4 3.9.2.5 3.9.2.6 3.9.2.7 3.9.2.8 3.9.2.9 3.9.3.1 3.9.3.2 3. 9.3.3 3.9.3.4 3.9.3.5 3.9.3.6 3.9.3.7 3.9.3.8 3.9.3.9 3.9.4.1 3.9.4.2 3.9.4.3 3.9.4.4 3.9.4.5 3.9.4.6 3.9.4.7 3.9.4.8 3.9.4.9 3.9. 5.1 3.9.5.2 3.9.5.3 3.9.5.4 3. 9.5.5 3.9.5.6 3.9.5.7 3.9.5.8 3.9.5.9 3.9.6.1 3.9.6.2 3.9.6.3 3.9.6.4 3.9.6.5 3. 9.6.6 3.9.6.7 3.9.6.8 3.9.6.9 3.9.7.1 3.9.7.2 3.9.7.3 3.9.7.4 3.9.7.5 3.9.7.6 3. 9.7.7 3.9.7.8 3.9.7.9 3.9.8.1 3.9.8.2 3.9.8.3 3.9.8.4 3.9.8.5 3.9.8 4. 2.5.3 4.2.5.4 4.2.5.5 4.2.5.6 4.2.5.7 4.2.5.8 4.2.5.9 4.2.6.1 4.2.6.2 4.2.6.3 4. 2.6.4 4.2.6.5 4.2.6.6 4.2.6.7 4.2.6.8 4.2.6.9 4.2.7.1 4.2.7.2 4.2.7.3 4.2.7.4 4. 2.7.5 4.2.7.6 4.2.7.7 4.2.7.8 4.2.7.9 4.2.8.1 4.2.8.2 4.2.8.3 4.2.8.4 4.2.8.5 4.2.8.6 4.2.8.7 4.2.8.8 4.2.8.9 4.2.9.1 4.2.9.2 4.2. 9.3 4.2.9.4 4.2.9.5 4.2.9.6 4. 2.9.7 4.2.9.8 4.2.9.9 4.3.1.1 4.3.1.2 4.3.1.3 4.3.1.4 4.3.1.5 4.3.1.6 4.3.1.7 4. 3.1.8 4.3.1.9 4.3.2.1 4.3.2.2 4.3.2.3 4.3.2.4 4.3.2.5 4.3.2.6 4.3.2.7 4.3.2.34. 3.2.9 4.3.3.1 4.3.3.2 4.3.3.3 4.3.3.4 4.3.3.5 4.3.3.6 4.3.3.7 4.3.3.8 4.3.3.9 4.3.4.1 4.3.4.2 4.3.4.3 4.3.4.4 4.3.4.5 4.3.4.6 4.3. 4.7 4.3.4.8 4.3.4.9 4.3.5.1 4.3.5.2 4.3.5.3 4.3.5.4 4.3.5.5 4.3.5.6 4.3.5.7 4.3.5.8 4.3.5.9 4.3.6.1 4.3.6.2 4. 3.6.3 4.3.6.4 4.3.6.5 4.3.6.6 Table 2 - continued 4.3.6.7 4.3.6.8 4.3.6.9 4.3.7.1 4.3.7.2 4.3.7.3 4.3.7.4 4.3.7.5 4.3.7.6 4.3.7.7 4.3.7.8 4.3.7.9 4.3.8.1 4.3.8.2 4.3.8.3 4.3 .8.4 4.3.8.5 4.3.8.6 4.3.8.7 4.3.8.8 4.3.8.9 4.3.9.1 4.3.9.2 4.3.9.3 4.3.9.4 4.3.9.5 4. 3.9.6 4.3.9.7 4.3.9.8 4.3.9.9 4.4.1.1 4.4.1.2 4.4.1.3 4.4.1.4 4.4.1.5 4.4.1.6 4. 4.1.7 4.4.1.8 4.4.1.9 4.4.2.1 4.4.2.2 4.4.2.3 4.4.2.4 4.4.2.5 4.4.2.6 4.4.2.7 4. 4.2.8 4.4.2.9 4.4.3.1 4.4.3.2 4.4.3.3 4.4.3.4 4.4.3.5 4.4.3.6 4.4.3.7 4.4.3.8 4. 4.3.9 4.4.4.1 4.4.4.2 4.4.4.3 4.4.4.4 4.4.4.5 4.4.4.6 4.4.4.7 4.4.4.8 4.4.4.9 4.4.5.1 4.4.5.2 4.4.5.3 4.4.5.4 4.4.5.5 4.4.5.6 4.4. 5.7 4.4.5.8 4.4.5.9 4.4.6.1 4. 4.6.2 4.4.6.3 4.4.6.4 4.4.6.5 4.4.6.6 4.4.6.7 4.4.6.8 4.4.6.9 4.4.7.1 4.4.7.2 4. 4.7.3 4.4.7.4 4.4.7.5 4.4.7.6 4.4.7.7 4.4.7.8 4.4.7.9 4.4.8.1 4.4.8.2 4.4.8.3 4. 4.8.4 4.4.8.5 4.4.8.6 4.4.8.7 4.4.8.8 4.4.8.9 4.4.9.1 4.4.9.2 4.4.9.3 4.4.9.4 4. 4.9.5 4.4.9.6 4.4.9.7 4.4.9.8 4.4.9.9 4.5.1.1 4.5.1.2 4.5.1.3 4.5.1.4 4.5.1.5 4.5.1.6 4.5.1.7 4.5.1.8 4.5.1.9 4. 5.2.1 4.5.2.2 4.5.2.3 4.5.2.4 4.5.2.5 4.5.2.6 4.5.2.7 4.5.2.8 4.5.2.9 4.5.3.1 4.5.3.2 4.5.3.3 4.5.3.4 4.5.3.5 4.5.3.6 4.5.3.7 4.5. 3.8 4.5.3.9 4.5.4.1 4.5.4.2 4.5.4.3 4.5.4.4 4.5.4.5 4.5.4.6 4.5.4.7 .5.4.8 4.5.4.9 4.5.5.1 4.5.5.2 4.5.5.3 4.5.5.4 4.5.5.5 4.5.5.6 4.5.5.7 4.5.5. 4.5.5.9 4.5.6.1 4.5.6.2 4.5.6.3 4.5.6.4 4.5.6.5 4.5.6.6 4.5.6.7 4.5.6.8 4.5.6.9 4.5.7.1 4.5.7.2 4.5.7.3 4.5.7.4 4.5.7.5 4.5.7.6 4.5. 7.7 4.5.7.8 4.5.7.9 4.5.8.1 4.5.8.2 4.5.8.3 4.5.8.4 4.5.8.5 4.5.8.6 4.5.8.7 4.5.8.8 4.5.8.9 4.5.9.1 4.5.9.2 4.5.9.3 4.5.9.4 4.5.9.5 4.5 .9.6 4.5.9.7 4.5.9.8 4.5.9.9 4.6.1.1 4.6.1.2 4.6.1.3 4.6.1.4 4.6.1.5 4.6.1.6 4.6.1.7 4.6.1.8 4.6.1.9 4.6.2.1 4.6.2.2 4.6.2.3 4.6.2.4 4.6.2.5 4.6.2.6 4.6.2.7 4.6.2.8 4.6.2.9 4.6.3.1 4.6.3.2 4.6.3.3 4.6.3.4 4.6.3.5 4.6.3.6 4.6.3.7 4.6.3.8 4.6.3.9 4.6.4.1 4.6.4.2 4.6. 4.3 4.6.4.4 4.6.4.5 4.6.4.6 4.6.4.7 4.6.4.8 4.6.4.9 4.6.5.1 4.6.5.2 4.6.5.3 4.6.5.4 4.6.5.5 4.6.5.6 4.6.5.7 4.6.5 4.6.5.9 4.6.6.1 4.6 .6.2 4.6.6.3 4.6.6.4 4.6.6.5 4.6.6.6 4.6.6.7 4.6.6.8 4.6.6.9 4. 6.7.1 4.6.7.2 4.6.7.3 4.6.7.4 4.6.7.5 4.6.7.6 4.6.7.7 4.6.7.8 4.6.7.9 4.6.8.1 4.6.8.2 4.6.8.3 4.6.8.4 4.6.8.5 4.6.8.6 4.6.8.7 4.6. 8.8 4.6.8.9 4.6.9.1 4.6.9.2 4.6.9.3 4.6.9.4 4.6.9.5 4.6.9.6 4.6.9.7 4.6.9.8 4.6.9.9 4.7.1.1 4.7.1.2 4.7.1.3 4.7.1.4 4.7.1.5 4.7.1.6 4.7 .1.7 4.7.1.8 4.7.1.9 4.7.2.1 4.7.2.2 4.7.2.3 4.7.2.4 4.7.2.5 4.7.2.6 4.7.2.7 4.7.2.8 4.7.2.9 4.7.3.1 4.7.3.2 4.7.3.3 4.7.3.4 4.7.3.5 4.7.3.6 4.7.3.7 4.7.3.8 4.7.3.9 4.7.4.1 4.7.4.2 4.7.4.3 4.7.4.4 4.7.4.5 4.7.4.6 4.7.4.7 4.7.4.8 4.7.4.9 4.7.5.1 4.7.5.2 4.7.5.3 4.7. 5.4 4.7.5.5 4.7.5.6 4.7.5.7 4.7.5.8 4.7.5.9 4.7.6.1 4.7.6.2 4.7.6.3 4.7.6.4 4.7.6.5 4.7.6.6 4.7.6.7 4.7.6.8 4.7.6.9 4.7.7.1 4.7.7.2 4.7 .7.3 4.7.7.4 4.7.7.5 4.7.7.6 4.7.7.7 4.7.7.8 4.7.7.9 4.7.8.1 4.7.8.2 4.7.8.3 4.7.8.4 4.7.8.5 4.7.8.6 4.7.8.7 4.7.8.8 4.7.8.9 4. 8.6.8 4.8.6.9 4.8.7.1 4.8.7.2 4.8.7.3 4.8.7.4 4.8.7.5 4.8.7.6 4.8.7.7 4.8.7. 4.8.7.9 4.8.8.1 4.8.8.2 4.8.8.3 4.8.8.4 4.8.8.5 4.8.8.6 4.8.8.7 4.8.8 4.8.8.9 4. 8.9.1 4.8.9.2 4.8.9.3 4.8.9.4 4.8.9.5 4.8.9.6 4.8.9.7 4.8.9.8 4.8.9.9 4.9.1.1 4. 9.1.2 4.9.1.3 4.9.1.4 4.9.1.5 4.9.1.6 4.9.1.7 4.9.1.8 4.9.1.9 4.9.2.1 4.9.2.2 4. 9.2.3 4.9.2.4 4.9.2.5 4.9.2.6 4.9.2.7 4.9.2.8 4.9.2.9 4.9.3.1 4.9.3.2 4.9.3.3 4. 9.3.4 4.9.3.5 4.9.3.6 4.9.3.7 4.9.3.8 4.9.3.9 4.9.4.1 4.9.4.2 4.9.4.3 4.9.4.4 4.9.4.5 4.9.4.6 4.9.4.7 4.9.4.8 4.9.4.9 4.9.5.1 4.9. 5.2 4.9.5.3 4.9.5.4 4.9.5.5 4. 9.5.6 4.9.5.7 4.9.5.8 4.9.5.9 Table 2 - continued 4.9.6.1 4.9.6.2 4.9.6.3 4.9.6.4 4.9.6.5 4.9.6.6 4.9.6.7 4.9.6.8 4.9.6.9 4.9.7.1 4.9.7.2 4.9.7.3 4.9.7.4 4.9.7.5 4.9.7.6 4.9 .7.7 4.9.7.8 4.9.7.9 4.9.8.1 4.9.8.2 4.9.8.3 4.9.8.4 4.9.8.5 4.9.8.6 4.9.8.7 4.9.8.8 4.9.8.9 4.9.9.1 4.9.9.2 4.9.9.3 4.9.9.4 4.9.9.5 4.9.9.6 4.9.9.7 4.9.9.8 4.9.9.9 5. 1.1.1 5.1.1.2 5.1.1.3 5.1.1.4 5.1.1.5 5.1.1.6 5.1.1.7 5.1.1.8 5.1.1.9 5.1.2.1 5. 1.2.2 5.1.2.3 5.1.2.4 5.1.2.5 5.1.2.6 5.1.2.7 5.1.2.8 5.1.2.9 5.1.3.1 5.1.3.2 5. 1.3.3 5.1.3.4 5.1.3.5 5.1.3.6 5.1.3.7 5.1.3.8 5.1.3.9 5.1.4.1 5.1.4.2 5.1.4.3 5.1.4.4 5.1.4.5 5.1.4.6 5.1.4.7 5.1.4.8 5.1.4.9 5.1. 5.1 5.1.5.2 5.1.5.3 5.1.5.4 5. 1.5.5 5.1.5.6 5.1.5.7 5.1.5.8 5.1.5.9 5.1.6.1 5.1.6.2 5.1.6.3 5.1.6.4 5.1.6.5 5. 1.6.6 5.1.6.7 5.1.6.8 5.1.6.9 5.1.7.1 5.1.7.2 5.1.7.3 5.1.7.4 5.1.7.5 5.1.7.6 5. 1.7.7 5.1.7.8 5.1.7.9 5.1.8.1 5.1.8.2 5.1.8.3 5.1.8.4 5.1.8.5 5.1.8.6 5.1.8.7 5. 1.8.8 5.1.8.9 5.1.9.1 5.1.9.2 5.1.9.3 5.1.9.4 5.1.9.5 5.1.9.6 5.1.9.7 5.1.9.8 5.1.9.9 5.2.1.1 5.2.1.2 5.2.1.3 5. 2.1.4 5.2.1.5 5.2.1.6 5.2.1.7 5.2.1. 5.2.1.9 5.2.2.1 5.2.2.2 5.2.2.3 5.2.2.4 5.2.2.5 5.2.2.6 5.2.2.7 5.2.2.8 5.2.2.9 5.2.3.1 5.2.3.2 5.2.3.3 5.2.3.4 5.2.3.5 5.2.3.6 5.2. 3.7 5.2.3.8 5.2.3.9 5.2.4.1 5.2.4.2 5.2.4.3 5.2.4.4 5.2.4.5 5.2.4.6 5.2.4.7 5.2.4.8 5.2.4.9 5.2.5.1 5.2.5.2 5.2.5.3 5.2.5.4 5.2.5.5 5.2 .5.6 5.2.5.7 5.2.5.8 5.2.5.9 5.2.6.1 5.2.6.2 5.2.6.3 5.2.6.4 5.2.6.5 5.2.6.6 5.2.6.7 5.2.6.8 5.2.6.9 5.2.7.1 5.2.7.2 5.2.7.3 5.2.7.4 5.2.7.5 5.2.7.6 5.2.7.7 5.2.7.8 5.2.7.9 5.2.8.1 5.2.8.2 5.2.8.3 5.2.8.4 5.2.8.5 5.2.8.6 5.2.8.7 5.2.8.8 5.2.8.9 5.2.9.1 5.2.9.2 5.2. 9.3 5.2.9.4 5.2.9.5 5.2.9.6 5.2.9.7 5.2.9.8 5.2.9.9 5.3.1.1 5.3.1.2 5.3.1.3 5.3.1.4 5.3.1.5 5.3.1.6 5.3.1.7 5.3.1 5.3.1.9 5.3.2.1 5.3 .2.2 5.3.2.3 5.3.2.4 5.3.2.5 5.3.2.6 5.3.2.7 5.3.2.8 5.3.2. 5.3.3.1 5.3.3.2 5.3.3.3 5.3.3.4 5.3.3.5 5.3.3.6 5.3.3.7 5.3.3.8 5.3.3.9 5.3.4.1 5.3.4.2 5.3.4.3 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7.1.1.7 7.1.1.8 7.1.1.9 7.1.2.1 7.1.2.2 7.1.2.3 7.1.2.4 7.1.2.5 7.1.2.6 7.1.2.7 7.1.2.8 7.1.2.9 7.1. 3.1 7.1.3.2 7.1.3.3 7.1.3.4 7. 1.3.5 7.1.3.6 7.1.3.7 7.1.3.8 7.1.3.9 7.1.4.1 7.1.4.2 7.1.4.3 7.1.4.4 7.1.4.5 7. 1.4.6 7.1.4.7 7.1.4.8 7.1.4.9 7.1.5.1 7.1.5.2 7.1.5.3 7.1.5.4 7.1.5.5 7.1.5.6 7. 1.5.7 7.1.5.8 7.1.5.9 7.1.6.1 7.1.6.2 7.1.6.3 7.1.6.4 7.1.6.5 7.1.6.6 7.1.6.7 7. 1.6.8 7.1.6.9 7.1.7.1 7.1.7.2 7.1.7.3 7.1.7.4 7.1.7.5 7.1.7.6 7.1.7.7 7.1.7.8 7.1.7.9 7.1.8.1 7.1.8.2 7.1.8.3 7. 1.8.4 7.1.8.5 7.1.8.6 7.1.8.7 7.1 7.1.8.9 7.1.9.1 7.1.9.2 7.1.9.3 7.1.9.4 7.1.9.5 7.1.9.6 7.1.9.7 7.1.9.8 7.1.9. 7.2.1.1 7.2.1.2 7.2.1.3 7.2.1.4 7.2.1.5 7.2.1.6 7.2.1.7 7.2.1.8 7.2.1.9 7.2.2.1 7.2.2.2 7.2.2.3 7.2.2.4 7.2.2.5 7.2.2.6 7.2.2.7 7.2. 2.8 7.2.2.9 7.2.3.1 7.2.3.2 7.2.3.3 7.2.3.4 7.2.3.5 7.2.3.6 7.2.3.7 7.2.3.8 7.2.3.9 7.2.4.1 7.2.4.2 7.2.4.3 7.2.4.4 7.2.4.5 7.2.4.6 7.2 .4.7 7.2.4.8 7.2.4.9 7.2.5.1 7.2.5.2 7.2.5.3 7.2.5.4 7.2.5.5 7.2.5.6 7.2.5.7 7.2.5.8 7.2.5.9 7.2.6.1 7.2.6.2 7.2.6.3 7.2.6.4 7.2.6.5 7.2.6.6 7.2.6.7 7.2.6.8 7.2.6.9 7.2.7.1 7.2.7.2 7.2.7.3 7.2.7.4 7.2.7.5 7.2.7.6 7.2.7.7 7.2.7.8 7.2.7.9 7.2.8.1 7.2.8.2 7.2.8.3 7.2. 8.4 7.2.8.5 7.2.8.6 7.2.8.7 7.2.8. 7.2.8.9 7.2.9.1 7.2.9.2 7.2.9.3 7.2.9.4 7.2.9.5 7.2.9.6 7.2.9.7 7.2.9.8 7.2.9.9 7.3.1.1 7.3.1.2 7.3.1.3 7.3.1.4 7.3.1.5 7.3.1.6 7.3. 1.7 7.3.1.8 7.3.1.9 7.3.2.1 7.3.2.2 7.3.2.3 7.3.2.4 7.3.2.5 7.3.2.6 7.3.2.7 7.3.2.8 7.3.2.9 7.3.3.1 7.3.3.2 7.3.3.3 7.3.3.4 7.3.3.5 7.3 .3.6 7.3.3.7 7.3.3.8 7.3.3.9 7.3.4.1 7.3.4.2 7.3.4.3 7. 3.4.4 7.3.4.5 7.3.4.6 7.3.4.7 7.3.4.8 7.3.4.9 7.3.5.1 7.3.5.2 7.3.5.3 7.3.5.4 7.3.5.5 7.3.5.6 7.3.5.7 7.3.5.8 7.3.5.9 7.3.6.1 7.3. 6.2 7.3.6.3 7.3.6.4 7.3.6.5 7.3.6.7 7.3.6.7 7.3.6.8 7.3.6.9 7.3.7.1 7.3.7.2 7.3.7.3 7.3.7.4 7.3.7.5 7.3.7.6 7.3.7.7 7.3.7.8 7.3.7.9 7.3 .8.1 7.3.8.2 7.3.8.3 7.3.8.4 7.3.8.5 7.3.8.6 7.3, 7.3.8.8 7.3.8.9 7.3.9.1 7.3.9.2 7.3.9.3 7.3.9.4 7.3.9.5 7.3.9.6 7.3.9.7 7.3.9. 7.3.9.9 7.4.1.1 7.4.1.2 7.4.1.3 7.4.1.4 7.4.1.5 7.4.1.6 7.4.1.7 7.4.1. 7.4.1.9 7.4.2.1 7.4.2.2 7.4.2.3 7.4.2.4 7.4.2.5 7.4.2.6 7.4.2.7 7.4.2.8 7.4.2.9 7.4.3.1 7.4.3.2 7.4.3.3 7.4.3.4 7.4.3.5 7.4.3.6 7.4. 3.7 7.4.3.8 7.4.3.9 7.4.4.1 7.4.4.2 7.4.4.3 7.4.4.4 7.4.4.5 7.4.4.6 7.4.4.7 7.4.4.8 7.4.4.9 7.4.5.1 7.4.5.2 7.4.5.3 7.4.5.4 7.4.5.5 7.4 .5.6 7.4.5.7 7.4.5.8 7.4.5.9 7.4.6.1 7.4.6.2 7.4.6.3 7.4.6.4 7.4.6.5 7.4.6.6 7.4.6.7 7.4.6.8 7.4.6.9 7.4.7.1 7.4.7.2 7.4.7.3 7.4.7.4 7.4.7.5 7.4.7.6 7.4.7.7 7.4.7.8 7.4.7.9 7.4.8.1 7.4.8.2 7.4.8.3 7.4.8.4 7.4.8.5 7.4.8.6 7.4.8.7 7.4.8.8 7.4.8.9 7.4.9.1 7. 4.9.2 7.4.9.3 7.4.9.4 7.4.9.5 7.4.9.6 7.4.9.7 7. 4.9.8 7.4.9.9 7.5.1.1 7.5.1.2 7.5.1.3 7.5.1.4 7.5.1.5 7.5.1.6 7.5.1.7 7.5.1 7. 5.1.9 7.5.2.1 7.5.2.2 7.5.2.3 7.5.2.4 7.5.2.5 7.5.2.6 7.5.2.7 7.5.2.8 7.5.2.9 7. 5.3.1 7.5.3.2 7.5.3.3 7.5.3.4 7.5.3.5 7.5.3.6 7.5.3.7 7.5.3.8 7.5.3.9 7.5.4.1 7. 5.4.2 7.5.4.3 7.5.4.4 7.5.4.5 7.5.4.6 7.5.4.7 7.5.4.8 7.5.4.9 7.5.5.1 7.5.5.2 7.5.5.3 7.5.5.4 7.5.5.5 7.5.5.6 7.5.5.7 7.5.5.8 7.5. 5.9 7.5.6.1 7.5.6.2 7.5.6.3 7. 5.6.4 7.5.6.5 7.5.6.6 7.5.6.7 7.5.6.8 7.5.6.9 7.5.7.1 7.5.7.2 7.5.7.3 7.5.7.4 7. 5.7.5 7.5.7.6 7.5.7.7 7.5.7.8 7.5.7.9 7.5.8.1 7.5.8.2 7.5.8.3 7.5.8.4 7.5.8.5 7. 5.8.6 7.5.8.7 7.5.8.8 7.5.8.9 7.5.9.1 7.5.9.2 7.5.9.3 7.5.9.4 7.5.9.5 7.5.9.6 7. 5.9.7 7.5.9.8 7.5.9.9 7.6.1.1 7.6.1.2 7.6.1.3 7.6.1.4 7.6.1.5 7.6.1.6 7.6.1.7 7.6.1.8 7.6.1.9 7.6.2.1 7.6.2.2 7.6.2.3 7.6.2.4 7.6. 2.5 7.6.2.6 7.6.2.7 7.6.2. 7. 6.2.9 7.6.3.1 7.6.3.2 7.6.3.3 Table 2 - continued 7.6.3.4 7.6.3.5 7.6.3 7. 6.9.6 7.6.9.7 7.6.9.8 7.6.9.9 7.7.1.1 7.7.1.2 7.7.1.3 7.7.1.4 7.7.1.5 7.7.1.6 7.7.1.7 7.7.1.8 7.7.1.9 7.7.2.1 7.7.2.2 7.7.2.3 7.7. 2.4 7.7.2.5 7.7.2.6 7.7.2.7 7.7.2.B 7.7.2.9 7.7.3.1 7.7.3.2 7.7.3.3 7.7.3.4 7.7.3.5 7.7.3.6 7.7.3.7 7.7.3.8 7.7.3.9 7.7.4.1 7.7. 4.2 7.7.4.3 7.7.4.4 7.7.4.5 7.7.4.6 7.7.4.7 7.7.4.8 7.7.4.9 7. 7.5.1 7.7.5.2 7.7.5.3 7.7.5.4 7.7.5.5 7.7.5.6 7.7.5.7 7.7.5.8 7.7.5.9 7.7.6.1 7. 7.6.2 7.7.6.3 7.7.6.4 7.7.6.5 7.7.6.6 7.7.6.7 7.7.6.8 7.7.6.9 7.7.7.1 7.7.7.2 7.7.7.3 7.7.7.4 7.7.7.5 7.7.7.6 7. 7.7.7 7.7.7.8 7.7.7.9 7.7.8.1 7.7.8.2 7.7.8.3 7. 7.8.4 7.7.8.5 7.7.8.6 7.7.8.7 7.7.8.8 7.7.8.9 7.7.9.1 7.7.9.2 7.7.9.3 7.7.9.4 7. 7.9.5 7.7.9.6 7.7.9.7 7.7.9.8 7.7.9.9 7.8.1.1 7.8.1.2 7.8.1.3 7.8.1.4 7.8.1.5 7. 8.1.6 7.8.1.7 7.8.1.8 7.8.1.9 7.8.2.1 7.8.2.2 7.8.2.3 7.8.2.4 7.8.2.5 2.6 7. 8.2.7 7.8.2.8 7.8.2.9 7.8.3.1 7.8.3.2 7.8.3.3 7.8.3.4 7.8.3.5 7.8.3.6 7.8.3.7 7.8.3.8 7.8.3.9 7.8.4.1 7.8.4.2 7.8.4.3 7.8.4.4 7.8. 4.5 7.8.4.6 7.8.4.7 7.8.4. 7. 8.4.9 7.8.5.1 7.8.5.2 7.8.5.3 7.8.5.4 7.8.5.5 7.8.5.6 7.8.5.7 7.8.5.8 7.8.5.9 7. 8.6.1 7.8.6.2 7.8.6.3 7.8.6.4 7.8.6.5 7.8.6.6 7.8.6.7 7.8.6.8 7.8.6.9 7.8.7.1 7. 8.7.2 7.8.7.3 7.8.7.4 7.8.7.5 7.8 7.6 7.8.7.7 7.8.7.8 7.8.7.9 7.8.8.1 7.8.8.2 7.8 8.3 7.8.8.4 7.8.8.5 7.8.8.6 7.8 8.7 7.8.8.8 7.8.8.9 7.8. 9.1 7.8.9.2 7.8.9.3 7.8 9.4 7.8.9.5 7.8.9.6 7.8.9.7 7.8.9.8 7.8.9.9 7.9.1.1 7.9.1.2 7.9.1.3 7.9.1.4 7. 9.1.5 7.9.1.6 7.9.1.7 7.9.1.8 7.9.1.9 7.9.2.1 7.9.2.2 7.9.2.3 7.9.2.4 7.9.2.5 7. 9.2.6 7.9.2.7 7.9.2.8 7.9.2.9 7.9.3.1 7.9.3.2 7.9.3.3 7.9.3.4 7.9.3.5 7.9.3.6 7. 9.3.7 7.9.3.8 7.9.3.9 7.9.4.1 7.9.4.2 7.9.4.3 7.9.4.4 7.9.4.5 7.9.4.6 7.9.4.7 7.9.4.8 7.9.4.9 7.9.5.1 7.9.5.2 7.9.5.3 7.9.5.4 7.9. 5.5 7.9.5.6 7.9.5.7 7.9.5 7.9.5.9 7.9.6.1 7.9.6.2 7.9.6.3 7.9.6.4 7.9.6.5 7.9.6.6 7.9.6.7 7.9.6. 7.9.6.9 7.9.7.1 7.9.7.2 7.9.7.3 7.9.7.3 7.9.7.4 7.9.7.6 7.9.7.6 7.9.7.7 7.9.7.8 7.9.7.9 7.9.8.7 7.9.8.2 7.9.8.2 7.9.8.3 7.9.8.4 7.9.8.5 7.9.8.6 7.9.8.6 7.9.8.6 7.9.8.6 7.9.8.6 7.9.8.6 7.9.8.6 7.9.8.6 7.9.8.6 7.9.8.6 7.9.8.6 7.9.8.6 7.9.8.6 7.9.8.6 7.9.8.6 7.9.8.6 7.9.8.6 8.7 7.9.8.8 7.9.8.9 7.9.9.1 7.9.9.2 7.9.9.3 7.9.9.4 7.9.9.5 7.9.9.6 7.9.9.7 7.9.9.8 7.9.9.9 8.1.1.1 .1.1.2 1.1.3 8.1.1.4 8.1.1.5 8.1.1.6 8.1.1.7 8.1.1.8 8.1.1.9 8.1.2.1 8.1.2.2 8.1.2.3 8.1.2.4 8 1.2.5 8.1.2.6 8.1.2.7 8.1.2.8 8.1.2.9 8.1.3.1 8.1.3.2 8.1.3.3 1.3 .4 8.1.3.5 8.1.3.6 8.1.3.7 8.1.3.8 8.1.3.9 8.1.4.1 8.1.4.2 8.1.4.3 8.1.4.3 8.1.4.4 8.1.4.5 8.1.4.6 8.1.4.7 8.1.4.8 8.1.4.9 8.1.5.1 8.1.5.2 8.1.5.3 8.1.5.4 8.1.5.5 .1.5.6 8.1.5.7 8.1.5.8 8.1.5.9 8.1.6.1 8.1.6.2 8.1.6.3 8.1.6.4 8.1.6.5 8.1.6.6 1.6.7 8.1.6. 8.1.6.9 8.1.7.1 8.1.7.2 8.1.7.3 8.1.7.4 8.1.7.5 8.1.7.6 8.1.7.7 1.7 1.7.9 8.1.8.1 8.1.8.2 8.1.8.3 8.1.8.4 8. 1.8.5 8.1.8.6 8.1.8.7 8.1.8.8 .1.8.9 .1.9.1 8.1.9.2 8.1.9.3 8.1.9.4 8.1.9.5 8.1.9.6 8.1.9.7 8.1.9.8 8.1.9.9 8.2.1.1 .2.1. 2 8.2.1.3 8.2.1.4 8.2.1.5 8.2.1.6 8.2.1.7 8.2.1.8 8.2.1.9 8.2.2.1 2.2.2 2.2.3 8.2.2.4 8.2.2.5 8.2.2.6 8.2.2.7 8.2.2.8 8.2.2.9 8.2 .3.1 8.2.3.2 2.3.3 2.3.4 8.2.3.5 8.2.3.6 8.2.3.7 8.2.3.8 8.2.3.9 8.2.4.1 8.2.4.2 8.2.4.3 2.4.4 2.4.5 8.2.4.6 8.2.4.7 8.2.4.8 8.2.4.9 8.2.5.1 8.2.5.2 8.2.5.3 8.2.5.4 .2.5.5 2.5.6 8.2.5.7 8.2.5.8 8.2.5.9 8.2.6.1 8.2.6.2 8.2.6.3 8.2.6.4 8.2.6.5 2.6.6 8.2 .6.7 8.2.6.8 8.2.6.9 8.2.7.1 8.2.7.2 8.2.7.3 8.2.7.4 8.2.7.5 8.2.7.6 2.7.7 8.2.7 8.2.7.9 8.2.8.1 8.2.8.2 8.2.8.3 8.2.8.4 8.2.8.5 8.2.8.6 8.2.8.7 8.2.8.8 8.2.8.9 8.2.9.1 8.2.9.2 8.2.9.3 8.2.9.4 8.2.9.5 8.2.9.6 8.2.9.7 8.2.9.8 .2.9.9 8.3.1.1 8.3.1.2 8.3.1.3 8.3 .1.4 8.3.1.5 8.3.1.6 8.3.1.7 8.3.1.8 8.3.1.9 3.2.1 8.3.2.2 8.3.2.3 8.3.2.4 8.3.2.5 8.3.2.6 Table 2- Continued 8.3.2.7 8.3.2.8 8.3.2.9 8.3.3.1 8.3.3.2 8.3.3.3 8.3.3.4 8.3.3.5 8.3.3.6 8.3.3.7 8.3.3.8 8.3.3.9 8.3.4.1 8.3.4.2 8.3.4.3 8.3 .4.4 8.3.4.5 8.3.4.6 8.3.4.7 8.3.4.8 8.3.4.9 8.3.5.1 8.3.5.2 8.3.5.3 8.3.5.4 8.3.5.5 8. 3.5.6 8.3.5.7 8.3.5.8 8.3.5.9 8.3.6.1 8.3.6.2 8.3.6.3 8.3.6.4 8.3.6.5 8.3.6.6 8. 3.6.7 8.3.6.8 8.3.6.9 8.3.7.1 8.3.7.2 8.3.7.3 8.3.7.4 8.3.7.5 8.3.7.6 8.3.7.7 8. 3.7.8 8.3.7.9 8.3.8.1 8.3.8.2 8.3.8.3 8.3.8.4 8.3.8.5 8.3.8.6 8.3.8.7 8.3.8.8 8. 3.8.9 8.3.9.1 8.3.9.2 8.3.9.3 8.3.9.4 8.3.9.5 8.3.9.6 8.3.9.7 8.3.9.8 8.3.9.9 8.4.1.1 8.4.1.2 8.4.1.3 8.4.1.4 8.4.1.5 8.4.1.6 8.4. 1.7 8.4.1.8 8.4.1.9 8.4.2.1 8. 4.2.2 8.4.2.3 8.4.2.4 8.4.2.5 8.4.2.6 8.4.2.7 8.4.2.8 8.4.2.9 8.4.3.1 8.4.3.2 8. 4.3.3 8.4.3.4 8.4.3.5 8.4.3.6 8.4.3.7 8.4.3.8 8.4.3.9 8.4.4.1 8.4.4.2 8.4.4.3 8. 4.4.4 8.4.4.5 8.4.4.6 8.4.4.7 8.4.4.8 8.4.4.9 8.4.5.1 8.4.5.2 8.4.5.3 8.4.5.4 8. 4.5.5 8.4.5.6 8.4.5.7 8.4.5.8 8.4.5.9 8.4.6.1 8.4.6.2 8.4.6.3 8.4.6.4 8.4.6.5 8.4.6.6 8.4.6.7 8.4.6.8 8.4.6.9 8. 4.7.1 8.4.7.2 8.4.7.3 8.4.7.4 4.7.5 .4.7.6 8. 4.7.7 8.4.7.8 8.4.7.9 8., 4.8.1 8.4.8.2 8.4.8.3 8.4.8.4 8.4.8. 5 .4.8.6 4.8.7 8. 4.8.8 8.4.8.9 8.4.9.1 8., 4.9.2 8.4.9.3 8.4.9.4 8.4.9.5 8.4.9. , 6 4.9.7 8.4.9.8 8. 4.9.9 8.5.1.1 8.5.1.2 8., 5.1.3 8.5.1.4 8.5.1.5 8.5.1.6 8.5.1. , 7 5.1 5.1. 8. 5.2.1 8.5.2.2 8.5.2.3 8. .5.2.4 8.5.2.5 8.5.2.6 8.5.2.7 8.5.2. , 8 5.2.9 5.3.1 8. 5.3.2 8.5.3.3 8.5.3.4 8. .5.3.5 8.5.3.6 8.5.3.7 8.5.3.8 8.5.3. .9 .5.4.1 .5.4.2 8. 5.4.3 8.5.4.4 8.5.4.5 8. .5.4.6 8.5.4.7 8.5.4.8 8.5.4.9 8.5.5. .1 5.5.2 5.5.3 8. 5.5.4 8.5.5.5 8.5.5.6 8..5.5.7 8.5.5.8 8.5.5.9 8.5.6.1 8.5.6. .2 5.6.3 8.5.6.4 8. 5.6.5 8.5.6.6 8.5.6.7 8. .5.6.8 8.5.6.9 8.5.7.1 8.5.7.2 8.5.7, .3 5.7.4 8.5.7.5 8. 5.7.6 8.5.7.7 8.5.7.8 8. .5.7.9 8.5.8.1 8.5.8.2 8.5.8.3 8.5.8, .4 .5.8.5 8.5.8.6 8. 5.8.7 8.5.8.8 8.5.8.9 8, .5.9.1 8.5.9.2 8.5.9.3 8.5.9.4 8.5.9, .5 .5.9.6 8.5.9.7 8. 5.9.8 8.5.9.9 8.6.1.1 8, .6.1.2 8.6.1.3 8.6.1.4 8.6.1.5 8.6.1, .6 8.6.1.7 8.6.1. 8. 6.1.9 8.6.2.1 8.6.2.2 8, .6.2.3 8.6.2.4 8.6.2.5 8.6.2.6 8.6.2, .7 8.6.2.8 8.6.2.9 8. 6.3.1 8.6.3.2 8.6.3.3 8.6.3.4 8.6.3.5 8.6.3.6 8.6.3.7 8.6.3.8 6.3.9 6.4.1 8.6.4.2 8.6.4.3 8.6.4.4 8.6.4.5 8.6.4.6 8.6.4.7 8.6. 4.8 8.6.4.9 .6.5.1 .6.5.2 8.6.5.3 8.6.5.4 8.6.5.5 8.6.5.6 8.6.5.7 8.6.5.8 8.6.5.9 8.6.6.1 .6.6.2 8.6.6.3 8.6.6.4 8.6.6.5 8.6 .6.6 8.6.6.7 8.6.6.8 8.6.6.9 8.6.7.1 8.6.7.2 .6.7.3 .6.7.4 8.6.7.5 8.6.7.6 8.6.7.7 8.6.7.8 8.6.7.9 8.6.8.1 8.6.8.2 8.6.8.3. 6.8.4 6.8.5 8.6.8.6 8.6.8.7 8.6.8.8 8.6.8.9 8.6.9.1 8.6.9.2 8.6.9.3 8.6.9.4 8.6.9.5 6.9.6 8.6.9.7 8.6.9.8 8.6.9.9 8.7.1.1 8.7. 1.2 8.7.1.3 8.7.1.4 8.7.1.5 7.1.6 8.7.1.7 8.7.1.8 8.7.1.9 8.7.2.1 8.7.2.2 8.7.2.3 8.7.2.4 8.7.2.5 8.7.2.6 8.7.2.7 8.7.2.7. 8.7.2.9 8.7.3.1 8.7.3.2 8.7.3.3 8.7.3.4 8.7.3.5 8.7.3.6 8.7.3.7 8.7.3.8 8.7.3.9 8.7.4.1 8.7.4.2 8.7.4.3 8.7.4.4 8.7.4.5 8.7.4.6 8.7. 4.7 8.7.4.8 8.7.4.9 8.7.5.1 .7.5.2 8.7.5.3 8.7.5.4 8.7.5.5 .7.5.6 8.7.5.7 8.7.5.8 8.7.5.9 7.6.1 8.7.6.2 .7.6.3 8.7.6.4 8.7 .6.5 8.7.6.6 .7.6.7 8.7.6.8 8.7.6.9 8.7.7.1 8.7.7.2 8.7.7.3 8.7.7.4 8.7.7.5 8.7.7.6 8.7.7.7 8. 7.7.8 8.7.7.9 8.7.8.1 8.7.8.2 7.8.3 8.7.8.4 8. 7.8.5 8.7.8.6 8.7.8.7 8. 7.8.8 8. 7.8.9 8.7.9.1 8.7.9.2 8.7.9. 3 7.9.4 8.7.9.5 8 7.9.6 8.7.9.7 8.7.9.8 8 7.9.9 8 8.1.1 8.8.1.2 8.8.1.3 8.8.1 4 8.1.5 .8.1.6 8 8.1.7 8.8.1.8 8.8.1.9 8 8.2.1 8 8.2.2 8.8.2.3 8.8.2.4 8.8.2 5 .2.6 8.8.2.7 8 8.2.8 8.8.2.9 8.8.3.1 8 8.3.2 8 8.3.3 8.8.3.4 8.8.3.5 8.8.3 6 3.7 .3. 8 8.3.9 8.8.4.1 8.8.4.2 8 8.4.3 8 8.4.4 8.8.4.5 8.8.4.6 8.8.4 7 8.4.8 .4.9 8 8.5.1 8.8.5.2 8.8.5.3 8 8.5.4 8 8.5.5 8.8.5.6 8.8.5.7 8.8.5 8 8.5.9 8.8.6.1 8 8.6.2 8.8.6.3 8.8.6.4 8 8.6.5 8 8.6.6 8.8.6.7 8.8.6.8 8.8.6 9 7.1 7.2 8 8.7.3 8.8.7.4 8.8.7.5 8 .8.7.6 8 .8.7.7 8.8.7.8 8.8.7.9 8.8.8 .1 8.8.2 8.8.8.3 8 8.8.4 8.8.8.5 8.8.8.6 8 .8.8.7 8 .8.8.8 8.8.8.9 8.8.9.1 8.8.9 .2 .9.3 .9.4 8 .8.9.5 8.8.9.6 8 9. 1.2.6 9.1.2.7 9.1.2.8 9.1.2.9 9.1.3.1 9.1.3.2 9.1.3.3 9.1.3.4 9.1.3.5 9.1.3.6 9. 1.3.7 9.1.3.8 9.1.3.9 9.1.4.1 9.1.4.2 9.1.4.3 9.1.4.4 9.1.4.5 9.1.4.6 9.1.4.7 9. 1.4.8 9.1.4.9 9.1.5.1 9.1.5.2 9.1.5.3 9.1.5.4 9.1.5.5 9.1.5.6 9.1.5.7 9.1.5.8 9.1.5.9 9.1.6.1 9.1.6.2 9.1.6.3 9. 1.6.4 9.1.6.5 9.1.6.6 9.1.6.7 1.6.8 9.1.6.9 9.1.7.1 9.1.7.2 9.1.7.3 9.1.7.4 9.1.7.5 9.1.7.6 9.1.7.7 9.1.7.8 9.1.7.9 9.1.8.1 9.1. 8.2 9.1.8.3 9.1.8.4 9.1.8.5 9.1.8.6 9.1.8.7 9.1.8.8 9.1.8.9 '.1.9.1 9.1.9.2 9.1.9.3 9.1.9.4 9.1.9.5 9.1.9.6 9.1.9.7 9.1.9.8 9.1. 9.9 9.2.1.1 9.2.1.2 9.2.1.3 9.2.1.4 9.2.1.5 9.2.1.6 9.2.1.7 9.2.1.8 9.2.1.9 9.2.2.1 9.2.2.2 .2.2.3 9.2.2.4 9.2.2.5 9.2.2.6 9.2.2.7 9.2.2.8 9.2.2.9 9.2.3.1 9.2.3.2 9.2.3.3 9.2.3.4 9.2.3.5 9.2.3.6 9.2.3.7 9.2.3.8 9.2.3.9 9.2.4.1 9.2.4.2 9.2.4.3 9.2.4.4 9.2.4.5 9.2. 4.6 9.2.4.7 9.2.4.8 9.2.4.9 9.2.5.1 9.2.5.2 9.2.5.3 9.2.5.4 9.2.5.5 9.2.5.6 9.2.5.7 9.2.5.8 9.2.5.9 9.2.6.1 9.2.6.2 9.2.6.3 9.2.6.4 9.2 .6.5 9.2.6.6 9.2.6.7 9.2.6. 9.2.6.9 9.2.7.1 9.2.7.2 9.2.7.3 9.2.7.4 9.2.7.5 9.2.7.6 9.2.7.7 9.2.7.8 9.2.7.9 9.2.8.1 9.2.8.2 9.2.8.3 9.2.8.4 9.2.8.5 9.2.8.6 9.2. 8.7 9.2.8.8 9.2.8.9 9.2.9.1 9.2.9.2 9.2.9.3 9.2.9.4 9.2.9.5 9.2.9.6 9.2.9.7 9.2.9.8 9.2.9.9 9.3.1.1 9.3.1.2 9.3.1.3 9.3.1.4 9.3.1.5 9.3 .1.6 9.3.1.7 9.3.1.8 9.3.1.9 9.3.2.1 9.3.2.2 9.3.2.3 9. 3.2.4 9.3.2.5 9.3.2.6 9.3.2.7 9.3.2.8 9.3.2.9 9.3.3.1 9.3.3.2 9.3.3.3 9.3.3.4 9. 3.3.5 9.3.3.6 9.3.3.7 9.3.3.8 9.3.3.9 9.3.4.1 9.3.4.2 9.3.4.3 9.3.4.4 9.3.4.5 9.3.4.6 9.3.4.7 9.3.4.8 9.3.4.9 9.3.5.1 9.3.5.2 9.3. 5.3 9.3.5.4 9.3.5.5 9.3.5.6 9. 3.5.7 9.3.5.8 9.3.5.9 9.3.6.1 9.3.6.2 9.3.6.3 9.3.6.4 9.3.6.5 9.3.6.6 9.3.6.7 9. 3.6.8 9.3.6.9 9.3.7.1 9.3.7.2 9.3.7.3 9.3.7.4 9.3.7.5 9.3.7.6 9.3.7.7 9.3.7 9. 3.7.9 9.3.8.1 9.3.8.2 9.3.8.3 9.3.8.4 9.3.8.5 9.3.8.6 9.3.8.7 9.3. 9.3.8.9 9.3.9.1 9.3.9.2 9.3.9.3 9.3.9.4 9.3.9.5 9.3.9.6 9.3.9.7 9.3.9.8 9.3.9.9 9.4.1.1 9.4.1.2 9.4.1.3 9.4.1.4 9.4.1.5 9.4.1.6 9.4. 1.7 9.4.1.8 9.4.1.9 9.4.2.1 9.4.2.2 9. 4.2.3 9.4.2.4 9.4.2.5 9.4.2.6 9.4.2.7 9.4.2.8 9.4.2.9 9.4.3.1 9.4.3.2 9.4.3.3 9. 4.3.4 9.4.3.5 9.4.3.6 9.4.3.7 9.4.3.8 9.4.3.9 9.4.4.1 9.4.4.2 9.4.4.3 9.4.4.4 9. 4.4.5 9.4.4.6 9.4.4.7 9.4.4.8 9.4.4.9 9.4.5.1 9.4.5.2 9.4.5.3 9.4.5.4 9.4.5.5 9. 4.5.6 9.4.5.7 9.4.5.8 9.4.5.9 9.4.6.1 9.4.6.2 9.4.6.3 9.4.6.4 9.4.6.5 9.4.6.6 9.4.6.7 9.4.6.8 9.4.6.9 9.4.7.1 9. 4.7.2 9.4.7.3 9.4.7.4 9.4.7.5 9.4.7.6 9.4.7.7 9. 4.7.8 9.4.7.9 9.4.8.1 9.4.8.2 9.4.8.3 9.4.8.4 9.4.8.5 9.4.8.6 9.4.8.7 9.4.8.8 9. 4.8.9 9.4.9.1 9.4.9.2 9.4.9.3 9.4.9.4 9.4.9.5 9.4.9.6 9.4.9.7 9.4.9, 9.4.9.9 9. 5.1.1 9.5.1.2 9.5.1.3 9.5.1.4 9.5.1.5 9.5.1.6 9.5.1.7 9.5.1.8 9.5.1.9 9.5.2.1 9. 5.2.2 9.5.2.3 9.5.2.4 9.5.2.5 9.5.2.6 9.5.2.7 9.5.2.8 9.5.2.9 9.5.3.1 9.5.3.2 9.5.3.3 9.5.3.4 9.5.3.5 9.5.3.6 9.5.3.7 9.5.3.8 9.5. 3.9 9.5.4.1 9.5.4.2 .5.4.3 9. 5.4.4 9.5.4.5 9.5.4.6 9.5.4.7 9.5.4.8 9.5.4.9 9. 7.3.1 9.7.3.2 9.7.3.3 9.7.3.4 9.7.3.5 9.7.3.6 9.7.3.7 9.7.3.8 9.7.3.9 9.7.4.1 9. 7.4.2 9.7.4.3 9.7.4.4 9.7.4.5 9.7.4.6 9.7.4.7 9.7.4.8 9.7.4.9 9.7.5.1 9.7.5.2 9.7.5.3 9.7.5.4 9.7.5.5 9.7.5.6 9. 7.5.7 9.7.5.8 9.7.5.9 9.7.6.1 9.7.6.2 9.7.6.3 9. 7.6.4 9.7.6.5 9.7.6.6 9.7.6.7 9.7.6.8 9.7.6.9 9.7.7.1 9.7.7.2 9.7.7.3 9.7.7.4 9. 7.7.5 9.7.7.6 9.7.7.7 9.7.7.8 9.7.7.9 9.7.8.1 9.7.8.2 9.7.8.3 9.7.8.4 9.7.8.5 9. 7.8.6 9.7.8.7 9.7.8.8 9.7.8.9 9.7.9.1 9.7.9.2 9.7.9.3 9.7.9.4 9.7.9.5 9.7.9.6 9. 7.9.7 9.7.9.8 9.7.9.9 9.8.1.1 9.8.1.2 9.8.1.3 9.8.1.4 9.8.1.5 9.8.1.6 9.8.1.7 9.8.1.8 9.8.1.9 9.8.2.1 9.8.2.2 9.8.2.3 9.8.2.4 9.8. 2.5 9.8.2.6 9.8.2.7 9.8.2.8 9. 8.2.9 9.8.3.1 9.8.3.2 9.8.3.3 9.8.3.4 9.8.3.5 9.8.3.6 9.8.3.7 9.8.3.8 9.8.3.9 9. 8.4.1 9.8.4.2 9.8.4.3 9.8.4.4 9.8.4.5 9.8.4.6 9.8.4.7 9.8.4.8 9.8.4.9 9.8.5.1 9. 8.5.2 9.8.5.3 9.8.5.4 9.8.5.5 9.8.5.6 9.8.5.7 9.8.5.8 9.8.5.9 .8.6.1 9.8.6.2 9. 8.6.3 9.8.6.4 9.8.6.5 9.8.6.6 9.8.6.7 9.8.6.8 9.8.6.9 9.8.7.1 9.8.7.2 9.8.7.3 9.8.7.4 9.8.7.5 9.8.7.6 9.8.7.7 9.8.7.8 9.8.7.9 9.8. 8.1 9.8.8.2 9.8.8.3 9.8.8.4 9. 8.8.5 9.8.8.6 9.8.8.7 9.8.8.8 9.8.8.9 9.8.9.1 9.8.9.2 9.8.9.3 9.8.9.4 9.8.9.5 9. 8.9.6 9.8.9.7 9.8.9.8 9.8.9.9 9.9.1.1 9.9.1.2 9.9.1.3 9.9.1.4 9.9.1.5 9.9.1.6 9. 9.1.7 9.9.1.8 9.9.1.9 9.9.2.1 9.9.2.2 9.9.2.3 9.9.2.4 9.9.2.5 9.9.2.6 9.9.2.7 9. 9.2.8 9.9.2.9 9.9.3.1 9.9.3.2 9.9.3.3 9.9.3.4 9.9.3.5 9.9.3.6 9.9.3.7 9.9.3.8 9.9.3.9 9.9.4.1 9.9.4.2 9.9.4.3 9.9.4.4 9.9.4.5 9.9. 4.6 9.9.4.7 9.9.4.8 9.9.4.9 9. 9.5.1 9.9.5.2 9.9.5.3 9.9.5.4 9.9.5.5 9.9.5.6 9.9.5.7 9.9.5.8 9.9.5.9 9.9.6.1 9. 9.6.2 9.9.6.3 9.9.6.4 9.9.6.5 9.9.6.6 9.9.6.7 9.9.6.8 9.9.6.9 9.9.7.1 9.9.7.2 9. 9.7.3 9.9.7.4 9.9.7.5 9.9.7.6 9.9.7.7 9.9.7.8 9.9.7.9 9.9.8.1 9.9.8.2 9.9.8.3 9. 9.8.4 9.9.8.5 9.9.8.6 9.9.8.7 9.9.8.8 9.9.8.9 9.9.9.1 9.9.9.2 9.9.9.3 9.9.9.4 9.9.9.5 9.9.9.6 9.9.9.7 9.9.9.8 9.9.9.9 In another aspect, the Phosphonic acid monoester compounds are included in the invention having variable alternative VI 'and variables V2, V3, and V4 as described above. The compounds named in table 2 are designated by the numbers assigned to the variables of formulas V-VII using the following convention: V1 '. V2 V3 V. Variable V1 ': 1) -P (O) (OH) (OCH3) 2) -P (0) (OH) (OCH2CH3) 3) -P (0) ((OH) (Oi-propyl) 4) -P (0) [, -OCH2OC (0) -t-butyl] (OCH3) 5) -P (0) [OCH2OC (0) 0-i-propyl] (OCH3) 6) -P (0) [-N (H) CH (CH3) C (O) OCH2CH3] (OCH3) 7) -P (0) [N (H) C (CH3 ) 2C (O) OCH 2 CH 3] (OCH 3) 8) -P (0) [OCH (CH 3) OC (O) -t-butyl] (OCH 3) 9) -P (0) [-OCH (CH 3) OC (0 ) 0-i-propyl] (OCH3) In another aspect, the following compounds are included in the invention but the compounds are not limited to these illustrative compounds. The compounds are shown without detail of the stereochemistry since the compounds are biologically active as the diastereomeric mixture or as a simple stereoisomer. The compounds included are designated by the numbers assigned to the variables of formulas XI-XVI using the following convention: VI. V2 V3 V4 V5 V6. Each individual compound from 1.1.1.1.1.1 through 9.9.9.9.9.9 (for example, 2.3.4.5.6.7 or 8.7.3.5.2.1) is included in the present invention as an individual species and can be specifically established as a total by inclusion or it can be specifically excluded from the present invention. As the understanding is that it is included, it is clear from the description that, a Table is not included so as not to unduly lengthen the specification.
Formula XI Formula XIII Formula XIV 20 Formula XV 25 Formula XVI Variab 8) -CH = CH- (trans) 9) - null Variable V3: 1) -OCH3 2) iodine 3) bromine 4) chlorine 5) fluoro 6) methyl 7) trifluoromethyl 8) cyano 9) -OCF3 Variable V4 1) iodine 2) CH (CH 3) 2 3) - (3-trifluoromethylophenoxy) 4) - (3-ethylphenyl) 5) -C (0 ) NH-CH2-CH2-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, phosphonic acid monoester compounds are included in the invention having variable alternative V1 'and variables V2, V3, V4, V5, and V6 as described above. The compounds were designated by the numbers assigned to the variables of formulas XI-XVI using the following convention: V1 '. V2 V3 V4 V5 V6. Variable V1 ': 1) -P (O) (OH) (OCH3) 2) -P (O) (; OH) (OCH2CH3; 3 3)) --PP ((OO)) ((OH) (Oi) -propyl; 4) -P (O) [-OCH2OC (O) -t-butyl] (OCH3) 5) -P (O) [OCH2OC (0) 0-i-propyl] (OCH3; 6) -P ( O) [N (H) CH (CH3) C (O) OCH2CH3] (OCH3) 7) -P (O) [; -N (H) C (CH3) 2C (0) OCH2CH3] (OCH3) 8 8) ) - PP ((OO)) [[-OCH (CH3) OC (0) -t-butyl] (OCH3) 9) -P (O) [OCH (CH3) OC (O) Oi-propyl] (OCH3 In another aspect the following compounds are included in the invention but the compounds are not limited to these illustrative compounds. The compounds are shown without detail of the stereochemistry since the compounds are biologically active as the diastereomeric mixture or as a simple stereoisomer. The compounds included are designated by the numbers assigned to the variables of formulas XVII and XVIII using the following convention: V ^ V ^ V ^ V ^ V ^ 6 ^ 7 Each individual compound of 1.1.1.1.1.1.1 up to 9.9.9.9.9.9.2 (eg, 2.3.4.5.6.7.1 or 8.7.3.5.2.1.1) is included in the present invention as an individual species and can be specifically established as such by inclusion or can be specifically excluded of the present invention. As the understanding is that it is included, it is clear from the description that, a Table is not included so as not to unduly lengthen the specification.
Formula XVII Formula XVIII Variable V7: 1) -CH2- 2) - null In another aspect, phosphonic acid monoester compounds are included in the invention have variable alternative V1 'and variables V2, V3, V4, V5, V6, and V7 as described above. The compounds were designated by the numbers assigned to the variables of formulas XVII-XVIII using the following convention: V1 '.V2.V3.V4.V5.V6.V7. Variable V1 ': 1) -P (O) (OH) (OCH3) 2) -P (O) ((OH) (OCH2CH3) 3) -P (O) ((OH) (Oi-propyl) 4) -P (O) [[-OCH2OC (O) -t-butyl] ( OCH3) 5) -P (O) [[-OCH2OC (0) 0-i-propyl] (OCH3) 6) -P (O) [[-N (H) CH (CH3) C (O) OCH2CH3] ( OCH3) 7) -P (O) [[-N (H) C (CH3) 2C (O) OCH2CH3] (OCH3) 8) -P (O) [[-OCH (CH3) OC (O) -t- butyl] (OCH3) 9) -P (O) [[-OCH (CH3) OC (O) 0-i-propyl] (OCH3) The present invention provides the compounds of formula I including but 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, Rs is -OH, X is -P03H2; G is -O-, T is -N (H) C (0) -, R1 is -CH3, R2 is -CH3, R3 is CH (OH) (4-f luorophenyl), R4 is -H, R5 is - OH, X is -P03H2; G is -CH2-, T is -0CH2-, 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 P03H2; 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 (O) [-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-, 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 ) 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 -P (O) [-OCH2OC (O ) C (CH3) 3] 2; 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-f luorophenyl), 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 (0) [-OCH2OC (0) OCH (CH3) 2] 2 G is -0-, T is -CH2-, R1 is -Cl, R2 is -Cl, R3 is i-propyl, R4 is -H , R5 is -OH, X is -P (0) [-OCH2OC (0) OCH (CH3) 2] 2; G is -0-, T is -0CH2-, R1 is -I, R2 is -I, R3 is i-propyl, R4 is -H, R5 is -OH, X is -P (0) [-0CH20C (0 OCH (CH3) 2] 2; Bisamidates G is -0-, T is -CH2CH (NH2) -, R1 is -I, R2 is -I, R3 is -I, R4 is -H, R5 is -OH, X is -P (0) [N (H) CH (CH3) C (0) OCH2CH3] 2; G is -0-, T is -CH2CH (NH2) -, R1 is -I, R2 is -I, R3 is -I, R4 is -I, R5 is -OH, X is -P (0) [N ( H) CH (CH3) C (0) OCH2CH3] 2; G is -0-, T is -CH2-, R1 is -I, R2 is -I, R3 is -I, R4 is -H, R5 is -OH, X is -P (0) [N (H) CH (CH3) C (0) OCH2CH3] 2; G is -0-, T is -N (H) C (0) -, R1 is -CH3, R2 is -CH3, R3 is CH (OH) (4-f luorophenyl), R4 is -H, R5 is - OH, X is -P (0) [N (H) CH (CH3) C (0) OCH2CH3] 2; G is -CH2-, T is -0CH2-, R1 is -CH3, R2 is -CH3, R3 is i-propyl, R4 is -H, R5 is -OH, X is -P (0) [N (H) CH (CH3) C (0) OCH2CH3] 2; G is -0-, T is -CH2-, R1 is -Cl, R2 is -Cl, R3 is i-propyl, R4 is -H, R5 is -OH, X is -P (0) [N (H) CH (CH3) C (0) 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 -P (O) [N (H) CH (CH3) C (O) OCH2CH3] 2; Bisamidates # 2 G is -0-, T is -CH2CH (NH2) -, R1 is -I, R2 is -I, R3 is -I, R4 is -H, R5 is -OH, X is -P (0) [N (H) C (CH3) 2C (0) 0CH2CH3] 2; G is -0-, T is -CH2CH (NH2) -, R1 is -I, R2 is -I, R3 is -I, R4 is -I, R5 is -OH, X is -P (0) [N ( H) C (CH3) 2C (0) 0CH2CH3] 2; G is -0-, T is -CH2-, R1 is -I, R2 is -I, R3 is -I, R4 is -H, R5 is -OH, X is -P (0) [N (H) C (CH3) 2C (0) OCH2CH3] 2; G is -0-, 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) [N (H) C (CH3) 2C (0) OCH2CH3] 2; G is -CH2-, T is -0CH2-, R1 is -CH3, R2 is -CH3, R3 is i-propyl, R4 is -H, R5 is -OH, X is -P (0) [N (H) C (CH3) 2C (0) OCH2CH3] 2; G is -0-, T is -CH2-, R1 is -Cl, R2 is -Cl, R3 is i-propyl, R4 is -H, R5 is -OH, X is -P (0) [N (H) C (CH3) 2C (0) OCH2CH3] 2; G is -0-, T is -0CH2-, R1 is -I, R2 is -I, R3 is i-propyl, R4 is -H, R5 is -OH, X is -P (0) [N (H) C (CH3) 2C (0) OCH2CH3] 2; 4-aryl-2-oxo-2-? 5-l, 3, 2-dioxaphosphonanes G is -0-, T is -CH2CH (NH2) -, R1 is -I, R2 is -I, R3 is -I, R4 is -H, R5 is -OH, X is -P (0) [-0CH (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-chlorofenyl) 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), R 4 is -H, R 5 is -OH, X is -P (O) [-OCH (3-chlorophenyl) CH 2 CH 20-]; 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 -P (O) [-OCH (3-chlorophenyl) CH2CH20-]. The present invention further provides monoester compounds of the formula I including but 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 -P (0 (OH) (OCH3); 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 (0 (OH) (OCH3), G is -O-, T is -CH2-, R1 is -I, R2 is -I, R3 is -I, R4 is -H, R5 is -OH, X is -P (0 (OH) (OCH3); G is -O-, T is -N (H) C (0) -, R1 is -CH3, R2 is -CH3, R3 is CH (OH) (4-f luorophenyl), R4 is -H, R5 is - OH, X is -P (0 (OH) (OCH3), 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 (0 (OH) (0CH3); G is -0-, T is -CH2-, R1 is -Cl, R2 is -Cl, R3 is i-propyl, R4 is -H, R5 is -OH, X is -P (0 (OH) (0CH3), G is -0-, T is -0CH2-, R1 is -I, R2 is -I, R3 is i-propyl, R4 is -H, R5 is -OH, X is -P (0 (OH) (0CH3); Esters POM G is -0-, 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] (OCH3); 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] (OCH3); G is -0 -, T is -CH2-, R1 is -I, R2 is -I, R3 is -I, R4 is -H, R5 is -OH, X is -P (0) [-0CH20C (0) C (CH3) 3] (0CH3); G is -0-, T is -N (H) C (0) -, R1 is -CH3, R2 is -CH3, R3 is CH (OH) (4-f luorophenyl), R4 is -H, R5 is - OH, X is -P (0) [-0CH20C (0) C (CH3) 3] (0CH3); G is -CH2-, T is -0CH2-, R1 is -CH3, R2 is -CH3, R3 is i-propyl, R4 is -H, R5 is -OH, X is -P (0) [-0CH20C (0) C (CH3) 3] (0CH3); is -0-, T is -CH2-, R1 is -Cl, R2 is -Cl, R is i-propyl, R is -H, R3 is -OH, is -P (0) [-OCH2OC (0) C (CH3) 3] (0CH3); G is -O-, T is -OCH2-, R1 is -I, R is -I, R- is -propyl, R4 is -H, R5 is -OH, X is -P (0) [-0CH20C (0) C (CH3) 3] (OCH3); Carbonates G is -0-, T is -CH2CH (NH2) -, R1 is -I, R2 is -I, R3 is -I, R4 is -H, R5 is -OH, X is -P (0) [-0CH20C (0) OCH (CH3) 2] (0CH3); G is -0-, T is -CH2CH (NH2) -, R1 is -I, R2 is -I, R3 is -I, R4 is -I, R5 is -OH, X is -P (0) [-0CH20C (0) OCH (CH3) 2] (0CH3); G is -0-, T is -CH2-, R1 is -I, R2 is -I, R3 is -I, R4 is -H, R5 is -OH, X is -P (0) [-0CH20C (0) OCH (CH3) 2] (0CH3); 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] (0CH3); G is -CH2-, T is -0CH2-, R1 is -CH3, R2 is -CH3, R3 is i-propyl, R4 is -H, R5 is -OH, X is -P (0) [-OCH2OC (0) OCH (CH3) 2] (0CH3); G is -0-, T is -CH2-, R1 is -Cl, R2 is -Cl, R3 is i-propyl, R4 is -H, R5 is -OH, X is -P (0) [-OCH2OC (O) OCH (CH3) 2] (OCH3); G is -0-, T is -0CH2-, R1 is -I, R2 is -I, R3 is i-propyl, R4 is -H, R5 is -OH, X is -P (0) [-OCH2OC (0) OCH (CH3) 2] (OCH3); Amidates G is -0-, T is -CH2CH (NH2) -, R1 is -I, R2 is -I, R3 is -I, R4 is -H, R5 is -OH, X is -P (0) [N (H) CH (CH3) C (0) OCH2CH3] (0CH3); 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] (OCH3); 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] (OCH3); 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] (OCH 3); 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 (O) OCH2CH3] (OCH3); 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] (OCH3); G is -O-, T is -OCH2-, R1 is -I, R2 is -I, R3 is i-propyl, R4 is -H, R5 is -OH, X is -P (O) [N (H) CH (CH3) C (O) OCH2CH3] (OCH3); Amidates # 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] (OCH3); 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] (OCH3); 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] (OCH3); G is -O-, T is -N (H) C (0) -, R1 is -CH3, R2 is -CH3, R3 is CH (OH) (4-f luorophenyl), R4 is -H, R5 is - OH, X is -P (O) [N (H) C (CH3) 2C (O) 0CH2CH3] (OCH3); G is -CH5 T is -OCH2- R1 is -CH 3 / R is -CH 3? R > is i-propyl, R4 is -H, R5 is -OH, X is -P (O) [N (H) C (CH3) 2C (O) OCH2CH3] (OCH3); G is -O-, T is -CH2 R1 is -Cl, R2 is -Cl, R3 is i-propyl, R is -H, R is -OH, X is -P (O) [N (H) C ( CH3) 2C (0) OCH2CH3] (OCH3); G is -O-, T is -OCH2-, R1 is -I, R2 is -I, R3 is i-propyl, K * is -H, R is -OH, X is -P (O) [N (H) C (CH3) 2C (0) OCH2CH3] (OCH3). In one aspect, the invention relates to compounds selected from the group consisting of: 25 Y and monoesters thereof, and prodrugs of the compounds or monoesters of the compounds, and pharmaceutically acceptable salts thereof. In another aspect, the invention relates to compounds selected from the group consisting of: Y and monomethyl esters thereof, and pharmaceutically acceptable salts and prodrugs of the monomethyl compounds and esters thereof. In one embodiment, the prodrugs are prodrugs bis-POM, carbonate, bisamidate, or 4-aryl-2-oxo-2-? 5-l, 3,2-dioxaphosphonon of the compounds or prodrugs of bis-POM, carbonate, or bisamidate of the monoesters of the compounds.
In another aspect, the invention relates to prodrug compounds selected from the group consisting of: ; Y and pharmaceutically acceptable salts thereof. In a further aspect, the invention relates to prodrug compounds selected from the group consisting of: 25 or H.C "OH 25 25 H, C and pharmaceutically acceptable salts thereof. In one aspect, the invention relates to lower alkyl monoesters (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, petyl, hexyl) of each of the phosphonic acid-containing compounds exemplified in examples 1 -113. In another aspect, the invention relates to prodrugs of each of the compounds containing phosphonic acids exemplified in Examples 1-113 or prodrugs of monoesters of the phosphonic acid-containing compounds exemplified in Examples 1-113. In one embodiment, the prodrugs of the phosphonic acid-containing compounds in Examples 1-113 or monoesters of the phosphonic acid-containing compounds exemplified in Examples 1-113 comprise the prodrug portions described above under the definition of the phosphonate prodrugs . Additionally, 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 an inhibitor of cholesterol absorption, especially an HMG inhibitor. -CoA reductase, or an inhibitor of HMG-CoA synthase, or an inhibitor of gene expression of HMG-CoA reductase or synthase, a cholesteryl ester transfer protein (CETP) inhibitor (for example, torcetrapib), a bile acid sequestrant (for example, cholestyramine (Questran®), colesevelam and colestipol (Colestid®)), or an inhibitor of bile acid reabsorption (see, for example, US patent No 6,245,744, US Patent No. 6,221,897, US Patent No. 6,277,831, EP 0683 773, EP 0683 774), a cholesterol absorption inhibitor as described (e.g., ezetimibe, tiqueside, pamaqueside or see, for example, in WO 0250027), a PPARalpha agonist, a mixed PPAR alpha / gamma agonist such as, for example, AZ 242 (Tesaglitazar, (S) -3- (4- [2- (4-methanesulfonyloxyphenyl) ethoxy] phenyl) -2- ethoxypropionic), BMS 298585 (N- [(4-methoxyphenoxy) carbonyl] -N- [[4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] methyl] glycine) or as described in WO 99/62872, WO 99/62871, WO 01/40171, WO 01/40169, W096 / 38428, WO 01/81327, WO 01/21602, WO 03/020269, WO 00/64888 or WO 00/64876, an inhibitor of MTP such such as, for example, implitapide, a fibrate, an ACAT inhibitor (eg, avasimibe), an angiotensin II receptor antagonist, an squalene synthetase inhibitor, a squalene epoxidase inhibitor, an inhibitor of squalene cyclase, a combined inhibitor of squalene epoxidase / squalene cyclase, a lipoprotein lipase inhibitor, an ATP citrate lyase inhibitor, a lipoprotein (a) antagonist, an antioxidant or niacin (eg, 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 nutraceuticals 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; USA We 5,354,772;. 4,911,165; 4,739,073; 4,929,437; 5,189,164; 5,118,853; 5,290,946; 5,356,896), lactones of fluvastatin, atorvastatin (LIPITOR; see uS patents We 5,273,995;. 4,681,893; 5,489,691; 5,342,952), lactones of atorvastatin, 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 RE37) 314, and European Patent No. EP521471), lactones of rosuvastatin, itavastatin, nisvastatin, visastatin, atavastatin, bervastatin, compactin, dihydrocompactin, dalvastatin, fluindostatin, pitivastatin, mevastatin (see patents of E.U.A. No. 3,983,140), and velostatin (also referred to as sinovinolin). Other examples of HMG-CoA reductase inhibitors are described in the U.S. Patents. Us. 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 to 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 hydrochloride (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-ioeno, N- (cycloalkyl) alkylamines and polyglumas, insoluble quaternized 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 patents of E.U.A. Nos. 3,692,895 and 5,703,188 which are incorporated herein by reference. Suitable inorganic cholesterol scavengers include bismuth salicylate plus montmorillonite clay, aluminum hydroxides and calcium carbonate antacids. In the foregoing description, a fibrate-based compound is a medicament for inhibiting the synthesis and secretion of triglycerides in the liver and activating lipoprotein lipase, thereby lowering the level of triglycerides in the blood. Examples include bezafibrate, beclobrate, binifibrate, ciprofibrate, clinofibrate, clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pirifibrate, ronifibrate, simfibrate and teofibrate. Such an ACAT inhibitor includes, 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 pharmacologically 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-triisopropylphenyl) acetyl] sulphamate, and in the present invention CI-1011 including a salt / co-crystal pharmacologically acceptable, ester or prodrug thereof; a compound having the general formula (I) including a pharmacologically 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 (SS, 2S) -2- [3- (2, 2-dimethylpropyl) -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 including a pharmacologically acceptable salt / co-crystal, ester or prodrug thereof}; a compound including a pharmacologically 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, which chemical name is (S) -2 ', 3', 5 '-trimethyl-4' -hydroxy-a-dodecylthio-. alpha. p-phenylacetanilide, and in the present invention F-12511 including a pharmacologically acceptable salt / co-crystal, ester or prodrug thereof]; a compound having the general formula (I) including a pharmacologically acceptable salt / co-crystal, ester or prodrug thereof described in the 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 I presented invention T-2591 including a pharmacologically acceptable salt / co-crystal, ester or prodrug thereof]; a compound having the general formula (I) including a pharmacologically acceptable salt / co-crystal, ester or prodrug thereof described in WO 96/26948. { preferably FCE-28654, of which the chemical name is l- (2,6-diisopropylphenyl) -3- [(4R, 5R) -4,5-dimethyl-2- (4-phosphonophenyl) -1,3-dioxolan- 2-ylmethyl] urea, including a pharmacologically acceptable salt / co-crystal, ester or prodrug thereof}; a compound having the general formula (I) or a pharmacologically acceptable salt thereof described in the specification of WO 98/54153 (EP 987254). { preferably K-10085, of which the chemical name is N- [2, -bis (methylthio) -6-methyl-3-pyridyl] -2- [4- [2- (oxazolo [4,5-b] pyridine- 2-ylthio) ethyl] piperazin-1-yl] acetamide, including a pharmacologically 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) including a pharmacologically acceptable salt / co-crystal, ester or prodrug thereof described in the Japanese patent publication (Kokai) Hei 7-82232 (EP 718281). { preferably NTE-122, of which the chemical name is trans-1,4-bis [1-cydohexyl-3- (4-dimethylaminophenyl) ureidomethyl] cydohexane, and in the present invention NTE-122 includes pharmaceutically acceptable salts of NTE-122}; a compound including a pharmacologically 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-1- [3- (pyrazol-3-yl) benzyl] -3- [2,4-bis (methylthio) -6-methylpyridin-3-yl] urea, and in the present invention FR-186054 including a pharmacologically acceptable salt / co-crystal, ester or prodrug thereof}; a compound having the general formula (I) including a pharmacologically acceptable salt / co-crystal, ester or prodrug thereof described in WO 96/09287 (EP 0782986, U.S. Patent No. 5,990,150) [preferably N- (l-pentyl -4,6-dimethylindolin-7-yl) -2,2-dimethylpropanamide, and in the present invention including a pharmacologically acceptable salt / co-crystal, ester or prodrug thereof]; and a compound having the general formula (I) including a pharmacologically acceptable salt / co-crystal, ester or prodrug thereof described in WO 97/12860 (EP 0866059, U.S. Patent No. 6,063,806) [preferably N- (l- octyl-5-carboxymethyl-4,6-dimethylindolin-7-yl) -2,2-dimethylpropanamide, including a pharmacologically 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-dimethylindolin-7-yl) -2,2-dimethylpropanamide (hereinafter referred to as compound A), and N- (l-pentyl-4,6-dimethylindoline- 7-yl) -2, 2-dimethylpropanamide (hereinafter referred to as compound B), including a pharmacologically 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-dimethylindolin-7-yl) -2,2-dimethylpropanamide ( compound A), and N- (l-pentyl-4,6-dimethylindolin-7-yl) -2,2-dimethylpropanamide (compound B), including a pharmacologically acceptable salt / co-crystal, ester or prodrug thereof; most 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 biphenyl tetrazole compound or biphenylcarboxylic acid derivative such as: a compound having the general formula (I) including a pharmacologically 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 including a pharmacologically acceptable salt / co-crystal, ester or prodrug thereof}; a compound having the general formula (I) including a pharmacologically acceptable salt / co-crystal, ester or prodrug thereof described in the Japanese patent publication (Kohyo) Hei 4-506222 (WO 91/14679). { preferably irbesartan, of which the chemical name is 2-N-butyl-4-spiromocyclopentane-1 - [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -2-imidazoline-5-one, and in the present invention irbesartan including a pharmacologically acceptable salt / co-crystal, ester or prodrug thereof}; a compound having the general formula (I), an ester thereof, including a pharmacologically acceptable salt / co-crystal, ester or prodrug thereof described in the Japanese patent publication (Kokai) Hei 4-235149 (EP 433983). { preferably valsartan, of which the chemical name is (S) -N-valeryl-N- [2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] valine, and in the present invention valsartan including a salt / pharmacologically acceptable co-crystal, ester or prodrug thereof}; a carboxylic acid derivative having the general Formula (I), including a pharmacologically 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 '- (1H-tetrazol-5-yl) bipheni-4-ylmethyl] -lH-benzimidazole-7-carboxylate, and in the present invention candesartan including a pharmacologically acceptable salt / co-crystal, ester or prodrug thereof (TCV-116 or the like), including a pharmacologically acceptable salt / co-crystal, ester or prodrug thereof}; a carboxylic acid derivative having the general Formula (I), including a pharmacologically 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-1-methylethyl) -2-propyl-1- [2 '- (1H-tetrazol-5-yl ) biphenyl-4-ylmethyl] imidazole-5-carboxylate, and in the present invention olmesartan includes carboxylic acid derivatives thereof, pharmacologically acceptable esters of the carboxylic acid derivatives (CS-866 or the like), including a salt / co - pharmacologically acceptable crystal, ester or prodrug thereof}; and a compound having the general formula (I), including a pharmacologically acceptable salt / co-crystal, ester or prodrug thereof described in the 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, including a pharmacologically acceptable salt / co-crystal, ester or pug thereof} . The angiotensin II receptor antagonist is preferably losartan, irbesartan, valsartan, candesartan, olmesartan, or telmisartan; more preferred is losartan or olmesartan; and the worst is olmesartan. In addition to being useful in the treatment of or prevention of certain diseases and disorders, combination therapy with compounds of this invention may be useful in reducing the dosage of the second drug or agent (e.g., atorvastatin). In addition, the compounds of the present invention can be used in combination with an inhibitor of apolipoprotein B secretion and / or inhibitor of the microsomal triglyceride transfer protein (MTP). Some inhibitors of apolipoprotein B secretion and / or MTP inhibitors are described in U.S. 5,919,795. Any inhibitor of HMG-CoA reductase can be used as an additional compound in the aspect of the combination therapy of the present invention. The term "HMG-CoA reductase inhibitor" refers to a compound that inhibits the biotransformation of hydroxymethylglutaryl coenzyme A to mevalonic acid when catalyzed by the HMG-CoA reductase enzyme. Such inhibition can be easily determined by one skilled in the art in accordance with standard assays (eg, Methods of Enzymology, 71: 455-509 (1981), and references cited therein). A variety of these compounds are described and referenced below. The U.S. patent No. 4,231,938 discloses certain isolated compounds after culturing a microorganism belonging to the genus Aspergillus, such as lovastatin. Also the U.S. patent 4,444,784 describes synthetic derivatives of the aforementioned compounds, such as simvastatin. Additionally, U.S. 4,739,073 describes certain substituted characters, such as fluvastatin. In addition, the U.S. patent 4,346,227 describes derivatives of ML-236B, such as pravastatin. In addition, EP 491,226 teaches certain pyridyldihydroxyheptenoic acids, such as rivastatin. Also, U.S. No. 4,647,576 discloses certain 6- [2 (substituted pyrrol-1-yl) alkyl] -pyran-2-ones such as atorvastatin. Other inhibitors of HMG-CoA reductase will be known to those skilled in the art. Examples of pcts 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 "HMGCoA 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 HMG-CoA synthase. Such inhibition can be easily 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: 1926 (1985); and references cited therein. ). A variety of these compounds are described and referenced below. The U.S. patent 5,120,729 describes certain beta lactam derivatives. The U.S. patent No. 5,064,856 discloses certain spiro lactone derivatives preempted by culturing microorganism MF5253. The U.S. patent 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 inhibitors of HMG-CoA synthase useful in the methods, compositions and kits of the present invention will be known to those skilled in the art. Any compound that decreases gene expression of HMG-CoA reductase can be used as an additional compound in the combination therapy aspect of this invention. These agents can be transcription inhibitors of HMG-CoA reductase, which block the transcription of DNA or translation inhibitors that prevent translation of mRNA encoding the HMG-CoA reductase in the protein. Such inhibitors can either directly affect transcription or translation, or they can be biotransformed into compounds having the above-mentioned attributes by one or more enzymes in the cholesterol biosynthetic cascade, or they can lead to the accumulation of an isoprene metabolite that has the activities mentioned above. Such regulation is readily determined by those skilled in the art according to standard assays (Methods of Enzymology, 110: 9-19 (1985)). Several such compounds are described and referenced below; however, other inhibitors of HMG-CoA reductase gene expression will be known to those skilled in the art, for example, U.S. Pat. 5,041,432 describes certain 15-substituted derivatives of lanosterol which are inhibitors of the expression of HMG-CoA reductase genes. Other oxygenated sterols that suppress the biosynthesis of HMG-CoA reductase are discussed by E. I. Mercer (Prog. Lip. Res., 32: 357-416 (1993)). Any compound having activity as a CETP inhibitor can serve as the second compound in the combination therapy aspect of the current invention. The term "CETP inhibitor" refers to compounds that inhibit transport mediated by the protein of cholesteryl ester transfer (CETP) from various cholesteryl esters and triglycerides from HDL to LDL and VLDL. A variety of these compounds are described and referenced below; however, other CETP inhibitors will be known to those skilled in the art. The U.S. patent 5,512,548 discloses certain polypeptide derivatives having activity as inhibitors of CETP, while certain CETP-inhibiting rosenonolactone derivatives and cholesteryl ester phosphate-containing 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 combination therapy aspect of this invention. The term ACAT inhibitor refers to a compound that inhibits the intracellular esterification of dietary cholesterol by the enzyme acyl CoA: cholesterol acyltransferase. Such inhibition can be readily determined by one skilled in the art in accordance with standard assays, such as the method of Heider et al., In Journal of Lipid Research, 24: 1127 (1983). A variety of these compounds are described and referenced below; however, other ACAT inhibitors will be known to those skilled in the art. The U.S. patent 5,510,379 describes certain carboxysulfonates, while WO 96/26948 and WO 96/10559 both describe urea derivatives having ACAT inhibitory activity. Any compound that has activity as an inhibitor of squalene synthetase can serve as an additional compound in the aspect of combination therapy of the current invention. The term "squalene synthetase inhibitor" refers to compounds that inhibit the condensation of two molecules of farnesylpyrrophosphate to form squalene, a reaction that is catalyzed by the enzyme squalene synthetase. Such inhibition is easily determined by those skilled in the art according to standard methodology (Methods of Enzymology 15: 393 454 (1969); and Methods of Enzymology 110: 359-373 (1985); and references cited there). A summary of the squalene synthetase inhibitors has been compiled in Curr. Op. Ther Patents, 861-4, (1993). EP 0 567 026 A1 describes certain 4, 1-benzoxazepine derivatives as squalene synthetase inhibitors and their use in the treatment of hypercholesterolemia and as fungicides. EP 0 645 378 A1 describes certain heterocycles of seven or eight members as squalene synthetase inhibitors and their use in the treatment and prevention of hypercholesterolemia and fungal infections. EP 0 645 377 A1 discloses certain benzoxazepine derivatives as squalene synthetase inhibitors useful for the treatment of hypercholesterolemia or coronary sclerosis. EP 0 611 749 Al discloses certain substituted amino acid derivatives useful for the treatment of arteriosclerosis. EP 0 705 607 A2 describes certain seven or eight member condensed heterocyclic compounds as anti-hypertriglyceride agents. WO 96/09827 describes certain combinations of cholesterol absorption inhibitors and inhibitors of cholesterol biosynthesis including benzoxazepine derivatives and benzothiazepine derivatives. EP 0 701 725 A1 discloses a process for the preparation of certain optimally active compounds, including benzoxazepine derivatives, which have plasma cholesterol activities and activities that decrease triglycerides. Other compounds that are currently marketed or previously 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. It is also contemplated that the compounds of the present invention will be administered with a lipase inhibitor and / or a glucosidase inhibitor, which are typically used in the treatment of conditions resulting from the presence of excess triglycerides, free fatty acids, 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 comprise gastric or pancreatic lipase inhibitors. In a further aspect, the glucosidase inhibitors comprise 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 tendamistat and the various cyclic peptides related thereto described in U.S. Pat. No. 4,451,455, AI-3688 and the various cyclic polypeptides related thereto described in the U.S.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 the U.S. patent. No. 4,273,765. A lipase inhibitor is a compound that inhibits the metabolic division of dietary triglycerides into free fatty acids and monoglycerides. Under physiological conditions Normally, lipolysis occurs by means of a two-step process involving the acylation of an activated portion of serine from the lipase enzyme. This leads to the production of an intermediate of hemiacetal of lipase and fatty acids, which is then divided to release a diglyceride. Also after deacylation, the fatty acid lipase intermediate is divided, resulting in free lipase, a monoglyceride and a fatty acid. The resulting free fatty acids and monoglycerides are incorporated into the mycelia of bile acid phospholipids, which are subsequently absorbed at the level of the border of the villi of the small intestine. The micelles eventually enter the peripheral circulation as chylomicrons. Thus, compounds, including lipase inhibitors that selectively limit or inhibit the absorption of ingested fat precursors are useful in the treatment of conditions including obesity, hyperlipidemia, hyperlipoproteinemia, Syndrome X, and the like. Pancreatic lipase mediates the metabolic division of fatty acids from triglycerides at positions 1 and 3 of carbon. The primary site of metabolism of ingested fat is in the duodenum and nearby jejunum for pancreatic lipase, which usually segregates into a vast excess of the amounts necessary for the breakdown of fats in the upper small intestine. Because Pancreatic lipase is the primary enzyme required for the absorption of dietary triglycerides; inhibitors have utility in the treatment of obesity and other related conditions. Gastric lipase is an immunologically different lipase that is responsible for approximately 10 to 40% of the digestion of dietary fats. Gastric lipase is secreted in response to mechanical stimulation, ingestion of food, the presence of a fatty food or by sympathetic agents. Gastric lipolysis of ingested fats is of physiological importance in the provision of fatty acids necessary to trigger the pancreatic activity of lipase in the intestine and also of importance for the absorption of fats 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 those of ordinary skill in the art. However, in the practice of the methods, pharmaceutical compositions, and kits of the current invention, generally the lipase inhibitors are those inhibitors that are selected from the group consisting of lipstatin, tetrahydrolipstatin (orlistat), FL-386, WAY-121898 , Bay-N-3176, valilactone, esterastin, ebelactone A, ebelactone B and RHC 80267.
The pancreatic inhibitors of lipase lipstatin, 2S, 3S, SS, 7Z, 10Z) lactone-5 - [(S) -2-formamido-4-methyl-valeryloxy] -2-hexyl-3-hydroxy-7, 1 (t-hexadecanoic, and tetrahydrolipostatin (orlistat), 2S, 3S, 55) -5- [(S) -2-formamido-4-methyl-valeryloxy] -2-hexyl-3-hydroxy-hexadecanoic acid lactone, and the variously substituted derivatives of N-formilleucine and stereosisomers thereof are described in the US patent 4,598,089. The pancreatic lipase inhibitor FL 386, 1- [4- (2-methylpropyl) cyclohexyl] -2- [(phenylsulfonyl) oxy] -ethanone, and the variously substituted sulfonate derivatives related thereto, are described in US Pat. 4,452,813. The pancreatic lipase inhibitor WAY-121898, 4-phenoxyphenyl-4-methylpiperidin-1-yl carboxylate, and the various ed carbamate esters and related pharmaceutically acceptable salts thereof are described in the patents of E.U.A. 5,512,565; 5,391,571 and 5,602,151. The lipase inhibitor Bay-N-3176, N-3 trifluoromethylphenyl-N '-3-chloro-4-trifluoromethylphenylurea, and the various urea derivatives related thereto, are described in US Pat. 4,405,644. The pancreatic lipase inhibitor valilactone, and a process for the preparation thereof by the microbial culture of the Aetinomycetes strain MG147-CF2, are described in Kitahara, et al., J. Antibiotics, 40 (11): 1647 50 (1987). The lipase inhibitor esteracin, and diertos processes for the preparation thereof by the microbial culture of the Streptomyces strain ATCC 31336, are described in the patents of 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 the Actinomycetes strain MG7-G1, are described in Umeza a, et al., J. Antibiotics, 33, 1594 1596 (1980). The use of ebelactones A and B in suppressing the formation of monoglycerides is described in Japanese Kokai 08-143457, published Jun. 4, 1996. The lipase inhibitor RHC 80267, cycle 0.0 '- [(1, 6-hexanediyl) -bis- (iminocarbonyl)] dioxime, and the various bis (iminocarbonyl) dioxins 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 the activity of myocardial lipoprotein lipase 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 the 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 agonist, a cholecystokinin A agonist, a monoamine reuptake inhibitor, a sympathomimetic agent, a serotoninergic agent, a dopamine agonist, an agonist or mimetic of the melanocyte-stimulating hormone receptor, an analogue of the melanocyte-stimulating hormone receptor, a cannabionic antagonist receptor, a melanin-concentrating hormone antagonist, leptin, a leptin analogue, a leptin receptor agonist, a galanin antagonist, a lipase inhibitor, an agonist of bombesin, a neuropeptide Y antagonist, a thyromimetic agent, dehydroepiandrosterone or an analog thereof, a glucocorticoid receptor agonist or antagonist, an orexin receptor antagonist, an urocortin binding protein antagonist, a peptide receptor agonist 1 type glucagon, and a ciliary neurotrophic factor. In a further aspect, 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. { Four . { 2- (2- [6-aminopyridin-3-yl] -2 (R) -hydroxyethylamino) ethoxy] phenyl} benzoic, acid. { 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 weakened glucose tolerance, insulin resistance, insulin-dependent diabetes mellitus (Type I) and diabetes mellitus not dependent on insulin (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 non-insulin dependent diabetes mellitus, 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, an amount Therapeutically effective of a compound of the present invention. It is also contemplated 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, toibutamide, tolazamide, acetohexamide, glipizide, glimepiride, repaglinide, nateglinide, meglitinide; biguanides: metformin, phenformin, buformin; A2 antagonists and imidazolines: midaglizol, isaglidol, deriglidol, idazoxan, efaroxan, fluparoxan; other secretagogues of insulin linogliride, A-4166; glitazones: ciglitazone, pioglitazone, englitazone, troglitazone, darglitazone, BRL49653; inhibitors of fatty acid oxidation: clomoxir, etomoxir; α-glucosidase inhibitors: acarbose, miglitol, emiglitate, voglibose, MDL25,637, camiglibose, MDL 73.945; ~ 3-agonists: BRL 35135, BRL 37344, RO 16-8714, ICI D7114, CL 316.243; Phosphodiesterase inhibitors: -386,398; agents that decrease benfluorex lipids; antiobesity agents: fenfiuramine; vanadate and vanadium complexes (e.g., bis (cysteinamide N-octyl) oxovanadium) and peroxovanadium complexes; amylin antagonists; glucagon antagonists; gluconeogenesis inhibitors; Somatostatin analogues; agents antilipolytics: 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 above. 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 (FBPase) inhibitor can serve as the second compound in the combination therapy aspect of the current invention (eg, 2-Amino-5-isobutyl-4-) {2- [5- (N, N'-bis ((SJ-l-ethoxycarbonyl) ethyl) phosphonamido] furanyl.] Thiazoles.) FBPase is a key regulatory enzyme in gluconeogenesis, the metabolic pathway through which the liver synthesizes the glucose of the 3-carbon precursors.The term inhibitor of FBPase refers to compounds that inhibit the activity of the enzyme FBPase and thereby block the conversion of fructose-1,6-bisphosphate, the substrate of the enzyme, to fructose 6-phosphate Inhibition of FBPase can be determined directly at the level of the enzyme by those skilled in the art according to 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 assessed according to standard methodology by measuring the inhibition of glucose production by isolated hepatocytes or in a liver with perfusion, or by measuring the decrease in blood glucose in normal or diabetic animals (for example, Vincent MF, Erion MD, Gruber HE, Van den Berghe, Diabetologie, 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 may be inactive in the selection of enzyme inhibition, may or may not be active in hepatocytes, but is active in vivo as evidenced by the decrease in glucose in normal models, fasting rats and / or in animal models of diabetes. A variety of FBPase inhibitors are described and referenced below; however, other FBPase inhibitors will be known to those skilled in the art. Gruber et al., Patent of E.U.A. No. 5,658,889 described the use of AMP site inhibitors of FBPase to treat diabetes; WO 98/39344 and US 6,284,748 describe purine inhibitors; WO 98/39343 and US 6,110,903 describe inhibitors of benzothiazole to treat diabetes; WO 98/39342 and US 6,054,587 describe indole inhibitors for treating diabetes; and WO 00/14095 and US 6,489,476 describe heteroaromatic phosphonate inhibitors for treating diabetes. Other inhibitors of FBPase 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, toibutamide, 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, Nimotop, Norvasc, and Plendil; Angiotensin-converting enzyme (ACE) inhibitors, such as Accupril, Altace, Captopril, Lotensin, Mavik, Monopril, Prinivil, Univasc, Vasotec and Zestril. Examples of compounds that can be used in combination with the compounds of the present invention for preventing or treating osteoporosis include: anti-resorption agents including progestins, polyphosphonates, bisphosphonate (s), estrogen agonists / antagonists, estrogen, estrogen / progestin combinations, Premarin, estrone, estriol or 17a- or 17β-ethynyl estradiol); progestins including algestone acetophenide, altrenogest, amadinone acetate, anagestone acetate, chlormadinone acetate, cingestol, clogestone acetate, clomegestone acetate, delmadinone acetate, desogestrel, dimethisterone, dihydrogesterone, etinerone, ethinodiol diacetate, etonogestrel, flurogestone acetate , gestaclone, gestodene, caproate of gestonorone, gestrinone, haloprogesterone, hydroxyprogesterone caproate, levonorgestrel, linestrenol, medrogestone, medroxyprogesterone acetate, melengestrol acetate, methynediol diacetate, norethindrone, norethindrone acetate, norethynodrel, norgestimate, norgestomet, norgestrel, fenpropionate of oxogestone, progesterone, quingestanol acetate, quingestrone, and tigestol; and polyphosphonates inhibitors of bone resorption including polyphosphonates such as of 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 gemological diphosphonates (also referred to as bis-phosphonates), disodium tiludronate, acid ibandronic acid, alendronate, resindronate, zoledronic acid, 6-amino-l-hydroxy-hexylidene-bisphosphonic acid and 1-hydroxy-3 (methylpentylamino) -propylidene-bisphosphonic acid. The salts, co-crystals and esters of the polyphosphonates are similarly included. Specific examples include ethane-1-hydroxy-1,1-diphosphonic acid, methane diphosphonic acid, pentane-1-hydroxy-1,1-diphosphonic acid, methane dichloro diphosphonic acid, methane hydroxy diphosphonic acid, ethane-1-amino acid, 1, 1-diphosphonic acid, ethane-2-amino-1, diphosphonic acid, propane-3-amino-1-hydroxy-1, diphosphonic acid, propane-N, N-dimethyl-3-amino-1 acid -hydroxy-1, diphosphonic acid, propane-3, 3-dimethyl-3-amino-1-hydroxy-1, diphosphonic acid, phenyl amino methane diphosphonic acid, N, N-dimethylamino methane diphosphonic acid, N ( 2-hydroxyethyl) amino methane diphosphonic acid, butane-4-amino-1-hydroxy-1, diphosphonic acid, pentane-5-amino-1-hydroxy-1, 1-diphosphonic acid, and hexane-6-amino acid -1-hydroxy-1,1-diphosphonic. The estrogen agonist / antagonist includes 3- (4- (1, 2-diphenyl-but-1-enyl) -phenyl) -acrylic acid, tamoxifen: (ethanamine, 2- (-4- (1, 2-difeni1- 1-butenyl) phenoxy) -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. Do not.
No. 4,623,660, the disclosure of which is incorporated herein by reference, Raloxifene: (methanone, (6-hydroxy-2- (4-hydroxyphenyl) benzo [b] thien-3-yl) (4- (2- (1 -piperidinyl) ethoxy) phenyl) -chlorohydrate) 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-dipheny1-1-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 incorporated herein by reference, centchroman: 1- (2- ((4- (methoxy-2, 2, dimethyl-3-phenyl-chroman-4-yl) -phenoxy) -ethyl) -pyrrolidine, which is described in the 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-1 -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] thiophen-6-ol which is described in U.S. Patent No. 5,488,058, the description of the 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 description of which is incorporated herein as 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 Ine, TSE-424 (Wyeth-Ayerst Laboratories) and arazoxifene, cis-6- (4-fluoro-phenyl) -5- (4- (2-piperidin-1-yl-ethoxy) - phenyl) -5,6,7,8-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-1, 2,3,4-tetrahydronaphthalene; 1- (4'-pyrrolidinoethoxyphenyl) -2- (4"-fluorophenyl) -6-hydroxy-1,2,3,4-tetrahydroisoquinoline; cis-6- (4-hydroxyphenyl) -5- (4- (2- piperidin-l-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalene-2-ol; 1- (4'-pyrrolidinolethoxyphenyl) -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 invention, include, for example, the following: thyroid parahormone (PTH) (an anabolic agent of the bones); secretagogues of the thyroid parahormone (PTH) (see, for example, US Pat. 6,132,774), particularly calcium receptor antagonists; calcitonin; and vitamin D and vitamin D analogues. Additional anti-osteoporosis agents include a selective androgen receptor modulator (SARM). Examples of suitable MRSA 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 cipherone, also known as (lb, 2b) -6-chloro-l, 2-dihydro-17-hydroxy-3'-H-cyclopropa [1,2] pregna-1,4,6-triene-3 , 20-dione is described in the US patent No. 3,234,093. Chlormadinone, also known as 17- (acetyloxy) -6-chloroprene-4,6-diene-3,20-dione, in its acetate form, 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® is described in the US patent. No. 4,097,578. Flutamide, also known as 2-methyl-N- [4-nitro-3- (trifluoromethyl) phenyl] propanamide and the trade name Eulexin® 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- methylpropion-m-toluidide and the trade name Casodex® is described in EP-100172. Enantiomers of biclutamide are discussed by Tucker and Chesterton, J. Med. Chem. 1988, 31, 885-887. Hydroxyflutamide, a known antagonist of the androgen receptor in most tissues, has been 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 MRSA's have been described in the U.S. patent. No. 6,017,924; WO 01/16108, WO 01/16133, WO 01/16139, WO 02/00617, WO 02/16310, publication of the patent application of E.U.A. No. US 2002/0099096, publication of the patent application of E.U.A. No. US 2003/0022868, WO 03/011302 and WO 03/011824. All of the above references are incorporated herein by reference.
Formulations The unit dose amounts and the dose schedule for the pharmaceutical compositions of the present invention can be determined using methods well 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 μg / 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 μg / 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 μg / kg to about 3.75 mg / kg. In another aspect the unit dose is from about 3.75 μg / 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 from about 1.88 μg / kg to about 0.188 mg / kg. In another aspect the unit dose is from 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 from about 1.25 μg / kg to about 0.125 mg / kg. In another aspect the unit dose is from 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 a day. 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 to control the release rate of the active ingredient may be preferred. The daily dose can be administered in multiple doses divided during the period of one day. Doses and dose schedules can be adjusted to the form of the drug or form of supply used. For example, different dosages and dose schedules can be used when the drug form is in a controlled release form or intravenous delivery 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 (e.g., bid). The administration of the compounds of this invention can occur at or near the time in which the other compound or agent is administered or in a different time. When 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 spray, topically, implantably or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and 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 form suitable for the intended method of administration. When they are used for oral use for example, tablets, pellets, troches, dragees, aqueous or oil suspensions, powders or dispersible granules, emulsions, hard or soft capsules, syrups or elixirs can 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 may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preservatives, in order to provide a palatable preparation. Tablets and pellets containing the active ingredient in admixture with a 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; granulation and disintegration 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 may be coated or uncoated by known techniques including microencapsulation to retard disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a prolonged period. For example, a material with time delay such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed. Formulations for oral use can also be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient is mixed with water or an oil 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 or wetting agents 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, heptadecaethyleneoxycetanol), a product of condensation 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 or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
Oil suspensions 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 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 previously established, and flavoring agents can 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. Dispersible powders, pellets, and granules of the invention suitable for the preparation of an aqueous suspension by the addition of water supplies the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents 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 may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or peanut oil, a mineral oil, such as liquid paraffin, or a mixture thereof. The suitable emulsifying agents include naturally occurring gums, such as acacia gum and tragacanth gum, naturally occurring phosphatides, such as soy lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and products of condensation of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain flavoring and sweetening agents. The syrups and elixirs can be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulsifier, a preservative, a flavoring or a 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 oleaginous suspension. This suspension can be formulated according to the known art by using those suitable dispersing or wetting agents and suspending agents which have been 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 or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic chloride solution of sodium. In addition, sterile, fixed oils may conventionally be employed as a solvent or medium in suspension. For this purpose any fixed soft oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be similarly 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 will vary depending on the host treated and the particular mode of administration. For example, a time release formulation intended for oral administration to humans may contain from 0.2 to 2000 μmol (approximately 0.1 to 1000 mg) of the active material compounded with a suitable and convenient amount of carrier material which may vary from about 5 to about 20 μmol. up to about 99.9% of the total compositions. It is preferred that the pharmaceutical composition be 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 order that the infusion of an adequate volume at a ratio of about 30 mL / h can happen. As noted above, the formulations suitable for oral administration may be presented as discrete units such as capsules, sachets, pellets, or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil 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 additional 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 (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose), dispersing or surface-active agent. The molded tablets can be made by molding in a suitable machine a mixture of the pulverized compound moistened with an inert liquid diluent. The tablets may optionally be supplied with an enteric coating, to deliver the release in parts of the intestine 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 may be administered by controlled release or delayed release means. Controlled-release pharmaceutical products have the common goal of improving drug therapy over that achieved with their non-controlled release counterparts. Ideally, the use of an optimally designed controlled release preparation in medical treatment is characterized by a minimum of active ingredient that is used to treat or control the condition in a minimum amount of time. The advantages of controlled release formulations include: 1) prolonged activity of the drug; 2) reduced dosing frequency; 3) improved compliance by the patient; 4) use of less drug in total; 5) reduction in local or systemic collateral effects; 6) minimization of drug accumulation; 7) reduction in fluctuations in the blood level; 8) improvement in treatment efficacy; 9) reduction or enhancement or loss of drug activity; and 10) improvement in the speed of control of diseases or conditions. (Kim, Cherng-ju, Controlled Relay Dosage Form Design, 2 Technomic Publishing, Lancaster, Pa.: 2000). Conventional dosage forms provide generally a rapid or immediate release of the drug from the formulation. Depending on the pharmacology and pharmacokinetics of the drug, the use of conventional dosage forms can lead to wide fluctuations in the concentrations of the drug in the blood of a patient and other tissues. These fluctuations can impact various parameters, such as dose frequency, onset of action, duration of efficacy, maintenance of therapeutic levels in the blood, toxicity, side effects, and the like. Advantageously, controlled release formulations can be used to control the onset of action of a drug, the duration of action, plasma levels within the therapeutic window, and peak levels in the blood. In particular, dosage forms or controlled or prolonged release formulations can be used to ensure that the maximum effectiveness of a drug is achieved while minimizing potential adverse effects and safety concerns, which can occur under both dosing of a drug. drug (that is, it goes below the minimum therapeutic levels) as well as exceeding the level of toxicity of the drug.
Most controlled-release formulations are designed to initially release a quantity of drug (active ingredient) that rapidly produces the desired therapeutic effect, and gradually and continuously release other amounts of drug to maintain this level of therapeutic or prophylactic effect for a prolonged period of time. In order to keep this level of drug constant in the body, the drug must be freed from the dosage form at a ratio that will replace the amount of drug that is 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 conditions or compounds. A variety of known controlled or prolonged release dosage forms, formulations, and devices can be adapted for use with the compositions of the invention. Examples include, but are not limited to, those described in the U.S.A. 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 can be used to deliver the slow or controlled release of one or more active ingredients when using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems (such as OROS® (Alza Corporation, Mountain View, Calif. USA)), multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying proportions. Additionally, ion exchange materials can be used to prepare immobilized forms of compositions of the invention and thus effect controlled delivery of the drug. Examples of specific anion exchangers 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 for 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 be easily adapted for the supply of compounds and compositions of the invention. Various aspects of the technology are described in the patents of E.U.A. Nos. 6,375,978 Bl; 6,368,626 B 1; 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 OROS, Retarded Push-Pull, Multi-Layer Push-Pull, and Tube-Push Systems. , all of which are well known. Additional OROS systems that can be used for controlled oral delivery of compounds and compositions of the invention include OROS-CT and L-OROS. Id .; see also, Delivery Times, vol. II, issue II (Alza Corporation). The conventional OROS oral dosage forms are made by compressing a drug powder (eg, a composition of a T3 mimetic 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 coating (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 drug delivery is not influenced by physiological or experiential conditions. Even a drug with a pH-dependent solubility can be delivered at a constant ratio regardless of the pH of the delivery medium. But because these advantages are supplied by an accumulation of the osmotic pressure within the dosage form after administration, the OROS drug delivery systems are not. they can be used to effectively deliver 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 formed therein and at least a portion of the wall is semipermeable; an expandable layer located within the cavity remote from the exit orifice and in fluid communication with the semipermeable portion of the wall; a dry or substantially dry state drug layer located within the cavity adjacent to the exit orifice and in a direct or indirect contact relationship with the expandable layer; and a layer that promotes the interposed flow between the interior surface of the wall and at least the outer surface of the drug layer located within the cavity, wherein the drug layer comprises a compound of the present invention, including a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof. See the patents of 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 formed therein, and less a portion of the wall is semipermeable; an expandable layer located within the cavity remote from the exit 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 a direct or indirect contact relationship with the expandable layer; the drug layer comprising a liquid, formulation of active agent absorbed into porous particles, the porous particles are adapted to withstand sufficient compaction forces to form a compacted drug layer without significant exudation of the liquid formulation of active agent, the form of Dosage optionally has a placebo layer between the exit orifice and the drug layer, wherein the active agent formulation comprises a compound of the present invention, including a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous form, or amorphous of it. See the patent of E.U.A. No. 6,342,249, the entirety of which is incorporated herein by reference. Transdermal Delivery 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, a transdermal patch comprises a compound of the present invention contained in a reservoir or a matrix, and an adhesive which allows the transdermal device to adhere to the skin, allowing the pso of the active agent from the transdermal device through the skin of the patient. Once the compound has penetrated the skin layer, the drug is absorbed into the bloodstream where it exerts the desired pharmaceutical effects. The transdermal patch releases the compound of the present invention in a controlled release form, 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 levels in the blood of the The compounds of the present invention are maintained at a concentration that is sufficient to reduce the side effects associated with immediate release dosage forms but not sufficient to negate the therapeutic effectiveness of the compound. Transdermal refers to the supply of a compound by passage through the skin or tissue of the mucosa and into the bloodstream. There are four main types of transdermal patches listed below. Drug in the Simple Layer Adhesive: 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 drug release. The adhesive layer is surrounded by a temporary coating and a backing. Drug in the Multi-layer Adhesive: The drug in the multi-layer adhesive is similar to the single layer system in that both layers of the adhesive are also responsible for the release of the drug. The multi-layer system is different however in that it adds another layer of the adhesive in the drug, usually separated by a membrane (but not in all cases). This patch also has a temporary coating layer and a permanent backing. Deposit: Unlike drug systems in the single-layer and multi-layer adhesive, the transdermal reservoir system has a separate drug layer. The drug layer is a liquid compartment containing a solution or suspension of drug separated by the adhesive layer. This patch is also supported by the backup layer. Matrix: The matrix system has a drug layer of a semisolid matrix that entrusts a drug solution or suspension. The adhesive layer in this patch surrounds the drug layer partially overlying it.
Other modes of transdermal delivery are known in the art and are included in the present invention. Formulations suitable for topical administration in the mouth include dragees comprising the ingredient active with a base of flavor, 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 buccal washes comprising the active ingredient in a suitable liquid carrier. Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be suitable. Formulations suitable for parenteral administration include sterile aqueous and non-aqueous isotonic injection solutions which may contain antioxidants, 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, for example, ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition that requires only the addition of a sterile liquid carrier, for example 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 dosage formulations are those containing a daily dose or unit, daily sub-dose, or an appropriate fraction thereof, of a drug. It will be understood, however, that the specific level of dose for any particular patient will depend on a variety of factors including the activity of the specific compound employed; age, body weight, health in general, sex and diet of the individual to be treated; the time and route of administration; the rate of excretion; other drugs which have been previously administered; and the severity of the particular disease that is subjected to therapy, as will be understood by those skilled in the art.
Synthesis of Compounds of the formula I The compounds in this invention can be prepared by the processes described in the following Reaction Schemes, as well as relevant procedures published in the literature that are used by those skilled in the art. It will be understood that the following reaction scheme will be provided solely for the purpose of illustration and do not limit the invention which is defined by the claims. Typically the synthesis of a 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 Reaction 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 Reaction Schemes can be carried performed according to procedures generally known in the art (for example, "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 may have stereogenic centers on the phosphorus atom and on any of the carbons including any of the R substituents. Consequently, 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 often these prodrugs are made from the phosphonic acids of Formula I because of their affinity. Phosphonic acids of Formula I can be alkylated with electrophiles such as alkyl halides and alkyl sulfonates under nucleophilic substitution conditions to give phosphonate esters. For example, compounds of the formula I-VII wherein YR11 is an acyloxyalkyl group can be prepared by the alkylation of compounds of the formula I-VII with an appropriate acyloxyalkyl halide (for example, Cl, Br, I; Phosphorus Sulfur 54: 143 (1990); Synthesis 62 (1988)) in the presence of a suitable base (e.g., pyridine, TEA, diisopropylethylamine) in suitable solvents such as DMF (J. Med. Chem. 37: 1875 (1994)). The carboxylate component of these acyloxyalkyl halides includes but is not limited to acetate, propionate, isobutyrate, pivalate, benzoate, carbonate and other carboxylates. The dialkyl acetals of dimethylformamide can also be used for the alkylation of phosphonic acids (Collect, Czech Chem. Commu. 59: 1853 (1994)). Compounds of the formula I wherein YR11 is a cyclic carbonate, a lactone or a phthalidyl group can also be synthesized by direct alkylation of the free phosphonic acids with appropriate halides in the presence of a suitable base such as NaH or diisopropylethylamine (J. Med. Chem. 38: 1372 (nineteen ninety five); J. Med. Chem. 37: 1857 (1994); J. Pharm. Sci. 76: 180 (1987)). Alternatively, these phosphonate prodrugs can be synthesized by the reactions of the corresponding dichlorophosphonates and an alcohol (Collect Czech Chem. Commun. 59: 1853 (1994)). For example, a dichlorophosphonate reacts with substituted phenols and arylalkyl alcohols in the presence of a base such as pyridine or TEA to give compounds of formula I-VII wherein YR 11 is an aryl group (J. Med. Chem. 39: 4109 (1996), J. Med. Chem. 38: 1372 (1995), J. Med. Chem. 37: 498 (1994)) or an arylalkyl group (J. Chem. Soc. Perkin Trans. 1 38: 2345 ( 1992)). Prodrugs containing bisulfide (Antiviral Res. 22: 155 (1993)) are they can be prepared from a dichlorophosphonate and 2-hydroxyethylbisulfide under standard conditions. Dichlorophosphonates are also useful for the preparation of various phosphonamides as prodrugs. For example, the treatment of a dichlorophosphonate with ammonia gives both a monophosphonamide and a diphosphonamide; the treatment of a dichlorophosphonate with l-amino-3-propanol gives a cyclic 1,3-propylphosphonamide; the treatment of a monophenyl ester of chlorophosphonate with an amino acid ester in the presence of a suitable base yields a monophenyl monophosphonamidate substituted. Such reactive dichlorophosphonates can be generated from the corresponding phosphonic acids with a chlorinating agent (for example, thionyl chloride, J. Med. Chem. 1857 (1994), oxalyl chloride, Tetrahedron Lett.:31: 3261 (1990) phosphorus pentachloride, Synthesis 490 (1974)). Alternatively, a dichlorophosphonate can be generated from its corresponding disilyl phosphonate esters (Synth Commu 17: 1071 (1987)) or dialkyl phosphonate esters (Tetrahedron Lett 24: 4405 (1983); Bull. Soc. Chim. 130: 485 (1993)). It is envisioned that the compounds of the formula I may be mixed phosphonate ester (eg, phenyl and benzyl esters, or phenyl esters and acyloxyalkyl) including the chemically combined mixed esters such as Combined phenyl and benzyl prodrugs reported in Bioorg. Med. Chem. Lett. 7:99 (1997). The 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 amino acid alkyl ester such as L-alanine ethyl ester) in the presence of a suitable base (for example triethylamine, pyridine, etc.) gives the corresponding bisphosphonamide; the treatment of a dichlorophosphonate with l-amino-3-propanol gives a cyclic 1,3-propylphosphonamide; the treatment of a monophenyl ester of chlorophosphonate with an amino acid ester in the presence of a suitable base yields a monophenyl monophosphonamidate substituted. Direct couplings of a phosphonic acid with an amine (for example an amino acid alkyl ester such as ethyl ester of L-alanine) are also reported to give the corresponding bisamidates under Mukaiyama conditions (J. Am. Chem. Soc., 94: 8528 (1972)). The SATE (S-acetyl thioethyl) drugs can be synthesized by the coupling reaction of the phosphonic acids of Formula I and S-acyl-2-thioethanol in the presence of DCC, EDCl or PyBOP (J. Med. Chem. 39 : 1981 (1996)). Cyclic phosphonate esters of substituted 1,3-propane diols can be synthesized either by reactions of the corresponding dichlorophosphonate with a substituted 1, 3-propanediol or by coupling reactions when using suitable coupling reagents (eg, DCC, EDCl, PyBOP; Synthesis 62 (1988)). Reactive dichlorophosphonate intermediates can be prepared from the corresponding acids and chlorinating agents such as thionyl chloride (J. Med. Chem. 1857 (1994)), oxalyl chloride (Tetrahedron Lett.31: 3261 (1990)) and phosphorus pentachloride (Synthesis 490 (1974)). Alternatively, these dichlorophosphonates can also be generated from disilyl esters (Synth Commun. 17: 1071 (1987)) and dialkyl esters (Tetrahedron Lett 24: 4405 (1983); Bull. Soc. Chim. Fr., 130: 485 (1993)). Alternatively, these cyclic phosphonate esters of substituted 1,3-propane 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)). The phosphonic acids can also be subjected to cyclic prodrug formation with cyclic acetals or cyclic orthoesters of propane-1, 3-diols substituted to provide prodrugs as in the case of carboxylic acid esters (Helv. Chim. Acta. 48: 1746 (1965)). Alternatively, 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, cyclic phosphonate esters of substituted 1,3-propane diols can be synthesized by transesterification reaction with substituted 1,3-propane diol under suitable conditions. Mixed anhydrides of precursor phosphonic acids generated in situ under appropriate conditions react with diols to give prodrugs as in the case of carboxylic acid esters (Bull, Chem. Soc. Jpn. 52: 1989 (1979)). Phosphonate aryl esters 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 simple isomers of phosphonic acid prodrugs of Formula I. Because phosphorus is a stereogenic atom, the formation of a prodrug with a racemic substituted 1,3-propane diol will produce a mixture of isomers. For example, the formation of a prodrug with a 1,3-propane diol 1- (V) -substituted racemic gives a racemic mixture of cis prodrugs and a racemic mixture of trans prodrugs. In another aspect, the use of the enantioenriched substituted 1,3-propane diol with the R configuration yields enantioenriched 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 the formula I wherein X is -P03H2 can be prepared from phosphonate esters by using the known division methods. Silyl halides are generally used to split various phosphonate esters and give the desired phosphonic acid with average hydrolysis of the resulting silylphosphonate esters. When necessary, acidic sequestrants (e.g., HMDS) can be used for the acid sensitive compounds. Such silyl halides include TMSC1 (J. Org. Chem. 28: 2975 (1963)), TMSBr (Tetrahedron Lett 155 (1977)) and TMSI (J. Chem. Soc, Chem. Commu. 870 (1978)). Alternatively, phosphonate esters can be divided under strong acid conditions (Tetrahedron Lett 33: 4137 (1992); Synthesis Stuttgart 10: 955 (1993)). These phosphonate esters can also be divided by means of dichlorophosphonates prepared by the treatment of phosphonate esters with halogenating agents. such as PC15, S0C12 and BF3 (J. Chem. Soc. 238 (1961)) followed by aqueous hydrolysis to give the phosphonic acids. The aryl and benzyl phosphonate esters can be divided under hydrogenolysis conditions (Synthesis 412 (1982), J. Med. Chem. 281208 (1985)) or metal reduction conditions (J. Chem. Soc. 99: 5118 (1977 )). Electrochemical conditions (J. Org. Chem. 44: 4508 (1979)) and pyrolysis conditions (Synth.Commu.10: 299 (1980)) have been used to divide several phosphonate esters.
Introduction of a phosphonate group The introduction of a phosphonate group can generally be carried out according to known methods. Compounds of the 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 (O) (OEt) 2 in the presence of a base such as NaH, K2C03, KO-t-Bu or TEA (Tetrahedron Lett 27: 1477 (1986); J. Chem. Soc. Perkin Tran 1 1987 (1994)) as described in Reaction Scheme 1. By following the procedures described as above, deprotection of the phosphonate ester 2 gives the desired phosphonic acid 3. Compounds of the 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 portion of phosphonate (Et0) 2P (0) (CRa2)? _2C02H in the presence of DCC or EDC according to the known methods (for example, J. Org. Chem. 42: 2019 (1977)) or converting an aniline 1 (M = NH) to an isocyanate with diphosgene followed by reacting with P ( OEt) 3 (J. Org. Chem. 1661 (1956); Tetrahedron Lett. 37: 5861 (1996)). Deprotection of the phosphonate ester 2 as described above leads to the phosphonic acid 3. For the compounds of the formula I wherein T is - (CRa2) k-, the phosphonate group can be introduced by various known methods. For example, the coupling reaction of a phenyl bromide (J. Org. Chem. 64: 120 (1999)), iodide (Phosphorus Sulfur 130: 59 (1997)) or triflate (J. Org. Chem. 66: 348 (2001)) 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. 81: 415 (1981)) can also be an efficient way of introducing the phosphonate group by coupling a benzyl or arylalkyl halide with triethyl phosphonate (when m is 1 -3) . For the compounds of the formula I wherein T is - (CRa2) n-CRb = CRb-, the phosphonate group can be introduced by coupling an aldehyde and tetramethyl methylene diphosphonate in the presence of a base such as NaH, NaOH or KO- t-Bu (Tetrahedron Lett. 29: 3007 (1988)). For the compounds of the formula I wherein T is -CRb = CRb- (CRa2) n- or - (CRa2) -CRb = CRb- (CRa2) ~, the phosphonate group can be introduced by the Michaelis-Arbuzov reaction of the corresponding olefinic halide with triethyl phosphite. For the compounds of the formula I wherein T is - (CRa2) m (CO) -, the phosphonate group can be introduced by reacting diethyl phosphite with an acid chloride (J. Org, Chem. 29: 3862 (1964); Tetrahedron 54: 12233 (1998)) or an aldehyde followed by oxidation (Tetrahedron 52: 9963 (1996)). Also, this type of compounds can be transformed into the compounds of the formula I, wherein T is - (CR2) nCH (NRbRc) - according to the known procedures (Tetrahedron Lett, 37: 407 (1996)). For the compounds of the formula I, wherein T is - (CO) (CRa2)? N-, the phosphonate group can be introduced by various known methods such as reacting in benzoyl chloride substituted with diethylphosphonoacetic acid (Synthetic Commu 30: 609 (2000)) or a copper phosphonate reagent (Tetrahedron Lett 31: 1833 (1990)). Alternatively, the coupling of triethyl phosphonate with a silyl enol ether (Synthetic Commu. 24: 629 (1994)) or an a-bromobenzophenone (Phosphorus Sulfur 90:47 (1994)) 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 according to the standard formation methods of the amide bond (Tetrahedron Lett., 31: 7119 (1990); Tetrahedron Lett. 30: 6917 (1989); J. Org. Chem. 58: 618 (1993)). For the compounds of the formula I, wherein T is - (CRa2) C (0) (CRa2) n- or (CRa2) nC (O) (CRa2), the phosphonate group can be introduced by reacting a benzyl bromide with a functionalized phosphonate (Tetrahedron Lett 30: 4787 (1989)). Alternatively, a coupling reaction of a substituted phenylacetate and methylphosphonate also produces the desired product (J. Am. Chem. Soc. 121: 1990 (1999) ) .
Reaction scheme 1 < 0 M = O. S. NH T = Q (CRa2kt. SIC "^. NR-ÍCR ^ Jn. NR ^ COMCR ^ Construction of the diaryl ring Compounds of the formula I, wherein G is -0- can be prepared according to known methods. As described in Reaction Scheme 2, 2a reacts 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. 38 : 695 (1995)). Deprotection of the methoxy group with suitable reagents such as boron tribromide, boron trichloride or boron trifluoride in CH2Cl2 gives the intermediate 5. The introduction of the phosphonate group followed by deprotection of the phosphonate ester as described in Reaction Scheme 1 leads to to the desired phosphonic acid 6. Those skilled in the art can use other known methods such as the coupling of an arylboronic acid and a phenol in the presence of Cu (0Ac) 2 (Tetrahedron Lett 39: 2937 (1998)), nucleophilic substitution of a fluorobenzene (Synthesis Stuttgart 1:63 (1991)) or iodobenzene (J. Am. Chem. Soc. 119: 10539 (1997)) with a phenol and the coupling of a bromobenzene with a phenol in the presence of Pd2 (dba ) 3 (Tetrahedron Lett 38: 8005 (1997)) to form a diaryl ether system.
Reaction scheme 2 FG = functional group that can be transformed into T For the compounds of the formula I, wherein G is -CH 2 -, the installation of the diaryl ring can be achieved by various known methods. For example, as described in the Reaction Scheme 3, benzyl alcohol 7 is formed by treating 3a with n-BuLi at -78 ° C in THF followed by reacting with 3b (Bioorg, Med.Chem.Lett.10: 2607 (2000)). Hydrogenolysis with Pd-C or dehydroxylation of benzyl alcohol 7 by NaBH4 (Synthetic Commu. 17: 1001 (1987)) and (i-Bu) 3Al (Synthesis 736 (1987)) followed by removal of the protecting group gives the diaryl intermediate 8. Phosphonic acid 9 is formed from 8 according to the same procedures as described in Diagram of Reaction 1. Alternatively, the coupling of benzyl bromide with a Grignard aryl reagent (Tetrahedron Lett 22: 2715 (1981)), an arylboronic acid (Tetrahedron, Lett 40: 7599 (1999)) or a zinc reagent (Chem. Lett. : 1241 (1999)) and reduction of a diaryl ketone (J. Org. Chem. 51: 3038 (1986)) are all widely used methods for the construction of the diaryl ring.
Diagram of procedure 3 PG = protective group FG = functional group that can be transformed into T For compounds of the formula I, wherein G is -S-, -S (= 0) - or -S (= 02) -, the formation of the diaryl ring can be achieved according to known methods. As illustrated in Reaction Scheme 4, 3a can react with 4a in the presence of a catalyst such as Pd2 (dba) 3 or CuBr to provide the diaryl sulfide 10 (Tetrahedron 57: 3069 (2001); Tetrahedron Lett 41: 1283 (2000)). Phosphonic acid 12 is formed from 10 after removal of the protecting groups followed by the same procedures as described in Reaction Scheme 1. Diaryl sulfide 10 can also be converted to sulfoxide 13 according to known methods (Synthetic Commu. 16: 1207 (1986); J. Org. Chem. 62: 4253 (1997); Tetrahedron Lett. 31: 4533 (1990)), which leads to phosphonic acid 15 following the same procedures as described in Reaction Scheme 1. Also, biaryl sulfide 10 can be converted to sulfone (Tetrahedron Lett., 32: 7353 (1991); J. Prakt.Chem. 160 (1942)) which leads to the phosphonic acid (G is -S (= 02) -) following the same procedures as described above. In addition, the nucleophilic substitution of chlorobenzene and bromobenzene with a thiol is also an efficient way of installing the diaryl sulfide ring (J. Med. Chem. 31: 254 (1988); J. Org. Chem. 63: 6338 (1998 )).
Reaction scheme PG = protective group FG = functional group that can be transformed into T For the compounds of formula I, wherein G is -NH- or -N (C? -C4 alkyl) -, the diarylamine column can be formed by various known methods. Among those conditions, one widely used by those skilled in the art is the coupling reaction of an aniline with an aryl bromide (J. Org. Chem. 64: 5575 (1999); J. Org. Chem. 62: 6066 (1997)).; Tetrahedron Lett., 37: 6993 (1996); Org. Lett., 1: 2057 (1999)) or an aryl tosylate (J. Org. Chem. 62: 1268 (1997)) in the presence of a catalyst such as PdCl2 or Pd2 (dba) 3. As illustrated in Reaction Scheme 5, the diarylamine intermediate 16 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, the diarylamine 17 is converted to the phosphonic acid 18 by following the same procedures as described in Reaction Scheme 1. Alternatively, the coupling of an aniline and aryl halide using other catalysts such as copper bronze (Org Synth 2: 446 (1943); J. Org Chem. 20 (1955)) and Cu (OAc) 2 (J. Med. Chem. 4: 470 (1986); Synthetic Commu. 26: 3877 (1996)) to construct the diarylamine column is also a feasible method.
Diagram of reaction i Vulnerability R - H, C1-C4 alkyl PG = Protective Group FG = Functional group that can be converted into T For the compounds of the formula I, wherein G is -CHF- or -CF2-, the diaryl column can be established from the benzyl alcohol 7. Thus, as described in Reaction Scheme 6, benzyl alcohol 7 can be converted to benzyl fluoride 19 by reacting with DAST in CH2C12 according to known procedures (J. Chem. Soc, Chem. Commu. 11: 511 (1981); Tetrahedron Lett. 36: 6271 (1995); 14: 2875 (1988)). Also, benzyl alcohol 7 can easily be oxidized to benzophenone 22 according to known methods such as oxidation with Mn0, PCC oxidation, Swern oxidation and Dess Martin oxidation, which is subsequently converted to benzyl difluoride 23 by treatment with DAST. (J. Fluorine 61: 117 (1993)) or other known reagents (J. Org. Chem. 51: 3508 (1986); Tetrahedron 55: 1881 (1999)). After removal of the protecting groups, the benzyl fluoride 20 and difluoride 24 are converted to the desired phosphonic acids following the same procedures as described in Reaction Scheme 1. Reaction Scheme S Compounds of the formula I, wherein G is -CH (OH) - or -C (O) - can be prepared from the interates 7 and 22. The removal of the protective groups of 7 and 22 followed by introduction of the phosphate and deprotection as described in Reaction Scheme 1 provides the desired phosphonic acids of Formula I. The compounds of formula VIII can be synthesized using the same methods described above by the synthesis of the compounds of formula I.
Synthesis of compounds of formula II The synthesis of compounds of formula II wherein A is -NH- and B is -CH- or -C-alkyl- can be achieved from the corresponding aminodiary precursor 1 by using the well known, for those skilled in the art, Fisher's character synthesis (Reaction Scheme 6a) (Phosphorus and Sulfur 37: 41-63 (1988)). Alternatively, the aryl-indole scaffold is constructed by using the previously described procedures and the phosphonic acid portion is introduced by making the anion following the nitrogen of the indole derivative, protected in the nitrogen, with a base such as BuLi and off the anion with diethyl chlorophosphate. Additional manipulations of the protecting group and the functional group of interates 2 provide compounds of formula II.
Reaction scheme 6a The compounds of formula II wherein A is -0- and B is -CH- are synthesized from the corresponding precursor of diaryl phenol 3 and cyclization of the ring with the dimethylacetal of bromoacetaldehyde to give benzofuran 4 (Reaction Scheme 6b) (J. Chem. Soc, Perkin Trans. 1, 4: 729 (1984)). The phosphonic acid portion can then be introduced by making the anion followed by the benzofuran oxygen with a base such as BuLi and quenching the anion with diethyl chlorophosphate to provide phosphonate 5. Additional manipulations of the protecting group and the functional group of the interate provide compounds of formula II.
Reaction scheme Sb Fénpra? I [ 5 The compounds of the formula II wherein A is -NH-, -O- or -S- and B is -N- can be made from condensation of the corresponding diaryl precursor 6 with an orthoformate such as triethyl orthoformate in the presence of the acid to give heterocycle 7 (Org. Prep. Int.Proc. 22 (5): 613-618 (1990)). The phosphonic acid moiety can then be introduced by making the anion in the 2-position of the heterocycle 7 with a base such as BuLi and quenching the anion with diethyl chlorophosphate to give phosphonate 8. Further manipulations of the protecting group and the functional group of the Interates 8 provide compounds of formula II.
Scheme d @ reaction 6 < * : = O, NH, S BuLi. aP (??? Etfe Rxpnulla 1 Synthesis of compounds of the formula III Scheme of reaction ß Formula E The general synthesis of compounds of the formula III wherein G is -O-, -S- or -NH- utilizes the displacement of a phenol, thiophenol or aniline 1 appropriately substituted with a pyridine pent asus ti tuida such as 3, 5 dichloro-2, 4,6-t-fluoro-pi-ridine 2 to provide interate 3 (Reaction Scheme 6d) (Org. Prep. Int.Proc. 32 (5): 502-504 (2000)). Subsequent displacement of the substituents 2-fluoro and 6-f luoro on the pyridine ring with nucleophiles 4 and HR7 sequentially provides interates 5 and 6. Examples of suitable nucleophiles include, but are not limited to, diethyl hydroxymethyl 1-phosphonate and diethyl aminome ti 1-fos fonato. Examples of HR7 reagents, include but are not limited to, alkylthiol, sodium alkoxide, alkylamine or benzylamine. Compounds of formula III where G is S (= 0) - and -S (= 0) 2_ can be derived from interates 5 and 6 when G is -S- by oxidation with an oxidizing agent such as mCPBA. Additional manipulations of the protecting group and the functional group of interates 5 and 6 will provide compounds of the formula III.
Reaction scheme 6e 1 111 Compounds of the formula III wherein G is -CH? - or -C (O) - are synthesized according to Reaction Scheme 6e. Condensation of benzyl cyanide 7 with pentasubstituted pyridine 2 provides the intermediate 8. The displacement of 2-fluoro with reagent 4 gives the intermediate 9. The oxidation of benzyl cyanide 9 provides the keto derivative 10 which after deprotection and manipulation of the functional group gives a compound of Formula III. Alternatively, the Reductive deoxygenation of the keto intermediate followed by deprotection and manipulation of the functional group gives a compound of Formula III.
Synthesis of phosphonic acid monoesters The compound of the invention wherein the acid group is a monoester of phosphonic acid can be prepared from the diester intermediate, used for the synthesis of phosphonic, thromomimetic acid, by monohydrolysis. The synthesis of the phosphonic acid monoester can be completed by the treatment of phosphonate diesters with aqueous alkaline solution such as NaOH, KOH or LiOH at room temperature or while heating. Sodium azide can also be used in DMF (Bioorg, Med Chem. Lett, 14 (13), 3559-62 (2004)) to achieve hydrolysis. Alternatively, organic bases such as morpholine or N-methyl-piperazine can be used to hydrolyze one of the phosphonate ester groups (Synth, Comm. 34 (2): 331-344 (2004)).
Synthesis of cyclic phosphonic acids Cyclic phosphonates can be synthesized by condensation of a di-benzyl alcohol with trimethylphosphite (Bull. Acad. Sci. USSR Div. Chem. Sci. 37: 1810-14 (1988)) to obtain the cyclic phosphite. which is then converted to the cyclic phosphonate by a reconfiguration of photo-Arbuzov (J.
Organomet. Chem. 646: 239-46 (2002)). Alternatively, the cyclic phosphite can be obtained by condensation of a di-benzyl alcohol with HMPT (J. Org. Chem. 57 (10): 2812-18). (1992)) or diethylphosphoramidium bichloride to obtain a cyclic phosphoramide diester which is then converted to the cyclic phosphite by reaction with an alcohol, such as methanol or phenol, in the presence of an activating agent such as tetrazole or methylthio-tetrazole (J. Org. Chem. 61: 7996-97 (nineteen ninety six)). Phosphonic acid leugo is obtained by selective monosaponification.
Synthesis of prodrugs of phosphonate monoesters The prodrugs can be introduced in different stages of the synthesis. Most often these prodrugs are made from the monoesters of phosphonic acid due to their affinity. Phosphonic acid monoesters can be alkylated with electrophiles such as alkyl halides and alkyl sulfonates under nucleophilic substitution conditions to give phosphonate esters. For example, compounds of the formula I wherein YR11 is an acyloxyalkyl group can be prepared by direct alkylation of the compounds of the formula I with an appropriate acyloxyalkyl halide (for example, Cl, Br, I; Phosphorus Sulfur 54: 143 (1990); Synthesis 62 (1988)) in the presence of a suitable base (e.g., pyridine, TEA, diisopropylethylamine) in suitable solvents such as DMF (J. Med. Chem. 37: 1875 (1994)). The carboxylate component of these acyloxyalkyl halides includes but is not limited to acetate, propionate, isobutyrate, pivalate, benzoate, carbonate and other carboxylates. Acetals of dimethylformamide dialkyl can also be used for the alkylation of monoesters of phosphonic acid (Collect, Czech Chem. Commu. 59: 1853 (1994)). Compounds of the formula I wherein YR11 is a cyclic carbonate, a lactone or a phthalidyl group can also be synthesized by direct alkylation of the free phosphonic acids with suitable halides in the presence of a suitable base such as NaH or diisopropylethylamine (J. Med. Chem. 38: 1372 (1995), J. Med. Chem. 37: 1857 (1994), J. Pharm. Sci. 76: 180 (1987)). Alternatively, these prodrugs of monoester phosphonate can be synthesized by the reactions of the corresponding chlorophosphonate and an alcohol (Collect Czech Chem. Commun. 59: 1853 (1994)). For example, a chlorophosphonate reacts 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. 39: 4109 ( 1996), J. Med. Chem. 38: 1372 (1995), J. Med. Chem. 37: 498 (1994)) or an arylalkyl group (J. Chem. Soc. Perkin Trans. 1 38: 2345 (1992)). Prodrugs containing bisulfide (Antiviral Res. 22: 155 (1993)) can be prepared from a chlorophosphonate and 2-hydroxyethylbisulfide under standard conditions. The chlorophosphonates are also useful for the preparation of various phosphonamides as prodrugs. For example, the treatment of a chlorophosphonate with ammonia gives phosphonamide. Such reactive dichlorophosphonates can be generated from the corresponding phosphonic acid monoesters with a chlorinating agent (for example, thionyl chloride, J. Med. Chem. 1857 (1994), oxalyl chloride, Tetrahedron Lett. 1990), phosphorus pentachloride, Synthesis 490 (1974)). Alternatively, a dichlorophosphonate can be generated from its corresponding silyl phosphonic acid monoester (Synth, Commu 17: 1071 (1987)). The chlorophosphonates are also useful for the preparation of various phosphonamides as prodrugs. For example, the treatment of a chlorophosphonate with an amine (for example an amino acid alkyl ester such as ethyl L-alanine ester) in the presence of a suitable base (for example triethylamine, pyridine, etc.) gives the corresponding phosphonamide. Direct couplings of phosphonic acid monoesters with an amine (for example an amino acid alkyl ester such as ethyl L-alanine ester) they are also reported to give the corresponding amidate under Mukaiyama conditions (J. Am. Chem. Soc. 94: 8528 (1972)).
The prodrugs of SATE (S-acetyl thioethyl) can be synthesized by the coupling reaction of the phosphonic acid monoesters of Formula I and S-acyl-2-thioethanol in the presence of DCC, EDCl or PyBOP (J. Med. Chem. 39: 1981 (nineteen ninety six) ) .
Preparation of Key Precursors A. Preparation of Compounds with Substituents on 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 by using an existing method in the literature or a modification of a known method. The syntheses of some of these compounds are described herein. The precursor 2a is prepared by reacting an anisole with iodo trifluoroacetate according to the reference procedures (J. Med. Chem. 38: 695 (1995)). Anisols with different groups R3 and R4 are either commercially available or can be prepared according to the procedures of the literature (eg, J. Med. Chem. 32: 320 (1989)). The starting material 2b is either commercially available or prepared according to known procedures. For example, the compounds of 2b wherein FG is a group derived from 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 (1997); J. Am. Chem. Soc. 120: 827 (1998)). Compounds of 2b wherein FG is a group derived from S can be prepared by reacting a feasible 4-aminoanisole with NaN02 and ethyl potassium xanthate (J. Am. Chem. Soc. 68 (1946); Heterocycles 26: 973 (1987). ). The useful precursor 3a can be either commercially available reagents or prepared according to the existing methods. As described in Reaction Scheme 7, simple protection of commercially available 4-bromophenol 7b with different groups R3 and R4 according to procedures known in the art leads to 3a. Compound 3a can also be prepared by bromination of the protected phenol 7d (J. Org. Chem. 53: 5545 (1988); J. Org. Chem. 59: 4473 (1994); Synthesis Stuttgart 10: 868 (1986)). The introduction of various groups R3 and R4 to 4-bromophenol 7a can be carried out to give 7b which leads to 7a after protection (Tetrahedron Lett 36: 8453 (1995); J. Heterocyclic Chem. 28: 1395 ( 1991), J. Fluorine Chem. 40:23 (1988), Synthesis Stuttgart 11: 1878 (1999), Synthetic Commu. 16: 681 (1986)). 7b can also be prepared by the bromination of phenol 7c (J. Comb. Chem. 2: 434 (2000); Chem. Soc. Jpn. 61: 2681 (1988); Synthesis Stuttgart 5: 467 (1992); Org. Synth. (1993)).
Reaction scheme 7 Iromacoon Bromination 7 © 7 < Fl Various 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. 51: 177 (1998), Bioorg, Med.Chem.Lett.10: 2607 (2000)). ) or carbon monoxide in the presence of a palladium catalyst (Bull, Chem. Soc. Jpn 67: 2329 (1994)). 3b can be formed by the oxidation of the benzylic alcohol 8c by using common methods such as MnO2 oxidation, PCC oxidation, Swern oxidation and Dess Martin oxidation. The reduction of benzonitrile 8b and benzoyl chloride 8d also produces benzaldehyde 3b (Org Synth 3: 551 (1995), J. Org Chem 46: 602 (1981)).
Reaction scheme 8 Reduction 8a 3b Reduction Sd For some of the compounds of formula II-V, the R3 and R4 groups can be introduced after the biaryl ring column is installed. As illustrated in Reaction Scheme 9, intermediate 4 (R3, R4 = H) is converted to benzylaldehyde 26 with treatment with SnCl4 and methoxymethylbichloride. Various alkyl groups (C 1 -C 2) are introduced by reacting benzylaldehyde 26 with a Wittig reagent followed by reduction of the resulting alkene with Et 3 SiH to result in intermediate 27 (J. Med.
Chem. 31:37 (1988)). Also, benzylaldehyde 31 can be oxidized by NaOCl 2 to give benzoic acid 29 (Bioorg, Med. Chem. Lett., 13: 379 (2003)) which can react with an alcohol or amine under standard conditions to give the ester or amide 30. Intermediates 27 and 30 can be converted to the corresponding phosphonic acids. and 33 following the same procedures as described in Reaction Scheme 2. In addition, deprotection of intermediate 4 provides phenol 32 which can be converted to a variety of sulfonamides 33 with treatment with C1S03H and an amine. Phosphonic acid (R3 = S (= 0) 2NRfR9) can be formed following the same procedures as described in Reaction Scheme 1.
Reaction scheme § 4? , W - ^ n L CISO ^ H, 2. NHRfRT Reaction scheme 11 R = NRfR9, OR * 1 B. Preparation of 1,3-diols Various methods can be used to prepare 1,3-propanediols such as 1,3-propanediols 1 -substituted, 2 -substituted, 1,2 or 1, 3-ringed. 1. 1,3-propanediols 1-their compounds The 1,3-propanediols useful in the synthesis of compounds in the present invention can be prepared by using various synthetic methods. As described in Reaction Scheme 10, the additions of an aryl Grignard to a 1-hydroxy-propan-3-al gives 1,3-substituted propanediols in 1 aryl (path a). This method is suitable for the conversion of various alkyl halides to 1,3-propanediols 1-arylsubstuides (J. Org. Chem. 53: 911 (1988)). Conversions of aryl halides to 1,3-propanediols 1 -su tutes can also be achieved by using Heck reactions (eg couplings with a 1,3-diox-4-ene) followed by reductions and subsequent reactions of hydrolysis (Tetrahedron Lett 33: 6845 (1992)). Various aromatic aldehydes can also be converted to 1,3-propanediols 1-substituted by using Grignard alkenyl addition reactions followed by hydroboration-oxidation reactions (path b).
Reaction scheme 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., Evans aldol reactions) are especially useful for the asymmetric synthesis of 1,3 enantioenriched propanediols. For example, the reaction of a metal enolate of t-butyl acetate with an aromatic aldehyde followed by reduction of the ester (path e) gives a 1,3-propanediol (J. Org. Chem. 55: 4744 (1990)). Alternatively, the epoxidation of cinnamyl alcohols using known methods (eg, Sharpless epoxidations and other asymmetric epoxidation reactions) followed by reduction reactions (eg, using Red-Al) gives various 1,3-propanediols (path c). ). The enantioenriched 1,3-propanediols can be obtained by means ofof asymmetric reduction reactions (e.g., enantioselective borane reductions) of 3-hydroxy ketones (Tetrahedron Lett 38: 761 (1997)). Alternatively, the resolution of racemic 1, 3-propanediols by using various methods (eg, chemical or enzymatic methods) can also give 1,3-propanediol enantioenriched. 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 by using N-oxide-forming reactions by a reaction of reconfiguration under conditions of acetic anhydride (trajectory d) (Tetrahedron 37: 1871 (1981)). 2. 1, 3-substituted 2-propanediols A variety of 2-substituted 1, 3-propanediols useful for the synthesis of compounds of the formula I-VII can be prepared from various other 1,3-propanediols (for example 2- (hydroxymethyl) 1, 3-propanediols) when using conventional chemistry (Comprehensive Organic Transformations, VCH, New York, 1989). For example, as described in Reaction Scheme 11, reductions of a trialcoxycarbonylmethane under known conditions gives a triol by means of complete reduction (path a) or a bis (hydroxymethyl) acetic acid by means of selective hydrolysis of the ester groups followed by reduction of the other two remaining ester groups. The nitrotrioles are also known to give triols by means of reductive elimination (path b) (Synthesis 8: 742 (1987)). Additionally, a 2 (hydroxymethyl) -1,3-propanediol can be converted to a mono-acylated derivative (eg, acetyl, methoxycarbonyl) by using an acyl chloride or an alkyl chloroformate (eg, acetyl chloride or chloroformate). methyl) (trajectory d) when 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 an aryl Grignard ( trajectory c). The aldehydes can also be converted to alkylamines by means of reductive amination reactions (path e). Reaction scheme 11 3. 1,3-Propane diols Ringed Compounds of the formula I-VII wherein V and Z or V and 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 1,3,5 cyclohexanotriols which are useful for the preparations of the compounds of the formula I wherein R 11 and R 11 together are wherein together V and W are connected by means of 3 atoms to form a cyclic group containing 6 carbon atoms substituted with a hydroxy group. It is envisioned that these modifications can be made either before or after the formation of a cyclic 1,3-propanediol phosphonate ester. Various 1,3-cyclohexanediols can also be prepared by using Dieder Alder reactions (for example, by using a pyrone such as the diene: Tetrahedron Lett 32: 5295 (1991)). The 2-hydroxymethylcyclohexanols and 2-hydroxymethylcyclopentanols are useful for the preparations of compounds of the formula I wherein R11 and R11 together are wherein together V and Z are connected by means of 2 or 3 atoms to form a cyclic group containing 5 or 6 carbon atoms. The 1,3-cyclohexanediol derivatives are also prepared by means of other cycloaddition reaction methodologies. For example, the cycloadducts of the cycloaddition reactions of a nitrile oxide and an olefin can be converted to a 2-ketoethanol derivative, which can be further converted to a 1,3-propanediol (including 1,3-cyclohexanediol, 2-hydroxymethylcyclohexanol and 2-hydroxymethylcyclopentanol) by using known chemistry (J. Am. Chem. Soc. 107: 6023 (1985)). Alternatively, precursors for 1,3-cyclohexanediol can be made from quinic acid (Tetrahedron Lett 32: 547 (1991)).
Experimental Example 1: Compound 1: N- [3,5-dimethyl-1,4- (3'-iso-propyl-4'-hydroxy-phenoxy)] carbamoylphosphonic acid Step a: A mixture of 3,5-dimethyl-4- (3 '-iso-propyl-4' -methoxyphenoxy) aniline (J. Med. Chem. 38: 695 (1995), 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%): XH NMR (300 MHz, CDC13 ): d 8.44 (s, 1 H), 7.17 (s, 2 H), 6.10-6.60 (m, 3 H), 4.10 (m, 4 H), 3.58 (s, 3 H), 3.07 (m, 1 H), 1.92 (s, 3 H), 1.93 (s, 3 H), 1.22 (m, 6 H), 0.99 (m, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (3: 1); Rf = 0.3.
Step b: To a solution of diethyl N- [3,5-dimethyl-4- (3'-iso-propyl-4 '-methoxy-phenoxy)] carbamoylphosphonate (0.1 g, 0.22 mmol) in CH 2 Cl 2 (1.5 mL) a -78 ° C bromotrimethylsilane was added (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 CH2Cl2 (2.0 mL) 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 4, 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; Analysis Calculated for (C? 8H22N06P + 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- (4'-hydroxy-3 '-iodophenoxy) phenyl] ethylphosphonic acid 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. A white solid was collected and dried in the air. 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, 2 H), 4.94 (s, 2 H), 3.80-4.10 ( m, 4 H), 3.80 (s, 1 H), 3.76 (s, 1 H), 1.16 (t, J = 6.0 Hz, 6 H); 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 (2x100 mL). The organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was dissolved in THF (14.0 mL) and (BOC) 20 (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 CH2C1 to give diethyl 2- (4-benzyloxyphenyl) -1- (tert-butoxycarbonylamino) ethylphosphonate as an oil (1.12 g, 46%): X H NMR (300 MHz, CD 3 OD): d 7.38 (m, 5 H), 7.13 (d, J = 8.4 Hz, 2 H), 6.88 (d, J = 8.4 Hz, 2 H ), 4.88 (s, 2 H), 4.12 (m, 5 H), 3.08 (m, 1 H), 2.70 (m, 1 H), 1.34 (m, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = CH30H-CH2C12 (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 atmosphere of H2 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 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 diethyl 1- (tert-butoxycarbonylamino) -2- (3,5-di-iodo-4-hydroxyphenyl) Ethylphosphonate as a yellow solid (1.30 g, 88%): XH NMR (300 MHz, CD3OD): d 7.67 (s, 2 H), 7.13 (d, J = 8.4 Hz, 1 H), 4.00-4.25 (m, 5 H), 3.00 (m, 1 H), 2.64 (m, 1 H), 1.38 (m, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = CH30H-CH2C12 (5:95); Rf = 0.70.
Step d: To a mixture of diethyl 1- (tert-butoxycarbonyl-mino) -2- (3, 5-diiodo-4-hydroxyphenyl) ethylphosphonate (0.6 g, 0.96 mmol), 4- (ert-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 is 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 provide diethyl 1- (tert- butoxycarbonylamino) -2- [4- (4 '- (tert-butyldimethylsilyloxy) phenoxy) -3,5-diiodophenyl] ethylphosphonate as a white solid (0.48 g, 60%): XH 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-butoxycarbonyl-amino) -2- [4- (4- (tert-butyldimethylsilanyloxy) phenoxy) -3,5-di-iodophenyl] 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 diethyl 1- (tert-butoxycarbonylamino) -2- [3, 5-diiodo-4- (4 '- hydroxyphenoxy) phenyl] ethylphosphonate as a white solid (0.24 g, 62%): XH 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-butoxycarbonyl-amino) -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 mL) 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 H0 (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 MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with 4% CH30H in CH2Cl2 to provide diethyl l-amino-2- [3,5-diiodo-4- (4'-hydroxy-3'-iodo). phenoxy) phenyl] ethylphosphonate as a yellow solid (0.10 g, 69%): 1 H NMR (300 MHz, CD 3 OD): 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 (m, 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 l-amino-2- [3,5-diiodo-4- (4'-hydroxy-3'-iodo-phenoxy) phenyl] ethylphosphonate (0.05 g, 0.07 mmol) in CH 2 Cl 2 (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; LCMS m / z = 688 [C? 4H? 3I3N05P + H] +; Analysis Calculated for (C? 4H? 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 3: 2- [3,5-diiodo-4- (4'-hydroxy-3 '-iodophenoxy) phenyl] ethylphosphonic acid Step a: To a solution of tetraethylmethylene diphosphonate (1.6 g, 5.6 mmol) in THF (16.0 mL) at 0 ° C was slowly added hydride : 56 sodium (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, 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 a H 2 atmosphere for 16 h, filtered through a plug of Celite and concentrated under reduced pressure to give diethyl 2- (4-hydroxyphenyl) ethylphosphonate as an oil (1.10 g, 91% ): X H NMR (300 MHz, CD 3 OD): 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 %): 1R NMR (300 MHz, CD3OD): d 7.62 (s, 2 H), 4.05 (m, 4 H), 2.77 (m, 2 H), 2.05 (m, 2 H), 1.29 (t, J = 6.9 Hz, 6 H); conditions of CCD: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (1: 1); Rf = 0.57.
Step c: Diethyl 2- [3,5-diiodo-4- (4'-hydroxyphenoxy) phenyl] ethylphosphonate was synthesized from diethyl 2- (3,5-diiodo-4-hydroxyphenyl) ethylphosphonate (0.5 g, 0.98 mmol) following the procedure described in example 2, step d followed by example 2, step e: a white solid (0.15 g, 25%) XH NMR (300 MHz, CD3OD): 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 (m, 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'-hydroxy) phenoxy) phenyl] ethylphosphonate (0.15 g, 0.25 mmol) in ethanol (5.0 mL) at 0 ° C was slowly added 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 CH2C1 to give diethyl 2- [3,5-diiodo-4- (4'-hydroxy-3'-iodophenoxy) phenyl] ethylphosphonate as a white solid (0.10 g, 56%): H NMR (300 MHz, CD30D): 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 diethyl 2- [3,5-diiodo-4- (4'-hydroxy-3 '-iodophenoxy) phenyl] ethylphosphonate (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 mixture was stirred at room temperature 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 provide 2- [3,5-diiodo-4- (4'-hydroxy-3'-iodophenoxy) phenyl] ethylphosphonic acid as an opaque white solid (0.05 g, 96%): mp 188 ° C, dec; LC-MS m / z = 673 [C? 4H? 2I305P + H] +; Analysis Calculated for (C? 4H? 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-phenoxy) phenyl] ethylphosphonic acid Step a: To a mixture of bis (4-methoxy-3-iso-propylphenyl) iodonium tetrafluoroborate (0.30 g, 0.59 mmol, Yokoyama et al., J. Med. Chem. 38: 695 (1995)) and copper (0.05 g, 0.78 mmol) in CH2C12 (1.5 mL) at 0 ° C was added slowly a solution of diethyl 2- (3,5-diiodo-4-hydroxyphenyl) ethylphosphonate (0.2 g, 0.39 mmol) and TEA (0.10 mL, 0.66 mmol) in CH2C12 (0.6 mL). The reaction mixture was stirred at room temperature 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 give diethyl 2- [3,5-diiodo-4- (4'-methoxy-3'-iso-propy1phenoxy) phenyl] ethylphosphonate as an opaque white solid (0.25 g, %): 1 H NMR (300 MHz, CD 3 OD): 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 '-methoxy-3'-iso-propylphenoxy) phenyl] ethylphosphonate (0.25 g, 0.38 mmol) in CH 2 Cl 2 (3.0 mL) at 0 ° C was slowly added bromotrimethylsilane (0.60 mL, 3.8 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 (3.0mL) and cooled to -78 ° C. Boron tribromide (1.80 mL, 1.80 mmol, 1.0 M CH2C12) was added slowly and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture 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-propyl-phenoxy) phenyl] ethylphosphonic acid as an opaque white solid (0.20 g, 91%): mp 184-186 ° C; LC-MS m / z = 589 [C? 7H? 9I205P + H] +; Analysis Calculated for C 17 H 19 I 2 O 5 P: C, 34.72; H, 3.26. Found: C, 34.75; H, 3.12.
Example 5 Compound 5: 3,5-diiodo-4- (4'-hydroxy-3'-iso-propylphenoxy) benzylphosphonic acid Step a: A mixture of 4-benzyloxybenzyl bromide (Chow et al., J. Org. Chem. 62: 5116-21 (1997)) (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 mixture was cooled to room temperature, quenched with H20 (10 mL) 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 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 CH3OH (12.0 mL) and Pd-C (10%, 0.33 g) was added. The reaction mixture was stirred under a H 2 atmosphere for 16 h, filtered through a plug of Celite and concentrate under reduced pressure to provide diethyl 4-hydroxybenzylphosphonate as an oil (0.9 g, 84%): X H NMR (300 MHz, CD 3 OD): d 7.12 (d, J = 8.4 Hz, 2 H), 6.73 (d, J = 8.4 Hz, 2 H), 4.05 (m, 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: Diethyl 3,5-diiodo-4-hydroxybenzylphosphonate (0.85 g, 85%) was synthesized from diethyl 4-hydroxybenzylphosphonate (0.5 g, 2.1 mmol) following the procedure described in Example 3, step b: XH 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: Diethyl 3, 5-diiodo-4- (4'-methoxy-3'-iso-propylphenoxy) benzylphosphonate (0.22 g, 88%) was synthesized from diethyl 3,5-diiodo-4-hydroxybenzylphosphonate (0.2 g) , 0.4 mmol) following the procedure described in example 4, step a: 1 H NMR (300 MHz, CD 3 OD): 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 diethyl 3, 5-diiodo-4- (3 '-iso -propyl-4 '-methoxyphenoxy) benzylphosphonate (0.22 g, 0.34 mmol) following the procedure described in example 4, step b: pf > 220 ° C; LC-MS m / z = 575 [C? 6H17I204P + H] +; Analysis Calculated for (C? 6H? 7I2O5P + 0.3 H2O + 0.5CH3OH): C, 33.28; H, 3.32; I, 42.62. Found: C, 33.49; H, 3.23; I, 42.51.
Example 6 Compound S: 3,5-diiodo-4- (4'-hydroxy-3 '-iodophenoxy) benzylphosphonic acid Step a: Diethyl 3, 5-diiodo-4- (4'-hydroxyphenoxy) benzylphosphonate (0.11 g, 17%) was obtained from diethyl 3,5-diiodo-4-hydroxybenzylphosphonate (0.55 g, 1.1 mmol) following the procedure described in example 3, step c: XH NMR (300 MHz, CD3OD): 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 (m, 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: Diethyl 3, 5-diiodo-4- (4 '-hydroxy-3'-iodophenoxy) benzylphosphonate (0.08 g, 63%) was obtained from diethyl 3,5-diiodo-4- (4'-hydroxyphenoxy) benzylphosphonate (0.1 g, 0.1 mmol) following the procedure described in example 3, step d: XH 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 (dd, 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'-Iodophenoxy) benzylphosphonic acid (0.06 g, 90%) was obtained from diethyl 4- (4'-hydroxy-3 '-iodophenoxy) - 3,5-diiodobenzylphosphonate (0.08 g, 0.1 mmol) following the procedure described in example 3, step e: mp 168 ° C, dec; LC-MS m / z = 659 [C? 3H? 0I3O5P + H] +; Analysis Calculated for (C? 3H? 0I3O5P + 1 .6H20 + 0.5CH3OH): 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- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy] methylphosphonic acid 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' -isole). propylbenzyl) phenol (5.60 g, 17.8 mmol), (Chiellini et al., Bioorg, Med Chem. Lett 10: 2601 (2000)) 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 × 2). 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 acetone-hexanes (1: 3) to give diethyl [3,5-dimethyl-4- (4'-methoxymethoxy-3'-iso-propylbenzyl) phenoxy] methylphosphonate as a colorless oil (5.32 g, 64%): X H NMR (300 MHz, DMS0-6): 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 (m, 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'-iso-propyl-benzyl) 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 give [3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy] methylphosphonic acid as a pink solid (4.00 g, 95%): mp 55 -58 ° C; LC-MS m / z = 365 [C19H25O5P + H] +; Analysis Calculated for (C19H25O5P + 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 to 7-21 were prepared in a manner analogous to that described for the synthesis of compound 7.
Compound 7-1: [3,5-dimethyl-4- (4'-hydroxy-3'-phenylbenzyl) phenoxy] methylphosphonic acid The intermediate 3,5-dimethyl-4- (4'-methoxymethoxy-3'-phenylbenzyl) phenol was prepared from 2-phenylphenol according to the procedure described in Chiellini et al. , Bioorg. Med. Chem. Let t. 10: 2601 (2000) and transformed into the title compound by the procedure used for the synthesis of compound 7. XH 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] +; Analysis Calculated for (C 29 H 4 O → P + 1.7 H 20 + 0.4 CH 3 OH): C, 60.89; H, 6.39. Found: C, 60.53; H, 6.19.
Compound 7-2: [3,5-dimethoxy-4- (4'-hydroxy-3'-di-propylbenzyl) phenoxy] methylphosphonic acid The intermediate 3,5-dimethoxy-4- (3'-iso-propyl-4'-methoxymethoxybenzyl) phenol was prepared from 2,6-dimethoxy-4-hydroxybenzaldehyde according to the procedure described in Chiellini et al., Bioorg. Med. Chem. Lett. 10: 2601 (2000) and 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 [C19H25O7P + H] +; Analysis Calculated for (C? 9H2507P + 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] methylphsphonic acid 3, 5-dimethyl-4- (3 '-sec-butyl-4' -methoxymethoxybenzyl) Intermediate phenol was prepared from commercially available 2-sec-butylphenol according to the procedure described in Chiellini et al. , Bioorg. Med. Chem. Lett. 10: 2601 (2000) and transformed into the title compound by the procedure used for the synthesis of compound 7. 1ti NMR (200 MHz, DMSO-d6): 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] +; Analysis Calculated for (C2oH2705P + 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) phenoxy] methylphosphonic acid The intermediate 3, 5-dimethyl-4- (3'-iso-propyl- '-methoxybenzyl) phenol was prepared from 2-iso-propylanisole according to the procedure described in Chiellini et al. , Bioorg. Med. Chem. Lett. 10: 2601 (2000) and 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 (m, 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 [C2oH205P + H] "Analysis Calculated for (C20H27O5P + 0.3H20): C, 62.59; H, 7.25 Found: C, 62.37; H, 7.40.
Compound 7-5: [3,5-Dichloro-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy] methylphosphonic acid 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) in accordance with the procedure described in Chiellini et al., Bioorg. Med. Chem. Lett. 10: 2601 (2000) and transformed into the title compound by the procedure used for the synthesis of compound 7. mp .: 118 -120 ° C; XH NMR (300 MHz, CD3OD): 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); LCMS m / z = 405 [C? 7H19Cl205P] +; Analysis Calculated for: (C? 7Hi9Cl205P): 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) phenoxy] methylphosphonic acid The intermediate 3,5-dimethyl-4- (3'-iso-pro? Il-4'-methoxymethoxybenzyl) phenol was prepared from 2-isopropylphenol according to the procedure described in Chiellini et al., Bioorg. Med. Chem. Lett. 10: 2601 (2000) and transformed into the title compound by the procedure used for the synthesis of compound 7 using diethyl bromodifluoromethylphosphonate. * H NMR (300 MHz, DMSO-d6): d 9.02 (s, 1 H), 6.88 (m, 3 H), 6.65 (m, 1 H), 4.46 (m, 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, 100x4.6 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 Chiellini et al. , Bioorg. Med. Chem. Let t. 10: 2601 (2000) and transformed into the title compound by the procedure used for the synthesis of compound 7. pf > 230 ° C; X H NMR (300 MHz, DMSO-d 6): d 8.99 (s, ÍH), 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 [C? 7H2? 05P-H]; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = isopropyl alcohol / water / ammonium hydroxide [7: 2: 1]; Rf = 0.23; Analysis Calculated for (C17H21O5P + 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 Chiellini et al. , Bioorg. Med. Chem. Let t. 10: 2601 (2000) and transformed into the title compound by the procedure used for the synthesis of compound 7.? H NMR (300 MHz, DMSO-d6): d 8.96 (s, ÍH), 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); LCMS m / z = 349 [C? 8H2305P-H]; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = isopropyl alcohol / ammonium hydroxide / water [7: 2: 1]; Rf = 0.20; Analysis 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. : 165 (1985)) in accordance with the procedure described in Chiellini et al. ai., Bioorg. Med. Chem. Lett. 10: 2601 (2000) and transformed into the title compound by the procedure used for the synthesis of compound 7 mp: 60-64 ° C; l 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 [C 21 H 29 O 5 P + H] +; Analysis 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'-methyl benzyl) phenoxy] methylphosphonic 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. 12: 1350 (1980)) in accordance with the procedure described in Chiellini et al., Bioorg. Med. Chem. Lett. 10: 2601 (2000) and transformed into the title compound by the procedure used for the synthesis of compound 7 mp: 65-68 ° C; X H NMR (300 MHz, CD30D): 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] +; Analysis 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, cooling to room temperature, quenched with ice (50 g) and extracted with ether (20 mL × 2). The combined organic extracts were dried over MgSO 4, 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 give 4-bromo-6-fluoro-2-iso-propylanol (0.92 g, 38%): XH 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.
Stage b: To a solution of 4-bromo-6-fluoro-2-propylamine (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 for the next step without further purification: 1ti 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 (m, 1 H), 1.23 (d, J = 6.6 Hz, 6 H); 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 Chiellini et al. , Bioorg. Med. Chem. Lett. 10: 2601 (2000) and transformed into the title compound by the procedure used for the synthesis of the compound 7. mp: 166-168 ° C; X NMR (300 MHz, CD3OD): d 6.89 (d, J = 9.0 Hz, 1 H), 6.80 (s, 2 H), 6.03 (d, J = 9.0 Hz, l H), 4.25 (d, J = 8.4 Hz, 2 H), 3.91 (s, 2 H), 3.34 (m, 1 H), 2.18 (s, 6 H), 1.30 (d, J = 6.9 Hz, 6 H); LC-MS m / z = 383 [C? 9H24F05P + H] +; Analysis Calculated for (C19H4F05P + 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 cooled solution of 2-iso-propyl aniline (714 mg, 5.28 mmol) in dichloromethane (20 mL) at -50 ° C in an acetone / dry ice 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%); X H NMR (300 MHz, DMS0-d 6): d 7.01 (m, 2H), 6.55 (d, ÍH, J = 13 Hz), 5.05 (bs, 2H), 2.92 (m, ÍH), l.ll (d , 6H, J = 1 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% ); "" H NMR (300 MHz, DMSO-d6): d 9.39 (s, HH), 7.43 (d, HH, J = 2.4 Hz), 3.16 (m, HH), 2.04 (s, 3H), 1.13 ( d, 6H, J = 1 Hz), CCD conditions: Silica gel uniplaca, 250 microns, Mobile phase = dichloromethane, Rf = 0.21 3, 5-dimethyl-4- (5'-fluoro-3'-iso -propyl-4'-methoxymethoxybenzyl) phenol intermediate was prepared from N- (4-bromo-2-iso-propyl-phenyl) -acetamide according to the procedure described in Chiellini et al., Bioorg, Med. Chem. Let t.10: 2601 (2000) and transformed into the title compound by the procedure used for the synthesis of compound 7: mp> 230 ° C; LC-MS m / z = 404 [C21H28NO5P-H]; (300 MHz, DMSO-dff): d 9.23 (s, ÍH), 7.03 (m, 2H), 6.71 (s, 2H), 6.60 (d, ÍH, 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: Silica gel uniplaca, 250 microns; Mobile phase = isopropyl alcohol / water / ammonium hydroxide [7: 2: 1]; Rf = 0.26; Analysis Calculated for (C21H28 O5P + 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 '-iso-propyl-4'-methanesulfonylaminobenzyl) -3,5-dimethyl phenoxy] methylphosphonic acid Step a: The N- [4- (4'-hydroxy-2 ', 6'-dimethyl-benzyl) -2-iso-propyl-phenyl] -acetamide intermediate of the synthesis of compound 7-12 (320 mg, 0.68 mmol) was combined with HCl (10 mL) and water (2 mL) in a round-bottomed flask 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%). %): X H NMR (300 MHz, DMSO-d 6): d 8.934 (s, HH), 6.73 (d, HH, J 1.8 Hz), 6.43 (m, 5H), 4.58 (bs, 2H), 3.69 (s) , 2H), 2.92 (m, ÍH), 2.10 (s, 6H), 1.07 (d, 6H, J = 6.6 Hz); conditions of CCD: 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 removed 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 preparative plate CCD using a 2000 μm plate of silica gel eluting with ethyl acetate / dichloromethane [3: 1] to give diethyl [4- (4'-amino-3'-iso-propylbenzyl) 3,5-dimethylphenoxy] methylphosphonate (0.061 g, 49%): X H NMR (300 MHz, DMSO-d 6): d 6.74 (d, H, J = 1.8 Hz), 6.72 (s, 2 H), 6.45 (d , ÍH, J = 14.4 Hz), 6.36 (dd, ÍH, 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 (m, ÍH), 2.17 (s, 6H), 1.25 (t, 6H, J = 1 Hz), 1.07 (d, 6H, J = 7.2 Hz); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate / dichloromethane [1: 1]; Rf = 0.54.
Step c: To a solution consisting of diethyl [4- (4 '-amino-3' -iso-propylbenzyl) -3,5-dimethylphenoxy] methylphosphonate (43.6 mg, 0.104 mmol), in dichloromethane (2 mL) was added methan sulfonyl chloride (1 eq, 8 μl), and pyridine (1 eq, 8.4 μl). The reaction was stirred overnight at room temperature under an atmosphere of 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), lx 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 give pure diethyl [4- (3'-iso-propyl-4'-methansulfonylaminobenzyl) -3,5-dimethylphenoxy] methylphosphonate (0.047 g, 97%). : X NMR (300 MHz, DMSO-d6): d 8.94 (s, ÍH), 7.08 (m, 2H), 6.76 (s, 2H), 6.68 (dd, ÍH, J = 2.1 Hz, J = 8.7 Hz) , 4.36 (d, 2H, J = 10.2 Hz), 4.11 (m, 4H), 3.39 (m, ÍH), 2.94 (s, 3H), 2.23 (s, 6H), 1.25 (m, 6H), 1.08 ( d, 6H, J = 1 Hz); CCD conditions: 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'-methanesulfonylaminobenzyl) -3,5-dimethylphenoxy] methylphosphonate (43.8 mg, 0.09 mmol) and dichloromethane (2 mL) were 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 made acidic 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%): X H NMR (300 MHz, DMSO-d 6): d 8.93 (s, 1 H), 7.10 (m, 2 H), 6.67 (, 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; Analysis Calculated for (C2oH28? 6PS + 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] ethylphosphonic acid Step a: To a mixture of diethyl [3,5-dichloro-4- (3'-iso-propyl-4'-methoxymethoxybenzyl) phenoxy] methylphosphonate (0.25 g, 0.49 mmol, intermediate for the synthesis of compound 7-5) in methanol (3.0 mL) at 0 ° C, 2 N HCl (1.0 mL) was added. 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 4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with 30% acetone in hexanes to give diethyl [3,5-dichloro-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy] methylphosphonate (0.17 g, 74%) as a colorless oil: 1 H NMR (300 MHz, CD30D): 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: To a mixture of diethyl [3,5-dichloro-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy] methylphosphonate (0.16 g, 0.35 mmol) in CH 2 Cl 12 (3.0 mL) at 0 ° C tetrabutylammonium tribromide (0.18 g, 0.38 mmol) was added. The reaction mixture was stirred 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 diethyl [3,5-dichloro-4- (5'-bromo-4'-hydroxy-3'-iso-propylbenzyl. ) phenoxy] methylphosphonate (0.12 g, 64%) as yellow oil: XH 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); CCD conditions: 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; H NMR (300 MHz, CD3OD): 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] +; Analysis Calculated for (Ci7Hi8BrCl205P + 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 Chiellini et al. , Bioorg. Med. Chem. Let t. 10: 2601 (2000) and transformed into the title compound by the procedure used for the synthesis of compound 7: XH 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: reduced to 145 ° C; LC-MS m / z = 367 [C? 8H306P + H] +; Analysis Calculated for (C? 8H2306P + 0.2MeOH + 0.4H2O): 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'-methyl benzyl) phenoxy] methylphosphonic acid Step a: To a solution of ethyl 2-methoxy-6-methylbenzoate (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 MgSO 4, 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 a colorless oil. : 1H 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 an H 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-isopropyl-3-methylanisole (0.45 g, 100%) as a colorless oil, which was used for the next step without further purification: XH 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-isopropyl-3-methylanisole (0.44 g, 2.7 mmol) in CH 2 Cl 2 at room temperature was added a solution of tetrabutylammonium tribromide (1.42 g, 2.94 mmol) in CH 2 Cl 2. 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 give 4-bromo-2-iso-propyl-3-methylanisole as a yellowish oil (0.60g, 92%): X NMR (300 MHz, DMSO-d ^): 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 by the synthesis of compound 7-11: mp: 180-183 ° C; 1 H NMR (300 MHz, CD3OD): 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 [C20H27O5P + H] +; Analysis Calculated for (C20H27? 5P + 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) phenoxy] methylphosphonic acid Step a: To a stirred suspension of 2,5-dimethyl phenol (5.0 g, 40.9 mmol) in H2O (150 mL), tetrabutylammonium tribromide (19.9 g, 41.39 mmol) in CHC13 (150 mL) was added at room temperature. The reaction mixture was stirred for 2 h at room temperature, the organic layer was separated and dried over Na 2 SO 4 (filtered and concentrated) The residue was purified by column chromatography on silica gel eluting with hexane-ethyl acetate (1: 5) to provide 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: Silica gel uniplaca, 250 microns, Mobile phase = hexanes-ethyl acetate (9: 1) ); Rf = 0.52.
Step b: 2, 5-dimethyl-4- (3 '-iso-propyl-4' -methoxymethoxybenzyl) Intermediate phenol was prepared from 2,5-dimethyl-4-bromo-t-butyldimethylsilyloxyphenol, and 3-iso-propyl-4-methoxymethoxybenzaldehyde according to the procedure described in (Chiellini et al., Bioorg, Med. Chem. Let t.10: 2601 (2000)) and transformed into the title compound by the procedure used for the synthesis of compound 7-13, step b followed by example 7, step b, (0.14 g, 90%); l 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 [C2oH2506P + H] +; CLAR conditions: ODSAQ AQ-303-5 column; mobile phase = CH3OH: 0.05% TFA (7: 3) flow ratio = 1.0 mL / min; detection = UV @ 254 nm retention time in min: 10.96; Analysis Calculated for (C20H25? 6P + 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'-methoxy) methoxy-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. ethyl (100 mLx2). The combined organic layers were 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: 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 by the synthesis of Example 7 -17, stage b as a white solid (0.15 g, 75%) pf 190 ° C; ? ti 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] +; Analysis Calculated for (C2oH2506P + 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) phenoxymethyl] phosphonic 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-iso- propylbenzene according to the procedure described in Chiellini et al. , Bioorg. Med. Chem. Let t. 10: 2601 (2000) and transformed into the title compound according to the procedure described by the synthesis of compound 7-17, step b; (0.12 g, 85%); X 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 [C2oH25? 6P -H] +; (94%) CLAR conditions: ODSAQ AQ- 303-5 column; mobile phase = CH3OH: 0.05% TFA / H2O (7: 3) flow ratio = 1.0 mL / min; detection = UV @ 254 nm retention time in min: 10.92; Analysis Calculated for (C2oH25? 6P + 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 acid The intermediate 4- (4'-methoxymethoxy-3'-iso-propylbenzyl) -3-methyl-phenol was prepared from 4-bromo-3-methyl-phenol (J. Med. Chem. 12: 1350 (1980) ) and 4-methoxymethoxy-3-iso-propylbenzaldehyde according to the procedure described in Chiellini et al. , Bioorg. Med. Chem. Let t. 10: 2601 (2000) and transformed into the title compound by the procedure used for the synthesis of compound 7. 1 H NMR (300 MHz, DMS0-d 6): 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 (m, 2 H), 6.67 (s, 2 H), 4.03 (d, J = 10.5 Hz, 2 H), 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) phenoxy] methylphosphonic 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, IM in CH2C12). The reaction mixture was stirred at room temperature for 16 hrs. Ice was added and diluted with CH2C12. 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: 1) to provide 2,5-dimethyl-4-hydroxy-benzaldehyde as a yellow solid (0.43 g, 57%). : X H NMR (300 MHz, DMSO-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.
At room temperature, imidazole (0.43 g, 6.29 mmol) and chloro-triisopropyl-silane (0.74 mL, 3.43 mmol) were added. 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%). 1 H NMR (300 MHz, DMSO-dg): 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 Chiellini et al. , Bioorg. Med. Chem. Let t. 10: 2601 (2000) and transformed into the title compound by the procedure described by the synthesis of compound 7: 1 H NMR (300 MHz, DMSO-de): 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-liter 3-necked flask equipped with mechanical stirrer, nitrogen sparger, sodium hydroxide trap, and a cold water bath was charged with 2-iso-propyl phenol (157.8 g, 1 mol) and dichloromethane (1000 ml). While keeping the internal temperature at 15 ° C to 20 ° C, the bromine (179.4 g, 1.1 mol) was added dropwise over 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, Rf product = 0.8). The flask was purged with nitrogen to remove most of the hydrogen bromide. The reaction mixture was then concentrated to an oil (252.0 g, 100%) that is sufficiently pure to be used in the next step. NMR: See Berthelot et al., Can J. Chem. 61: 2061 (1989).
Step b: A 3-liter, 3-necked round-bottomed flask equipped with a mechanical stirrer, temperature probe, cooling bath, and addition funnel with nitrogen inlet. 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 plates, 10% EtOAC / hexanes, Rf S.M. = 0.5, Rf product = 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 give a clear oil (154 g, 79%). NMR See G. Chiellini et al. Biorg. Med. Chem. Lett. 10: 2607 (2000).
Alternative Step b A 5-neck, 4-necked, non-nickel, round bottom flask equipped with a mechanical multi-blade 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 time balls of dough are formed.
Additional P205 (75 g, 1.1 mol) was added and stirred for one hour. The reaction was completed by CCD (silica gel plates, 10% EtOAC / hexanes, Rf S.M. = 0.5, Rf product = 0.9). The reaction was carefully quenched by the addition of 10% K2C03 (2000 ml). After separation of the layers, the aqueous phase was extracted with methylene chloride (1000 ml).
The combined organic layers were dried over MgSO4, 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 provide a clear oil (99.9 g, 83%).
Step c: A 2-neck 3-necked round bottom flask equipped with mechanical stirrer, 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. Triisopropylsilyl chloride (95.0 g, 493 mmol) was added for 10 minutes. The temperature rises to 20 ° C. The solution becomes turbid, and a precipitate forms. The reaction mixture was stirred at room temperature for 2.5 hours. The reaction was completed by CCD (silica gel plates, % EtOAc / hexane, Rf S.M. = 0.3, Rf product = 0.9). The 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 give an oil (153 g, 96%). RMN See Chiellini et al., Bioorg. Med. Chem. Let t. 10: 2601 (2000).
Step d: A 3-liter 3-necked round bottom flask equipped with a mechanical stirrer, thermometer, cooling bath and 250 ml addition funnel was charged with 4-bromo-3,5-dimethylphenoxy-propriisopropylsilane (150 g, 420 mmol). and THF (1125 ml). The solution was cooled to -73 ° C. While maintaining the temperature to less than or equal to -70 ° C, n-butyllithium 2.5 M (252 ml, 630 mmol) was added for 1.5 hour. The solution was stirred at -73 ° C for an additional 2.5 hours. While maintaining the temperature to 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, the CCD indicates that the reaction was complete (silica gel plates, 10% EtOAc / hexane, Rf S.M. = 0.9, Rf product = 0.7). The reaction it 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 give an oil (113 g, 87%). NMR See Chiellini et al. , Bioorg. Med. Chem. Let t. 10: 2601 (2000).
Step e: A 5-liter 3-necked round bottom flask equipped with a cooling bath, mechanical stirrer, 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 to less than or equal to -70 ° C, a solution of n-butyllithium (310 ml, 775 mmol) was added for 45 minutes. The solution was stirred at -75 ° C for 1 hour. While maintaining the temperature to 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. The CCD indicates that the reaction was complete (silica gel plates, 10% EtOAc / hexane, Rf Bromide = 0.9, Rf Aldehyde = 0.7, Rf product = 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 divided equally, and each half was purified by column chromatography (1.8 kg silica gel, 5 to 10% EtOAc / hexane) to give the product as a clear oil containing some EtOAc (148 g of product , 69%). The fractions containing the product and an impurity are 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%). NMR See Chiellini et al. , Bioorg. Med. Chem. Lett. 10: 2601 (2000).
Step f: A 2 liter round bottom flask equipped with a magnetic stirrer 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 on 10% carbon (5.22 g). The flask was purged 3 times with nitrogen, and then a nitrogen balloon was bonded 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, Rf product = 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 saturated NaHC03 in water until the wash was basic (4 x 100 ml). The organic layer was dried over MgSO4 and then concentrated to an oil (62.5 g, 96%). NMR See Chiellini et al. , Bioorg. Med. Chem. Let t. 1 0: 2601 (2000).
Step g: A 1-liter 1-neck round-bottomed flask equipped with a magnetic stirrer was charged with 2,6-dimethyl- (4'-methoxymethoxy-3'-iso-propylbenzyl) -4-triisopropylsilyloxybenzene (62.5 g, 133 mmol) and THF (600 ml). The tetraethylammonium fluoride hydrate (25.9 g, 174 mmol) was ground slowly in a cuvette and then charged to the flask. The thickened mixture was stirred at room temperature for 1 hour until the CCD indicated that the reaction was complete (silica gel plates, 20% EtOAc / hexane, Rf S.M. = 0.9, Rf product = 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 Chiellini et al. , Bioorg. Med. Chem. Lett. 10: 2601 (2000).
Step h: A 5-liter 3-necked round bottom flask equipped with a cooling bath, mechanical stirrer, temperature probe, and addition funnel with nitrogen inlet was charged with 60% sodium hydride in mineral oil (10.62 g, 266 mmol). 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 < 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 maintaining the temperature to less than or equal to 10 ° C, a solution of 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, 2x 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 give the product as a clear oil containing some EtOAc (54.76 g of product, 66%). The fractions containing the product and diethyl p-toluenesulfonyloxymethyl combine to give a clear oil (6.03 g). This was purified by column chromatography (120 g silica gel, 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 a magnetic stirrer, temperature probe, addition funnel with a nitrogen inlet, and a cooling bath was charged with the diethyl [3,5-dimethyl-4 - (4'-methoxymethoxy-3'-iso-propylbenzyl) phenoxy] methylphosphonate (19.61 g, 42.2 mmol) and dichloromethane (200 ml). The solution was cooled to -30 ° C. Trimethylsilyl 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 from 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 give the title compound as an opaque white solid (14.36 g). NMR See compound 7, stage b.
Preparation of Diethyl p-toluenesulfonyloxymethylphosphonate A 3-neck, 3-necked round bottom flask was equipped with a mechanical stirrer, condenser, thermometer and heating mantle. 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 complete (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, dry (MgSO 4, 200 g), filtered through Celite 521, and concentrated under reduced pressure to provide 1004 g of a cloudy yellow oil (77.6%). 1 H NMR (CDC13): 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 (d. m, 4H), 2.41 (s, 3H), 1.16 (m, 6H), CCD conditions: Silica gel uniplaca, 250 microns, Mobile phase = 40% EtOAc / hexanes, Rf = 0.24.
Example 8 Compound 8: [3,5-Diiodo-4- (4'-hydroxy-3'-iso-propylphenoxy) phenoxy] methylphosphonic acid 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) iodonium 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, eluting with acetone-hexanes (1: 9) to provide 4-benzoyloxy-3,5-diiodophenol as an opaque white solid (0.22 g). , 50%): X H NMR (300 MHz, DMS0-d 6): 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 mL, 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 room temperature for 24 h and filtered through a Celite plug. 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 3,5-diiodo-4- (4'-methoxy-3-benzoate. '-iso-propylphenoxy) phenyl as a white opaque solid (0.61 g, 98%):? H NMR (300 MHz, DMSO-de): 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, ÍH), 6.73 (d, J = 3.0 Hz, ÍH), 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- ('-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 mL) was at room temperature for 24 h. The reaction mixture was neutralized with 2N HCl, diluted with H20 and extracted with CH2C12 (10 mLx2). The organic layers were concentrated under reduced pressure and the crude product was purified preparative CCD with acetone-hexanes (1: 4) as the mobile phase to provide 3,5-diiodo-4- ('-methoxy-3' -iso-propylphenoxy) phenol as a white opaque solid (0.079 g, 95%): 2 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 (m, 1 H), 3.72 (s, 3 H), 3.18 (m, 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 mL) at -78 ° C was added. added BBr3 (13.1 mL, 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 mLx2). 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 opaque white solid (0.18 g, 66%): X H NMR (300 MHz, DMS0-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, 1 H), 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 diethoxyphosphorylmethyl ester (0.040 g, 0.14 mmol) was added. The reaction mixture was stirred at room temperature for 5 h, quenched with 1 N 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 the mobile phase to give [3, 5-diiodo-4- (4'-hydroxy-3'-iso-propylphenoxy) phenoxy] methylphosphonate diethyl as a solid white opaque (0.048 g, 55%): 1 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 provide [3,5-diiodo-4- (4'-hydroxy-3'-iso-propylphenoxy) phenoxy] methylphosphonic acid as a white solid. opaque (0.080 g, 63%): mp 180 ° C, dec; LC-MS m / z = 589 [C? 6H17l2? 6P -H] "; CLAR conditions: Column = 3 Chromolith SpeedRODs RP-18e, 100x4.6 mm; Mobile phase = Solvent A (Acetonitrile) = HPLC grade acetonitrile; 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 rate = 4 mL / min, UV @ 255 nm. retention in minutes, (tr = 6.46, 97% purity) Using the appropriate starting material, compounds 8-1 and 8-2 were prepared in a manner analogous to that described for the synthesis of compound 8.
Compound 8-1: [3,5-dibromo-4- (3 '-iso-propyl-4' -hydroxyphenoxy) phenoxy] methylphosphonic acid 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] "; XH NMR (300 MHz, DMSO-ds): 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), Analysis Calculated for (Ci6H? 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 Prepared from 2,6-dichloro-4- (2-methoxyethoxy) f enol (Synth, Commu, 1997, 21, 107) according to the procedure described in compound 8. mp: 73-76 ° C; LCMS m / z = 407 [C? 6H? 7Cl206P-H] "; XH NMR (300 MHz, DMSO-d6): 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), Analysis Calculated for (Ci6H? 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., J. Med. Chem. 1995, 38, 695) and copper powder (1.14 g, 18.1 mmol) in CH 2 Cl 2 (30 mL) at 0 ° C was added a solution of 3,5-dichloro-4-hydroxybenzoate methyl (39, 2.0 g, 9.0 mmol) and Et 3 N (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; X 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 Cl 12 (50 mL) at -78 ° C was added BBr 3 (11. 4 mL, 11.4 mmol, 1 M solution in CH2C12). The reaction mixture was stirred at room temperature for 14 h, draining in ice water (100 mL) and stirred for 1 h. The reaction mixture was extracted with ethyl acetate (2x100 mL). The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was recrystallized from CH 2 Cl 2, filtered and dried under reduced pressure to provide 3,5-dichloro-4- (4'-hydroxyphenoxy) enzoic acid as a brown solid (1.02 g, 75%): mp 163-165 ° C; 1ti NMR (300 MHz, DMSO-d6): 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 stirred cold solution of CH3OH (35 mL) and chloride of acetyl (7 mL, 86.0 mmol) at 0 ° C was added dropwise a solution of 3,5-dichloro- (4'-hydroxyphenoxy) 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; * H NMR (300 MHz, DMSO-d6): 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, pouring into ice water and extracted with ethyl acetate (3x100 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.lg, 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 L) 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; XH 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 H), 1.63 - 1.59 (m, 4 H), 1.50 - 1.40 (m, 2 H); CCD conditions: Uniplaca of silica gel, 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 '- Methyl (N-piperidinylsulfonamido) phenoxy] benzoate (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 CH2Cl2). The reaction mixture was stirred at room temperature for 5 h, cooling 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 (2x100 mL). The combined organic layers were washed with brine, dried over Na 2 SO 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-) alcohol. piperidinylsulfonamido) phenoxy] benzyl as a white solid (0.66 g, 75%): mp 142-145 ° C; H NMR (300 MHz, DMSO-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 a2SO4, 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' - (? 7-piperidinylsulfonamido) phenoxy] benzyl bromide (0.12 g, 0.25 mmol) in toluene (5 mL) a 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 pressure reduced 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-piperidinylsulfonamido ) phenoxy] benzylphosphonate diethyl as a white solid (0.12 g, 90%): mp 132-135 ° C; XH RM? (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, l 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 diethyl 3,5-dichloro-4- [4 '-hydroxy-3' - (N-piperidinylsulfonamido) phenoxy] benzylphosphonate (0.1 g, 0.18 mmol) in CH 2 Cl (5 mL) at 0 ° C TMSBr (0.27 g, 0.3 mL, 1.8 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 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 provide 3,5-dichloro-4- [4'-hydroxy-3'- (N-) acid. piperidinyl sulfonamido) phenoxy)] benzylphosphonic acid as a white solid (0.07 g, 78%): mp 68-72 ° C; LC-MS m / z = 496 [Ci8H2oCl2N07PS + H] +; Calculated Analysis for (C 20 H 16 Cl 2 FO 5 P + O 5 CH 2 Cl 2): 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 '-hydroxy-3' - (N-exo-2-norbornylsulfonamido) phenoxy] benzyl benzoate was synthesized as a white solid (0.89 g, 55%) of the methyl- 3, 5-dichloro-4- (4'-hydroxy) phenoxybenzoate (1.3 g, 3.1 mmol) 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: The alcohol 3, 5-dichloro-4- [4 '-hydroxy-3' - (N-exo-2-norbornylsulfonamido) phenoxy] benzyl was prepared as a white solid (0.46 g, 85%) of 3, Methyl 5-dichloro-4- [4 '-hydroxy-3' - (N-exo-2-norbornylsulfonamido) phenoxy] benzoate (0.5 g, 0.97 mmol) 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. 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%) of the alcohol 3, 5-dichloro-4- [4 '-hydroxy-3'- (N-exo-2-norbornylsulfonamido) phenoxy] benzyl (0.1 g, 0.20 mmol) following the procedure described in example 9, stage 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%) of the bromide of 3, 5-dichloro-4- [4 '-hydroxy-3'- (N-exo-2-norbornylsulfonamido) phenoxy] benzyl (0.22 g, 0.40 mmol) following the procedure described in example 9, step g: XH RM? (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, l 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) following the procedure described in example 9, step h: mp 210 - 212 ° C; LC-MS m / z = 522 [C20H22Cl2NO7PS] +; Analysis Calculated 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 methyl 3,5-dichloro- (4'-hydroxyphenoxy) 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 TiCl 4 (7.6 mL, 7.6 mmol, 1 M solution in CH 2 Cl 2). The reaction mixture it was stirred at room temperature for 8 days, quenched with saturated aqueous NH4C1 (25 mL) and stirred for 2 h. The reaction mixture was extracted with CH2C1 (2x100 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 of methyl as a yellow solid. (0.39 g, 62%): mp 112-115 ° C; XH 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 mg, 0.78 mmol) and TFA (2 mL) in CH2C12 ( 50 mL) at room temperature was 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 4, filtered and concentrated under reduced pressure. The crude product was crushed 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, l H), 6.48 (d, J = 3.3, 9.0 Hz, 1 H), 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 LiAlH4 (0.26 g, 6.95 mmol) in THF (40 mL) at 0 ° C was slowly added 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 H0 (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'-methoxyphenoxy] benzyl alcohol 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 was added BBr3 (0.82 g, 3.2 mmol). The reaction mixture was stirred at room temperature for 16 h, draining in ice water (100 mL) and extracted with CH2C12 (200 mL). The organic layer was 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 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. he 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] benzylphosphonate diethyl ester as a colorless oil (0.2 g, 68%): XH 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 was added TMSBr (0.28 g, 0.3 mL). 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 CH30H (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 provide acid 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 [C 20 H 16 Cl 2 FO 5 P + H] +; Analysis Calculated for (C20H16Cl2FO5P + 0.8 CH2Cl2): 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- (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 CH3C? (5.0 mL) at 0 ° C was added pivaloyloxymethyl iodide (0.6 mL, 3.0 mmol). The reaction mixture was stirred at room temperature for 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%): XH RM? (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); LCMS m / z = 593 [C31H4509P + H] +; Analysis Calculated for (C3? H45O9P + 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 a manner analogous to that described for the synthesis of compound 12-1.
Compound 12-2: di (ethoxycarbonyloxymethyl) [3, 5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy] methylphosphonate: X H NMR (300 MHz, DMS0-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 [C27H30nP + H] +; Analysis 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: 1ti 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 (m, 1 H), 2.14 (s, 6 H), 1.21-1.16 (m, 12 H), 1.08-1.06 (d, J = 6.0 Hz, 6 H); LC-MS m / z = 597 [C 29 H 41 O 11 P + H] +; Analysis 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] methylf osf onate: 1ti NMR (300 MHz, DMSO-d6): d 8.95 (s, ÍH), 6.76, (s, ÍH), 6.72 (s, 2H), 6.64-6.61 (d, ÍH), 6.65-6.47 (d, ÍH) ), 5.73 (s, 2H), 5.68 (s, 2H), 4.48-4.45 (d, 2H), 3.81 (s, 2H), 2.93-2.90 (q, ÍH), 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; Analysis 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; X H NMR (300 MHz, DMSO-d 6): d 9.07 (s, ÍH), 7. 66 (s, ÍH), 6.68-6.66 (m, 2H), 6.26-6.22 (d, ÍH), 5.67-5.58 (q, 4H), 3.56-3.48 (d, 2H), 3.19-3.14 (m, ÍH) ), 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; Analysis 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 X H NMR (300 MHz, DMSO-d 6): d 9.17 (HH, s), 7.18-7.02 (m, 3H), 6.71-6.64 (m, 4H), 6.54 (m, HH), 4.45 (d, 2H, J = 10Hz), 3.76 (s, 4H), 2.12 (s, 6H), 1.13 (s, 18H); LC-MS m / z = 633 [C33H44? 9P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 50% ethyl acetate in hexane; Rf = 0.48; Analysis 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; X H NMR (300 MHz, DMSO-d 6): d 8.99 (s, ÍH), 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 (m, 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? Ol 2 P + H] +; CLAR conditions: Column = filter Agilent Zo SB-Aq RP-18, 150 x 3.0; Mobile phase = Solvent A (Acetonitrile) = acetonitrile grade CLAR; Solvent B (buffer) = ammonium phosphate buffer 20 mM (pH 6.1, 0.018 M NH4H2PO4 / 0.002 M (NH4) 2HP04). Flow ratio = 1.0 mL / min; UV @ 255 nm. Retention time in minutes, (tr = 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] methylphosphonate X H NMR (200 MHz, DMSO-dg): 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 [C 29 H 3 909 Cl 2 P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (3: 2); Rf = 0.62. Analysis 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-f-luoro-5- (4'-hydroxy-3'-iso-propylphenoxy) -pyr id-2-ylamino] methylphosphonate The title compound was prepared according to the procedure described by the synthesis of Example 12 using [4,6-dichloro-3-fluoro-5- (4'-hydroxy-3'-iso-propylphenoxy) -pyrid-2- ilamino] methylphosphonic (US 6747048 B2): XH NMR (200 MHz, DMSO-de): 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 (m, 2 H), 3.22 (m, 1 H), 1.07 - 1.17 (m, 24 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (3: 2); Rf = 0.51; LC-MS m / z = 654 [C27H36C12FN209P + H] +; Calculated Analysis for (C27H36C12FN209P + 0.2Et2OAc): C, 49.76; H, 5.65; N, 4.17. Found: C, 50.02; H, 6.02; N, 4.07.
Compound 12-10: [3, 5-Dibromo-4- (4'-hydroxy-3'-isopropylphenoxy) benzyl] methylphosphinite isopropyloxycarbonyloxymethyl mp: 58-61 ° C; X H NMR (200 MHz, DMSO-d 6): d 9.05 (s, ÍH), 7.65 (d, J = 2.4 Hz, 2H), 6.67 (m, 2H), 6.23 (dd, J = 2.8, 10.2 Hz, ), 5.56 (d, J = 11.0 Hz, 2H), 4.80 (m, ÍH), 3.36 (d, J = 10.2 Hz, 3H), 3.14 (m, ÍH), 1.48 (d, J = 10.2 Hz, 3H ), 1.25 (d, J = 6.8 Hz, 6H), 1.11 (d, J = 7.0 Hz, 6H); LC-MS m / z = 595 [C22H2 Br207P + H] +; Analysis Calculated for (C17H19 Br204P): C, 44.47; H, 4.58. Found: C, 44.19; H, 4.80.
Compound 12-11: Methyl ester of 2- [3,5-dimethyl-4- (3 '- (4'-fluorobenzyl) -4'-hydroxybenzyl) phenyl] ethylphosphonic isopropoxycarbonyloxymethyl ester X H NMR (300 MHz, DMSO-d 6): d 9.17 (s, ÍH), 6.88 - 7.22 (m, 4H), 6.88 (s, 2H), 6.71 (d, J = 2.1 Hz, ÍH), 6.65 (d , J = 8.1 Hz, ÍH), 6.55 (dd, J = 2.1, 8.1 Hz, ÍH), 5.55 (d, J = 12.9 Hz, 2H), 4.83 (m, ÍH), 3.79 (s, 2H), 3.76 (s, 2H), 3.63 (d, J = 11.1 Hz, 3H), 2.65 (, 2H), 2.12 (s, 6H), 2.05 (m, 2H), 1.22 (m, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (9: 1); Rf = 0.42; LC-MS m / z = 559 [C 30 H 36 FO 7 P + H] +; Analysis Calculated for (C30H36FO7P): C, 64.51; H, 6.50. Found: C, 64.54; H, 6.26.
Compound 12-12: Pivaloxymethyl methyl 3, 5-Dimethyl-4- (4 '-hydroxy-3' -isopropylbenzyl) benzylphosphonate X H NMR (300 MHz, CD 3 OD): d 7.03 (d, J = 2.1 Hz, 2 H), 6.83 (d, J = 2.1 Hz, H H), 6.54 (m, 2 H), 5.96 (m, 2 H), 3.96 ( s, 2H), 3.74 (d, J = 10.8 Hz, 3H), 3.25 (d, J = 21.0 Hz, 2H), 3.21 (m, ÍH), 2.25 (s, 6H), 1.25 (s, 9H), 1.13 ( d, J = 7.0 Hz, 6H); LC-MS m / z = 477 [C26H3706P + H] A Compound 12-13: [3,5-Dibromo-4- (4'-hydroxy-3'-iso-propylphenoxy) phenoxymethyl] methylphosphonate pivaloyloxymethyl X H NMR (300 MHz, DMSO-dg): d 9.04 (s, ÍH), 7.50 (s, 2H), 6. 66 (m, 2H), 6.30 (m, ÍH), 5.69 (d, J = 13.5 Hz, 2H), 4.51 (d, J = 7.5 Hz, 3H), 3.17 (m, ÍH), 1.68 (d, J = 15.0 Hz, 3H); 1.14 (m, 15H); LCMS m / z = 608 [C23H29 Br207P + H] A Compound 12 = 16: 1- (Pivaloyloxyethyl) [3, 5-dimethyl-4- (4 '-hydroxy-3'-iso-propylbenzyl) benzyl] methylphosphinate Step a: To a mixture of acetaldehyde (0.84 mL, 16.6 mmol) in zinc chloride (62 mg, 0.45 mmol) was added dropwise 2, 2-dimethyl-propionaldehyde (2.05 mL, 16.6 mmol). The mixture was then heated at 50 ° C for 16 h. The tone material Black was filtered through a plug of silica gel with dichloromethane to provide 1-chloro-ethyl ester of 2,2-dimethyl-propionic acid as an oil (2.4 g, 88%) after removal of dichloromethane under reduced pressure. 1 H NMR (300 MHz, CDC13): d 6.64-6.59 (m, ÍH), 1.82 (d, J = 6.7 Hz, 3H), 1.36 (s, 9H).
Step b: To a mixture of 1-chloro-ethyl ester of 2,2-dimethyl-propionic acid (2.4 g, 14.6 mmol) in acetonitrile (10 mL) was added sodium iodide (4.4 g, 30.0 mmol). The mixture was stirred in the absence of light for 16 h. The volatiles were removed under reduced mixture, taken up in hexanes (25 mL) and filtered through a plug of silica gel to provide 1-iodo-ethyl ester of 2,2-dimethyl-propionic acid as an oil (lg g). , 27%) after removal of hexanes under reduced pressure: 1 H NMR (300 MHz, CDC13): d 6.92-6.85 (m, HH), 2.21 (d, 3H), 1.36 (s, 9H).
Step c: The title compound was prepared from 3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) benzyl] methylphosphinic acid (example 72) in accordance with the procedure described by the synthesis of example 12, compound 12-1. XH NMR (300 MHz, CDC13): d 7.30- 6. 94 (m, 3H), 6.64-6.60 (m, ÍH), 6.53-6.50 (m, ÍH), 3.95 (s, 2H), 3.39-3.08 (m, 3H), 2.21 (s, 6H), 1.64- 1.20 (m, 21H), 1.13 (t, 6H); LC-MS m / z = 475.6 [C27H3905P + H] +; Analysis Calculated for (C27H39O5P + 0. H20): C, 68.33; H, 8.28. Found: C, 68.09; H, 8.29.
Example 12-16: Cis and Trans R-2- [(3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy) methyl] -4- (3-chlorophenyl) -2- oxo-2? 5- [1,3,2] -dioxaphosphonane c, The title compounds were prepared from α- (3-chlorophenyl) -1,3-propanediol and [3,5-dimethyl-4- (3'-di-propyl-4'-hydroxybenzyl) phenoxy] - methylphosphonic acid (compound 7) according to the procedure described in example 13-1.
Example 12-6-cis: PF 72-75 ° C; X H NMR (300 MHz, DMSO-d 6): d 9.00 (s, ÍH), 7. 51 (m, ÍH), 7.38-7.36 (m, 3H), 6.86 (d, J = 2.0 Hz, ÍH), 6. 77 (s, 2H), 6.68 (d, J = 8.0 Hz, ÍH), 6.43 (m, ÍH), 5.76- 5.71 (m, ÍH), 4.61-4.36 (m, 4H), 3.83 (s, 2H) , 3.15-3.05 (m, ÍH), 2.24-2.17 (m, 2H), 2.14 (s, 6H), 1.12 (d, J = 6.9 Hz, 6H); LC-MS m / z = 515 [C28H32C105P + H] +; Analysis Calculated for (C28H32C105P + 0.2 H20 + 0.2 CH3COCH3): C, 64.79; H, 6.39; Cl, 6.69. Found: C, 64.86; H, 6.48; Cl, 6.70; CCD conditions: Uniplaca of silica gel, 250 microns; mobile phase = 4: 1 ethyl acetate-hexanes; Rf = 0.19.
Example 12-16- trans: MP 81-83 ° C; X H NMR (300 MHz, DMSO-d 6): d 9.00 (s, ÍH), 7.50 (m, ÍH), 7.49-7.43 (m, 3H), 6.87 (d, J = 2.0 Hz, ÍH), 6.84 (s) , 2H), 6.63 (d, J = 11.0 Hz, HH), 6.47 (m, HH), 5.82 (m, HH), 4.80 (m, HH), 4.65 (d, J = 16.0 Hz, 2H), 3.83 (s, 2H), 3.14 (m, ÍH), 2.24-2.17 (m, 8H), 1.13 (d, J = 6.9 Hz, 6H); LC-MS m / z = 515 [C28H32C105P + H] +; Analysis Calculated for (C28H32C105P + 0.2 H20 + 0.2 CH3COCH3): C, 64.79; H, 6.39; Cl, 6.69. Found: C, 65.02; H, 6.46; Cl, 6.54; CCD conditions: Uniplaca of silica gel, 250 microns; mobile phase = 4: 1 ethyl acetate-hexanes; Rf = 0.44.
Example 12-19: Monomethyl ester of isopropyloxycarbonyloxymethyl [3, 5-dibromo-4- (4'-hydroxy-3'-isopropylphenoxy)] phenoxymethylphosphonate The title compound was prepared from monomethyl ester of [3,5-dibromo-4- (4'-hydroxy-3'-isopropylphenoxy)] phenoxymethylphosphonate (compound 69-6) in accordance with the procedures described by the synthesis of compound 12-3. H NMR (300 MHz, DMSO-d 6): d 9.04 (s, ÍH), 7.50 (s, 2H), 6.66 (m, 2H), 6.28 (m, ÍH), 5.69 (d, J = 12.0 Hz, 2H ), 4.84 (m, ÍH), 4.66 (d, J = 15.0 Hz, 2H), 3.80 (d, J = 20.0 Hz, 3H), 3.17 (m, ÍH), 1.24 (m, 7H), 1.14 (m , 7H); LCMS m / z = 627 [C22H27Br2? 9P + H] +; Analysis Calculated for (C22H27Br2? 9P + 0.3 CH3COCH3): C, 42.73; H, 4.51. Found: C, 43.09; H, 4.18; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate; Rf = 0.64.
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, cooling to room temperature and filtered through a stopper 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 CH 2 Cl 2 to provide Cís (0.06 g, 15%) and Trans (S) -2- [3, 5-Dimethyl-4- (4 '-hydroxy-3'-iso-propylbenzyl) phenoxy] methyl-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] +; Analysis 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.
The alternative improved method for the preparation of the compound: Compound 13-1-cis: Cis (S) -2- [(3,5-Dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy) methyl ] -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 is 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- [1,3,2] -dioxaphosphinan (1.9g, 83%):? H NMR (300 MHz , DMSO-d6): d 8.97 (s, ÍH), 7.47 (m, ÍH), 7.38-7.31 (m, 3H), 6.82 (d, J = 2.1 Hz, ÍH), 6.73 (s, 2H), 6.59 (d, J = 8.1 Hz, ÍH), 6.43 (dd, J = 8.1 and 2.0 Hz, ÍH), 5.76-5.71 (m, ÍH), 4.61-4.36 (m, 4H), 3.78 (s, 2H), 3.15-3.05 (m, ÍH), 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; Analysis 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] +; Analysis 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. : 88-93.0 ° C.
Using the appropriate starting material, compounds 13-2 through 13-14 were prepared in a manner analogous to that described for the synthesis of compound 13-1. Cis and 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] +; Analysis Calculated for (C2sH32Br05P): 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.
Compue s to 13 - 2 - trans: mp 80-85 ° C; LC-MS m / z = 559.561 [C28H32Br05P + H] +; Analysis 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 and 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] +; Analysis Calculated for (C2sH32F05P + 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] +; Analysis 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? - [1,3,2] -dioxaphosphonane: Compue to 13 - 4 - trans: mp 75-78 ° C: LCMS m / z = 482 [C27H32N05P + H] +; Analysis 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] +; Analysis 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? - [1,3,2] -dioxaphosphonane: Compue s to 13 - 5 - trans: (52%), mp 75-77 ° C; LC-MS m / z = 482 [C27H32N05P + H] A Analysis Calculated for (C27H32NO5P + 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-Me0H (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] -dioxaphosphonane: Compound 13-6- trans: mp 77-80 ° C; LC-MS m / z = 515 [C28H32C105P] +; Calculated Analysis: (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; LCMS m / z = 515 [C28H32C105P + H] A Calculated Analysis: (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-dichlorophenyl) -2-oxo-2? 5 - [1,3,2] -dioxaphosphonane: Compound 13-7- trans: mp 79-81 ° C; LC-MS m / z = 549 [C 27 H 32 Cl 2 O 5 P + H] +; Analysis Calculated for (C28H3? Cl2O5 +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? Cl2? 5P] +; Analysis Calculated for (C28H3? Cl2O5P + 0.1H20): 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; X H NMR (300 MHz, DMSO-d 6): d 8.91 (s, 1 H), 7.39-7.36 (m, 3H), 6.76 (s, ÍH), 6.75 (s, 2H), 6.60-5.57 (d, ÍH) ), 6.47-6.44 (d, ÍH), 5.75-5.71 (m, ÍH), 4.61-4.53 (m, 2H), 4.47-4.36 (m, 2H), 3.78 (s, 2H), 2.92-2.85 (q , ÍH), 2.25-2.20 (m, 2H), 2.14 (s, 6H), 1.51-1.36 (m, 2H), 1.05-1.03 (d, 3H), 0.74-0.70 (t, 3H); LC-MS m / z = 529.0 [C 29 H 34 C 10 5 P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (1: 1); Rf = 0.17; Analysis Calculated for (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-oxo2? 5- [1,3,2] dioxaphosphonan mp: 83-85 ° C; X H NMR (300 MHz, DMSO-d 6): d 9.06 (s, ÍH), 7.75 (s, 2H), 7.44-7.42 (m, 3H), 7.32-7.28 (m, ÍH), 6.68-6.65 (d, ÍH), 6.58 (s, ÍH), 6.31-6.27 (d, ÍH), 5.69-5.65 (d, ÍH), 4.59-4.51 (t, ÍH), 4.37-4.28 (t, ÍH), 3.61-3.53 ( d, 2H), 3.18-3.07 (m, HH), 2.29-2.17 (m, HH), 1.84-1.77 (m, HH), 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; Analysis 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? 5- [1,2] -dioxaphosphonane mp: 82-86 ° C; X H NMR (300 MHz, DMSO-d 6): X H NMR (300 MHz, DMSO-de): d 8.99 (s, 1 H), 7.62 (s, 1 H), 7.51 (m, 1 H), 7.44 (s, 2 H), 7.38 (m, 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, 1 H), 3.16 (m, 1 H) ), 2.26 (m, 1 H), 1.13 (d, J = 6.0 Hz, 6 H); LC-MS m / z = 741 [C 25 H 24 Cl 2? 6P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (4: 1); Rf = 0.17. Analysis Calculated for (C25H24CII2O6P + 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] -dioxaphosphonane X H NMR (300 MHz, DMS0-d 6): 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. Analysis Calculated for (C26H26C1305P + 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-propylphenoxy) -pyrid-2-ylaminomethyl] -4- (3-chlorophenyl) -2-oxo -2? 5- [1,3,2] -dioxaphosphonane To a stirred solution of [4,6-dichloro-3-fluoro-5- (4'-hydroxy-3'-iso-propylphenoxy) -pyrid-2- ilamino] methylphosphonic acid (0.2 g, 0.47 mmol, US 6747048 B2) and (S) -1- (3-chlorophenyl) -1,3-propanediol (0.18 g, 0.94 mmol) in DMF (6 mL) at room temperature was added pyridine (0.46 mL, 5.64 mmol) and EDCl (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 / 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 H NMR (300 MHz, DMSO-d < j): 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; LCMS m / z = 576 [C 24 H 23 Cl 3 FN 2? 5P + H] +; Analysis Calculated for (C 24 H 23 Cl 3 FN 2? 5 P + 0.2 CH 2 C 12 + 0.3 H 2 O): 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%): X H NMR (200 MHz, DMSO-de): 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 (d, J = 3.0, 9.0 Hz, 1 H), 5.65 (d, J = 10.4 Hz , 1 H), 4.21 - 4.61 (m, 2 H), 4.11 (m, 1 H), 3.80 (m, 1 H), 3.07 (m, 1 H), 2.11 (m, 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; LCMS m / z = 576 [C 24 H 23 Cl 3 FN 2? 5P + H] +; Analysis Calculated for (C24H23C13FN205P + 0.1CH2C12 + 0.4H2O): C, 48.94; H, 4.09; N, 4.74. Found: C, 48.57; H, 3.69; N, 4.92.
Step a: To a solution of diisopropyl amine (12.4 mL, 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 was added (16.1 mL, 163.2 mmol). After 1 h, 3-chlorobenzaldehyde was added and the reaction mixture allowed to warm to room temperature for 2 h. The reaction mixture was quenched with saturated 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 give ethyl 3- (3-chloro-phenyl) -3-hydroxypropionate as a yellow oil ( 10.0 g, 99.0%). X H NMR (400 MHz, d-DMSO): d 7.43-7.30 (m, 4H), 5.66 (d, ÍH), 5.01-4.95 (q, ÍH), 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. Og, 44.1 mmol) in THF (100 mL) and diethyl ether (100 mL) at -78 °. C was added methyl magnesium bromide (61.7 mL of a solution 3. OM in diethyl ether, 185.1 mmol). The reaction mixture was allowed to warm to room temperature and was stirred for 16 h. The reaction mixture was cooled to -50 ° C and quenched with saturated aqueous NH 4 Cl (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 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 give 1- (3-chloro-phenyl) -3-methyl-butane-1,3-diol as a yellow oil (5.65 g, 59.7%). X H NMR (400 MHz, d-DMSO): d 7.40-7.26 (m, 4H), 5.46 (d, ÍH), 4.90-4.85 (q, ÍH), 4.70 (s, ÍH), 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-1-6- (3-chlorophenyl) -2-oxo-2? 5- [1,3,2] -dioxaphosphonane X H NMR (400 MHz, d-DMSO): d 9.05 (s, 1 H), 7.59 (s, ÍH), 7.47-7.43 (m, 3H), 6.91 (s, ÍH), 6.81 (s, 2H), 6.68-6.65 (d, ÍH), 6.53-6.50 (d, ÍH), 5.92-5.87 (t, ÍH), 4.54-4.40 (m, 2H), 3.87 (s, 2H), 3.23-3.14 (q, ÍH) ), 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 [C3oH36C105P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (1: 1); Rf = 0.16; Analysis Calculated for (C30H36ClO5P + 1.0 CH3C02CH2CH3): C, 64.70; H, 7.03; Found: C, 64.50; H, 7.32.
Compound 13-13-fcrans: 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 LC-MS m / z = 544.8 [C 30 H 36 ClO 5 P + H] +; X H NMR (400 MHz, d-DMSO): d 9.00 (s, 1 H), 7.54 (s, ÍH), 7.49-7.44 (m, 3H), 6.86 (s, ÍH), 6.79 (s, 2H), 6.63-6.60 (d, ÍH), 6.46-6.43 (d, ÍH), 5.85-5.82 (t, ÍH), 4.46-4.43 (d, 2H), 3.82 (s, 2H), 3.16-3.11 (q, ÍH) ), 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 de silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (1: 1); Rf = 0.27; Analysis Calculated for (C30H36ClO5P + 1.4 CH3C02CH2CH3): C, 64.17; H, 7.14; Found: C, 64.06; H, 6.98.
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] -dioxaphosphonane (0.041 g, 14%) ^ H NMR (300 MHz, CD3OD): d 7.46 (s, ÍH), 7.28 (m, 3H), 7.11-6.91 (m, 4H), 6.63 (m, 5H), 5.72 ( d, HH, J = 11.4 Hz), 4.71 (m, HH), 4.51 (m, 3H), 3.84 (m, 4H), 2.44 (m, HH), 2.22 (m, HH), 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] +; Analysis 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, CD 3 OD): d 7.46 (s, ÍH), 7.28 (m, 3H), 7.11-6.91 (m, 4H), 6.63 (m, 5H), 5.86 (d, ÍH, J = 11.4 Hz ), 4.57 (m, 4H), 3.84 (m, 4H), 2.34 (m, HH), 2.25 (m, HH), 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 [C 32 H 4? ClF05P + H] +; Analysis Calculated for (C32H4? ClF05P +0.5 H20): C, 65.14; H, 5.47. Found: C, 65.24; H, 5.77.
Compound 13-15-c? S: Cis (S) -2- [(3, 5-Dimethyl-4- (5 '-iodo-4' hydroxy-3 '-isopropylbenzyl) phenoxy) methyl] -4- (3-chlorophenyl) -2-oxo-2? 5- [1,3,2] -dioxaphosphinan To a solution of cis (S) -2- [(3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy) methyl] -4- (3-chlorophenyl) -2-oxo -2? 5- [1,3,2] -dioxafosfinano (compound 13-1-cis, 0.20 g, 0.39 mmol) in CH2C12 (3.0 mL) at 0 ° C was added bis (pyridine) iodonium tetrafluoroborate (0.16) g, 0.43 mmol). The reaction mixture was stirred at 0 ° C for 1 h and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with 50% acetone in hexanes to give the title compound (0.20 g, 80%) as a yellow solid: mp: 73-76 ° C; XH NMR (300 MHz, CD3OD): d 7.50 (s, ÍH), 7.35 (m, 3H), 7.08 (d, J = 2.4 Hz, ÍH), 6.90 (d, J = 2.4 Hz, ÍH), 6.79 (s, 2H), 5.78 (m, ÍH), 4.53-4.80 (m, 2H), 4.54 (d, J = 11.2 Hz, ÍH), 3.94 (s, 2H), 3.28 2.45 (m, 2H), 2.24 (s, 6H), 1.17 (d, J = 7.0 Hz, 6H); LC-MS m / z = 641 [C28H3? ClI05P + H] +; Calculated Analysis for (C28H31C1I05P): C, 52. 48; H, 4.88. Found: C, 52.13; H, 4.52.
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), [3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy] methylphosphonic acid (0.10 g, 0.25 mmol) ), pyridine (1.0 mL) and dicyclohexylcarbodiimide (0.14 g, 0.69 mmol) in DMF (2.5 mL) was heated at 70 ° C for 16 h. The 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] +; Analysis 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- (i-1-ethoxycarbonylethylamino) [3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl)] phenoxy] methylphosphonamide To a stirred solution of [3, 5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl)] phenoxymethyl) phosphonic acid (1.3 g, 0.8 mmol) and DMF (0.1 mL, 0.08 mmol) in 1,2-dichloroethane (10 mL) at room temperature, oxalyl chloride (0.55 g, 2.8 mmol) was added. The reaction mixture it was heated at 50 ° C for 3 h, cooling 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 CHC12. The reaction mixture was stirred for 14 h at room temperature and concentrated under reduced pressure. The residue was partitioned between EtOAc (50 mL) and aqueous NaHCO3 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 m / z = 563 [C29H43N207P + H] A Analysis Calculated for: (C29H43N2? 7P + 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 a manner analogous to that described for the synthesis of compound 15-1.
Compound 15-2: di-N- (1-ethoxycarbonyl-1-methylethylamino) [3, 5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl)] phenoxy] methylphosphonamide LC-MS m / z = 591 [C 29 H 43 N 207 P + 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; 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 a manner analogous to that described by the synthesis of compound 15-1.
Compound 15-3: di-N- (l-ethoxycarbonyl-2-methyl-propylamino) [3, 5-dimethyl-4- (3 '-iso-propyl-4' -hydroxybenzyl) phenoxy] methylphosphonamide mp: 52-55 ° C; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (3: 1); Rf = 0.4; 1tt RM? (300 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 4.5 Hz, 1 H), 4.02-4.20 (m, 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 [C33H5? N207P + 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 H NMR (300 MHz, DMSO-d6): d 8.94 (s, ÍH), 6.77 (s, ÍH), 6.64-6.61 (m, 3H), 6.51-6.48 (d, ÍH), 4.87-4.75 (q, 2H), 4.09-3.99 (m, 4H), 3.81 (s, 2H), 2.95-2.88 (q, ÍH), 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 [C3oH45N207P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (1: 1); Rf = 0.58; Analysis Calculated for (C3oH45N207P + 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 RM? (300 MHz, DMSO-d6): d 9.08 (s, ÍH), 7.68 (s, 2H), 6. 69-6.66 (d, ÍH), 6.63 (s, ÍH), 6.31-6.28 (d, ÍH), 4.76-4.61 (q, 2H), 4.09-4.01 (m, 8H), 3.17-3.08 (q, ÍH) ), 1.27-1.10 (m, 18H); LC-MS m / z = 679.4 [C26H35Br2? 207P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = dichloromethane-ethyl acetate (1: 1); Rf = 0.34; Analysis Calculated for (C26H35Br2? 2? 7P + 0.6 CF3C02H): C, 43.92; H, 4.84; ?, 3.78. Found: C, 43.51; H, 4.78; ?, 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] +; Analysis 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' -isopropylbenzyl)] phenoxy] methylphosphonamide NMR (300 MHz, DMSO-d ^): 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 Cl 2 N 2? 7 P + H] +; Analysis Calculated for (C27H33Cl2N2? 7P + 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- (i-1-ethoxycarbonylethylamino) [3, 5-diiodo-4- (4 '-hydroxy-3' -isopropylphenoxy)] phenoxy] methylphosphonamide XH RM? (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 [C 26 H 15 I 2 N 2 O 8 P + H] +; Analysis Calculated for (C 26 H 35 I 2 N 2 O 8 P + 0.1 H 20): 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- (i-1-ethoxycarbonylethylamino) [3, 5-dimethyl-4- (3 '- (4-fluorobenzyl) -4' -hydroxybenzyl)] phenoxy] methylphosphonamide XH RM? (300 MHz, CD3OD): d 7.12 (m, 2H), 7.89 (m, 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, ÍH), 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; LCMS m / z = 629 [C33H42 F? 207P + H] +, Analysis Calculated for (C33H42F? 207P +1.1 H20): C, 61.12; H, 6.87,?, 4.32. Found: C, 60.85; H, 6.78,?, 4.72.
Compound 15-10: N- (1-1-ethoxycarbonylethylamino) [3, 5-dichloro-4- (3 '- (4-fluorobenzyl) -4'- hydroxybenzyl) phenoxymethyl] methylphosphinamide XH NMR (300 MHz, CD3OD): d 7.11 (m, 4H), 6.92 (t, 2H), J = 8.7 Hz), 6.76 (m, 2H), 6.63 (d, ÍH), J = 8 Hz), 4.26 (d, 2H), J = 7.8 Hz), 4.12 (m, 3H), 3.98 (m, 2H), 3.83 (s, 2H), 1.58 (m, 3H), 1.38 (m, 3H); CCD conditions: Uniplaca of silica gel, 250 microns; ethyl acetate-methanol [20: 1]; Rf = 0.2; LC-MS m / z 568 [C 27 H 29 Cl 2 NFO 5 P + H] +; Analysis Calculated for (C27H29Cl2FN05P): C, 56.27; H, 5.34; N, 2.40 Found: C, 56.17; H, 5.71; N, 2.62.
Compound 15-11: N- (-1-Ethoxycarbonylethylamino) [3,5-dibromo-4- (3 '- (4-fluorobenzyl) -4'-hydroxyphenoxy] methylphosphonamide methyl XH RM? (200 MHz, CD3OD): d 7.12 (s, 2H), 7.18 (m, 2H), 7.94 (t, J = 8 Hz, 2H), 6.70 (d, J = 8.8 Hz, ÍH), 4.33 (m, 2H), 4.08 (m, HH), 3.83 (s, 2H), 3.77 (m, 3H), 1.41 (m, 3H), 1.27 (m, 3H); CCD conditions: Uniplaca of silica gel, 250 microns; ethyl acetate; Rf = 0.30; CL-MS m / z 676 Compound 15-15: Di-N- (i-1-propylcarbonyl-l-methylethylamino) [3, 5-dimethyl-4 - (4'-hydroxy-3'-isopropylbenzyl) -benzyl] -phosphonamide The title compound was prepared from compound 7 according to the procedure described by the synthesis of compound 15-1, as a white foam: 1H RM? (300 MHz, DMSO-d6): d 9.00 (s, ÍH), 6.84 (s, ÍH), 6.69 (s, 2H), 6.62 (d, J = 7.8 Hz, ÍH), 6.47 (d, J = 7.8 Hz, ÍH), 4.58 (d, J = 11.1 Hz, 2H), 4.00 (m, 6H), 3.81 (s, 2H), 3.14 (m, ÍH), 2.18 (s, 6H), 1.62 (m, 4H ), 1.47 (d, J = 13.5 Hz, 12H), 1.11 (d, J = 6.9 Hz, 6H), 0.91 (m, 6H); LC-MS m / z = 619 [C3H55 207P + H] +; Analysis Calculated for (C35H55? 207P + 0.5 CH2C12): C, 60.85; H, 7.93; ?, 4.24. Found: C, 60.72; H, 7.83; ?, 4.16.
Compound 15-16: Di-N- (1-isopropylcarbonyl-1-methylethylamino) [3, 5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) -benzyl] -phosphonamide The title compound was prepared from compound 7 according to the procedure described by the synthesis of compound 15-1, as a white foam: XH NMR (300 MHz, DMSO-d6): d 9.00 (s, ÍH), 6.85 (s, ÍH), 6.69 (s, 2H), 6.62 (d, J = 8.1 Hz, ÍH), 6.47 (d, J = 8.1 Hz, ÍH), 4.89 (m, 2H), 4.54 (d, J = 10.8 Hz, 2H), 4.05 (d, J = 10.8 Hz, 2H), 3.81 (s, 2H), 3.11 (m, ÍH), 2.18 (s, 6H), 1.45 (d, J = 16.5 Hz, 12H ), 1.21 (m, 12H), 1.11 (d, J = 6.9 Hz, 6H); LC-MS m / z = 619 [C 35 H 55 N 207 P + H] +; Analysis Calculated for (C35H55N207P + 0.4H20): C, 63.32; H, 8.34; N, 4.48. Found: C, 63.36; H, 8.64; N, 4.44.
Compound 15-17: Di-N-. { 2-ethoxycarbonyl-methylamino} [4- (4'-hydroxy-3'-isopropylbenzyl) -2, 3, 5-trimethylphenoxymethyl] phosphonamide Step a: A solution consisting of [4- (4 '-hydroxy-3' -isopropylbenzyl) -2,3,5-trimethylphenoxymethyl] phosphonic acid (compound 61, 1.2 g, 3.1 mmol) and acetic anhydride (2 mL) in toluene (5 mL) was refluxed overnight. The volatiles were removed under vacuum and to the oily residue was added THF (3 mL) and H0 (1 mL). The mixture was stirred at t.a. for 5 hrs before concentrating under vacuum. Co-evaporation of the residue with toluene gave [4- (4'-acetoxy-3'-isopropylbenzyl) -2,3,5-trimethylphenoxymethyl] -phosphonic acid as an opaque white foam. XH NMR (300 MHz, DMSO-d6): d 7.11 (d, J = 2.1Hz, HH), 6.86 (d, J = 8.4Hz, HH), 6.79 (s, HH), 6.65 (dd, J = 8.4) Hz and 2.1 Hz, ÍH), 4.04 (d, J = 10.5 Hz, 2H), 3.96 (s, 2H), 2.96-2.87 (m, ÍH), 2.27 (s, 3H), 2.20 (s, 3H), 2.12 (s, 3H), 2.08 (s, 3H), 1.10 (d, J = 7.8 Hz, 6H); 31P NMR (DMSO-d6) d 15.32 (s); LC-MS m / z = 419 [C22H2906P-H] A Step b: A solution consisting of [4- (4'-acetoxy-3 '-isopropylbenzyl) -2,3,5-trimethylphenoxymethyl] phosphonic acid (216 mg, 0.51 mmol), oxalyl chloride (0.18 mL, 2.1 mmol ) and DMF (1 drop) in dichloroethane (15 mL) was heated at 50 ° C for 2 hrs. The reaction mixture was then concentrated under vacuum and the oil residue was dissolved in dichloromethane. After cooling to 0 ° C, ethyl glycine as a 5 M solution in dichloromethane (0.41 mL, 2.1 mmol) and Hunigs base (0.35 mmol, 2.1 mmol) were added. The resulting solution was allowed until reaching ta overnight. The reaction mixture was washed with a pH 7 phosphate buffer, dried over Na 2 SO 4 and concentrated under vacuum to provide a dark amber oil which was purified by preparative CCD (2 mm, SiO 2) using ethyl acetate / hexane. (9: 1) as eluent. The evaporation of the solvent gave. { i-ethoxycarbonyl-methylamino} - [4- (4'-Acetoxy-3'-isopropyl-benzyl) -2, 3, 5-trimethylphenoxymethyl] phosphonamide as an amber oil (174 mg, 57%): 1 H NMR (300 MHz, CDC13): d 7.01 (s, ÍH), 6.81 (d, J = 8.1 Hz, ÍH), 6.67 (d, J = 8.1 Hz, ÍH), 6.61 (s, ÍH), 4.27 (d, J = 9.6 Hz, 2H), 4.20 -4.08 (m, 4H), 3.99 (s, 2H), 3.96-3.74 (m, 4H), 3.00-2.91 (m, ÍH), 2.29 (s, 3H), 2.23 (s, 3H), 2.19 (s) , 3H), 2.12 (s, 3H), 1.28-1.22 (m, 6H), 1.16 (d, J = 6.6 Hz, 6H); 31P NMR (CDC13) d 22.63 (s); LC-MS m / z = 591 [C3oH43N? 8P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate; Rf = 0.47.
Stage c: A solution of. { i-Ethoxycarbonyl-methylamino} - [4- (4'-acetoxy-3'-isopropylbenzyl) -2, 3, 5-trimethylphenoxymethyl] phosphonamide (174 mg, 0.30 mmol) and anhydrous hydrazine (0.03 mL, 0.84 mmol) in t-BuOH (3 mL) it was heated at 30 ° C for 48 hrs. The mixture was concentrated under vacuum and the residue was dissolved in ethyl acetate. After washing with a solution of H20 / AcOH (5: 1), the organic portion was dried over Na2SO4 and concentrated in vacuo to give crude product which was purified by preparative CCD (2 mm, SiO2) using dichloromethane / methanol ( 20: 1) as eluent. Evaporation of the solvent gave the title compound as an amber oil (64 mg, 40%): X H NMR (300 MHz, DMSO-d 6): d 8.96 (s, ÍH), 6.85 (s, ÍH), 6.70 (s) , HH), 6.59 (d, J = 8.4 Hz, HH), 6.43 (d, J = 8.4 Hz, HH), 4.83 (t, J = 10.5 Hz, HH), 4.70 (t, J = 10.5 Hz, HH ), 4.08-3.90 (m, 8H), 3.83 (s, 2H), 3.17-3.08 (m, ÍH), 2.19 (s, 3H), 2.09 (s, 3H), 2.07 (s, 3H), 1.29 ( d, J = 6.9 Hz, 6H), 1.17-1.09 (m, 6H); 31P NMR (DMSO-d6) d 21.56 (s); LC-MS m / z = 549 [C28H4? N207P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = dichloromethane / methanol (10: 1); Rf = 0.42; Analysis Calculated for (C28H4? N207P + 0.2 H20): C, 60.90; H, 7.56; N, 5.07. Found: C, 60.95, H, 7.63; N, 5.21.
Compound 15-18: Di-N-. { I-1-ethoxycarbonyl-ethylamino} - [4- (4'-hydroxy-3'-isopropylbenzyl) -2, 3, 5-trimethylphenoxymethyl] phosphonamide The title compound was prepared from [4- (4'-acetoxy-3 '-isopropylbenzyl) -2 acid, 3,5-trimethylphenoxymethyl] phosphonic acid (compound 15-17, step b) according to the procedure described by the synthesis of compound 15-17, step c as an amber oil (51%): 1 H NMR (300 MHz, DMSO-d6): d 8.96 (s, ÍH), 6.85 (s, ÍH), 6.70 (s, ÍH), 6.59 (d, J = 8.4 Hz, ÍH), 6.43 (d, J = 8.4 Hz, ÍH) , 4.83 (t, J = 10.5 Hz, ÍH), 4.70 (t, J = 10.5 Hz, ÍH), 4.08-3.90 (m, 8H), 3.83 (s, 2H), 3.17-3.08 (m, ÍH), 2.19 (s, 3H), 2.09 (s, 3H), 2.07 (s, 3H), 1.29 (d, J = 6.9 Hz, 6H), 1.17-1.12 (m, 6H), 1.10 (d, J = 7.2 Hz , 6H); 31P NMR (DMSO-d6) d 19.33 (s); LC-MS m / z = 577 [C 30 H 45 N 2 O 7 P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = dichloromethane / methanol (10: 1); Rf = 0.47; Analysis Calculated for (C3oH45N2? 7P + 0.5 H20): C, 61.52; H, 7.92; N, 4.78. Found: C, 61.75, H, 8.02; N, 5.02.
Compound 15-19: Di-N-. { i-1-ethoxycarbonyl-l-methylethylamino} [4- (4 '-hydroxy-3' -isopropylbenzyl) -2, 3, 5-trimethylphenoxymethyl] phosphonamide Step b: The title compound was prepared from [4- (4'-acetoxy-3'-isopropylbenzyl) -2,3,5-trimethylphenoxymethyl] phosphonic acid (compound 15-17, step b) in accordance with procedure described by the synthesis of compound 15-17, step c as an amber oil (62%): 1 H NMR (300 MHz, DMSO-de): d 8.96 (s, ÍH), 6.85 (s, ÍH), 6.70 (s, ÍH), 6.59 (d, J = 8.4 Hz, ÍH), 6.43 (d, J = 8.4 Hz, ÍH), 4.56 (d, J = 10.8 Hz, 2H), 4.13-4.00 (m, 6H) , 3.83 (s, 2H), 3.17-3.08 (m, ÍH), 2.19 (s, 3H), 2.14 (s, 3H), 2.08 (s, 3H), 1.49 (s, 6H), 1.42 (s, 6H) ), 1.19 (t, J = 7.2 Hz, 6H), 1.10 (d, J = 6.9 Hz, 6H); 31P NMR (DMSO-dg) d 16.97 (s); LC-MS m / z = 606 [C 32 H 9 N 207 P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = dichloromethane / methanol (10: 1); Rf = 0.54; Analysis Calculated for (C32H49 2? 7P): C, 63.56; H, 8.17; N, 4.63. Found: C, 63.58, H, 7.97; N, 4.45.
Compound 15-20: Di-N- (I-l-ethoxycarbonyl-2-methyl-propylamino) [3, 5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy] methylphosphonamide The title compound was prepared from [3,5-dimethyl-4- (3'-iso-propyl-4 '-hydroxybenzyl) phenoxy] methylphosphonic acid (compound 7) according to the procedure described by the synthesis of the compound 15-1 as a white foam: 1 H NMR (300 MHz, DMSO-d 6): d 9.00 (s, ÍH), 6.82 (s, ÍH), 6.63 (s, 2H), 6.61 (d, J = 8.1 Hz, ÍH), 6.47 (d, J = 8.1 Hz, ÍH), 4.87 (m, 2H), 4.54 (m, ÍH), 4.12 (m, 3H), 3.82 (s, 2H), 3.68 (m, 2H), 3.14 (m, ÍH), 2.17 (s, 6H), 1.98 (m, 2H), 1.23 (d, J = 6.3 Hz, 6H), 1.12 (m, 12H), 0.89 (m, 12H); LC-MS m / z = 647 [C 35 H 55 N 2? 7P + H] +; Analysis Calculated for (C3H55N2? 7P + 0.3H2O): C, 64.46; H, 8.59; N, 4.30. Found: C, 64.29; H, 8.49; N, 4.13.
Compound 15-21: Di-N- (2-l-propyloxycarbonyl-2-methyl-propylamino) [3, 5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) phenoxy] methylphosphonamide The title compound was prepared from [3,5-dimethyl-4- (3'-iso-propyl-4 '-hydroxybenzyl) phenoxy] methylphosphonic acid (compound 7) in accordance with the procedure described by the synthesis of Compound 15-1 as a white foam: 1 H NMR (300 MHz, DMSOde): d 9.00 (s, ÍH), 6.83 (d, J = 2.1 Hz, ÍH), 6.61 (m, 3H), 6.47 (dd, J = 8.1, 2.1 Hz, 1H), 4.57 (t, J = 8.7 Hz, ÍH), 4.24 (t, J = 8.7 Hz, ÍH), 3.92 (m, 6H), 3.81 (s, 2H), 3.68 (m , 2H), 3.14 (m, ÍH), 2.17 (s, 6H), 1.98 (m, 2H), 1.57 (m, 4H), 1.11 (d, J = 6.9 Hz, 6H), 0.89 (m, 18H); LC-MS m / z = 647 [C 35 H 55 N 207 P + H] +; Analysis Calculated for (C35H55N2? 7P): C, 64.99; H, 8.57; N, 4.33. Found: C, 64.60; H, 8.78; N, 4.39.
Compound 15-22: Acetic acid salt of di-N- (2-1-ethoxycarbonyl-1- (5-pentylamino)) [3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl ) phenoxy] methylphosphonamide The title compound was prepared from [3,5-dimethyl-4- (3'-iso-propyl-4 '-hydroxybenzyl) phenoxy] methylphosphonic acid (compound 7) in accordance with the procedure described by the synthesis of the compound 15-1 as a white foam: 1H RM? (300 MHz, DMSO-d6): d 6.83 (d, J = 2.1 Hz, ÍH), 6.61 (m, 3H), 6.47 (dd, J = 8. 1, 2.1 Hz, HH), 4.77 (t, J = 8.7 Hz, ÍH), 4.61 (t, J = 8.7 Hz, HH), 4.02 (m, 6H), 3.81 (s, 4H), 3.14 (m, ÍH), 2.58 (m, 4H), 2.17 (s, 6H), 1.83 (s, 6H), 1.61 (m, 4H), 1.38 (m, 8H), 1.11 (m, 12H); LC-MS m / z = 677 [C 35 H 57 N 4? 7 P + H] +; Analysis Calculated for (C35H57N4? 7P + 2AcOH + 0.2EtOH + 1.5H20): C, 56.80; H, 8.37; N, 6.72. Found: C, 56.51; H, 8.07; N, 7.04.
Compound 15-23: Di-N- (ethoxycarbonyl-methylamino) [3, 5-dimethyl-4- (3 '- (4-fluorobenzyl) -4'-hydroxybenzyl) phenoxy] methylphosphonamide The title compound was prepared from [3,5-dimethyl-4- (3 '- (4-fluorobenzyl) -4'-hydroxybenzyl) phenoxy] methylphosphonic acid (compound 40) in accordance with the procedure described by the synthesis of compound 15-17 as a white foam: XH RM? (300 MHz, DMSO-d6): d 9.17 (s, ÍH), 7.11 (m, 4H), 6.64 (m, 5H), 4.77 (m, 2H), 4.06 (m, 6H), 3.77 (s, 4H ), 3.66 (s, 4H), 2.14 (s, 6H), 1.17 (t, J = 6.9 Hz, 6H); LC-MS m / z = 601 [C31H38F? 207P + H] +; Analysis Calculated for (C3? H38F? 207P + 0.3H2O): C, 61.44; H, 6.42; N, 4.62. Found: C, 61.14; H, 6.10; N, 4.48. Compound 15-24: Di-N- (2-1-ethoxycarbonyl-ethylamino) [3, 5-dimethyl-4- (3 '- (4-fluorobenzyl) -4' -hydroxybenzyl) phenoxy] methylphosphonamide The title compound was prepared from [3,5-dimethyl-4- (3 '- (4-fluorobenzyl) -4'-hydroxybenzyl) phenoxy] methylphosphonic acid (compound 40) in accordance with the procedure described by the synthesis of compound 15-17 as a white foam: 1H RM? (300 MHz, DMSO-de): d 9.17 (s, ÍH), 7.11 (m, 4H), 6.64 (m, 5H), 4.77 (m, 2H), 4.06 (m, 8H), 3.77 (s, 4H ), 2.14 (s, 6H), 1.26 (d, J = 6.9 Hz, 6H), 1.14 (m, 6H); LC-MS m / z = 629 [C33H42F? 207P + H] +; Analysis Calculated for (C33H42F? 207P): C, 63.05; H, 6.73; ?, 4.46. Found: C, 62.77; H, 6.50; ?, 4.26.
Compound 15-25: Di-N- (i-1-ethoxycarbonyl-l-methyl-ethylamino) [3, 5-dimethyl-4- (3 '(4-flurobenzyl) -4'-hydroxybenzyl) phenoxy] methyl-phosphonamide The title compound was prepared from [3,5-dimethyl-4- (3 '- (4-fluorobenzyl) -4'-hydroxybenzyl) phenoxy] methylphosphonic acid (compound 40) in accordance with the procedure described by the synthesis of compound 15-17 as a white foam:? NMR (300 MHz, DMSO-de): d 9.17 (s, ÍH), 7.11 (m, 4H), 6.64 (m, 5H), 4.57 (d, J = 7.2 Hz, 2H), 4.06 (m, 6H) , 3.74 (s, 4H), 2.11 (s, 6H), 1.44 (s, 6H), 1.40 (s, 6H), 1.16 (d, J = 6.9 Hz, 6H); LCMS m / z = 657 [C35H46FN2? 7P + H] +; Analysis Calculated for (C35H46FN207P + TFA 0.5): C, 60.58; H, 6.57; N, 3.92. Found: C, 60.28; H, 6.24; N, 3.68.
Compound 15-26: Di-N- (i-1-ethoxycarbonyl-l-ethylamino) -4,6-dimethyl-5- (4'-hydroxy-3'-isopropylbenzyl) benzofuran-2-phosphonamide The title compound was prepared from 4,6-dimethyl-5- (4'-hydroxy-3'-isopropylbenzyl) benzofuran-2-phosphonic acid (Example 45) in accordance with the procedure described by the synthesis of Example 15 -1. MP: 66-69 ° C; 1 H NMR (300 MHz, CD 3 OD): d 7.52 (d, J = 2.1 Hz, ÍH), 7.28 (s, HH), 6.84 (d, J = 2.1 Hz, HH), 6.56 (m, 2H), 4.08 ( m, 8H), 3.20 (m, ÍH), 2.46 (s, 3H), 2.37 (s, 3H), 1.42 (m, 6H), 1.24 (t, J = 6.9 Hz, 3H), 1.15 (m, 9H ); LC-MS m / z = 573 [C 30 H 4? N 2 O 7 P + H] +; Analysis Calculated for (C3oH41N207P): C, 62.92; H, 7.22; N, 4.89. Found: C, 62.98; H, 7.26; N, 4.71.
Compound 15-27: Di-N- (ethoxycarbonyl-methylamino) -4,6-dimethyl-5- (4'-hydroxy-3'-isopropylbenzyl) benzofuran-2-phosphonamide The title compound was prepared from 4,6-dimethyl-5- (4'-hydroxy-3'-isopropylbenzyl) benzofuran-2-phosphonic acid (Example 45) in accordance with the procedure described by the synthesis of Example 15 -1. PF: 58-61 ° C; l RM? (300 MHz, CD3OD): d 7.56 (d, J = 2.1 Hz, 1H), 7.28 (s, 1H), 6.84 (d, J = 2.1 Hz, ÍH), 6.56 (m, 2H), 4.17 (q, J = 6.9 Hz, 4H), 4.08 (s, 2H), 3.83 (m, 4H), 3.22 (m, ÍH), 2.47 (s, 3H), 2.37 (s, 3H), 1.24 (m, 6H), 1.14 (d, J = 7.1 Hz, 6H); LC-MS m / z = 545 [C28H37N2? 7P + H] +; Analysis Calculated for (C28H37N207P): C, 61.76; H, 6.85; N, 5.14. Found: C, 61.47; H, 6.88; N, 5.01.
Compound 15-28: Di-N- (2-1-ethoxycarbonyl-1-methyl-1-ethylamino) -4,6-dimethyl-5- (4'-hydroxy-3'-isopropylbenzyl) ben zofuran-2-phosphonamide The title compound was prepared from 4,6-dimethyl-5- (4'-hydroxy-3'-isopropylbenzyl) benzofuran-2-phosphonic acid (Example 45) in accordance with the procedure described by the synthesis of Example 15 -1. PF: 50-53 ° C; XH RM? (300 MHz, CD3OD): d 7.45 (d, J = 2.1 Hz, ÍH), 7.30 (s, ÍH), 6.84 (d, J = 2.1 Hz, ÍH), 6.56 (m, 2H), 4.17 (q, J = 6.9 Hz, 4H), 4.10 (s, 2H), 3.22 (m, ÍH), 2.47 (s, 3H), 2.37 (s, 3H), 1.60 (s, 6H), 1.49 (s, 6H), 1.24 (t, J = 6.9 Hz, 6H), 1.14 (d, J = 7.1 Hz, 6H); LC-MS m / z = 601 [C32H45? 207P + H] +; Analysis Calculated for (C32H45? 207P + 0.7 H20): C, 62.67; H, 7.63; ?, 4.57. Found: C, 62.40; H, 7.90; ?, 4.79.
Example 15-29: Di-N- (1-1-isopropoxycarbonylethylamino) [3, 5-dimethyl-4- (4'-hydroxy-3'-iso- propylbenzyl) phenoxy] methylphosphonamide The title compound was prepared from [3,5-dimethyl-4- (3'-iso-propyl-4 '-hydroxybenzyl) phenoxy] methylphosphonic acid (compound 7) according to the procedure described by the synthesis of the compound 15-1 as a white foam, mp 55-58 ° C; 1 H NMR (300 MHz, DMSO-ds): d 8.99 (s, ÍH), 6.84 (s, ÍH), 6.63 (m, 3H), 6.48 (m, ÍH), 4.87-4.71 (m, 4H), 4.06 (d, J = 15.0 Hz, 2H), 3.88 (m, 2H), 3.81 (s, 2H), 3.20 (m, 1H), 2.17 (s, 6H), 1.30 (m, 6H), 1.20-1.09 ( m, 18H); LC-MS m / z = 591 [C3? H47N207P + H] +; Analysis Calculated for (C3? H47N207P + 0.4 H20): C, 62.27; H, 8.06; N, 4.69. Found: C, 62.24; H, 7.99; N, 4.76; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (2: 5); Rf = 0.33.
Example 15-30: Di-N- (i-l-ethoxycarbonyl-2-phenylethylamino) - [3,5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) phenoxy] methylphosphonamide The title compound was prepared from [3,5-dimethyl-4- (3'-iso-propyl-4 '-hydroxybenzyl) phenoxy] methylphosphonic acid (compound 7) according to the procedure described by the synthesis of the compound 15-1 as a white foam, mp 60-63 ° C; 1 H NMR (300 MHz, DMS0-d 6): d 9.00 (s, ÍH), 7.30-7.15 (m, 10H), 6.84 (s, ÍH), 6.64 (m, ÍH), 6.50 (m, 3H), 4.75 (m, ÍH), 4.38 (m, ÍH), 4.00 (m, 6H), 3.95 (s, 2H), 3.65 (d, J = 15.0 Hz, 2H), 3.20 (m, ÍH), 2.95 (m, 5H), 2.15 (s, 6H), 1.12 (m, 12H); LC-MS m / z = 715 [C4? H5? N20P + H] +; Analysis Calculated for (C4? H5? N207P + 0.4 H20): C, 68.20; H, 7.23; N, 3.88. Found: C, 68.16; H, 7.26; N, 3.86; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (2: 5); Rf = 0.35.
Example 15-31: Di-N- (1-1-propyloxycarbonyl-ethylamino) [3, 5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy] methylphosphonamide The title compound was prepared from [3,5-dimethyl-4- (3 '-isopropyl-4'-hydroxybenzyl) phenoxy] methylphosphonic acid (compound 7) in accordance with the procedure described by the synthesis of the compound 15-1 as a white foam. 1 NMR (300 MHz, DMSO-d6): d 8.99 (s, ÍH), 6.83 (s, ÍH), 6.63 (m, 3H), 6.48 (m, ÍH), 4.83-4.75 (m, 2H), 4.08 (d, J = 15.0 Hz, 2H), 3.99-3.94 (m, 6H), 3.81 (s, 2H), 3.18 (m, HI), 2.17 (s, 6H), 1.55 (m, 4H), 1.29 ( d, J = 6.0 Hz, 2H), 1.11 (d, J = 7.0 Hz, 2H), 0.88 (m, 6H); LC-MS m / z = 591 [C3? H47N207P + H] +; Analysis Calculated for (C31H47N207P + 0.3 H20): C, 62.46; H, 8.05; N, 4.70. Found: C, 62.44; H, 7.95; N, 4.73; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (2: 5); Rf = 0.13.
Example 15-32: Di-N- (ethoxycarbonylmethylamino) [3, 5-dibromo-4- (4'-hydroxy-3'-iso-propylphenoxy) phenoxy] methylphosphonamide The title compound was prepared from acid [3,5-dibromo-4- (4'-hydroxy-3'-isopropylphenoxy)] phenoxymethylphosphonic acid (compound 8-1) according to the procedures described by the synthesis of compound 15-17. mp 63-66 ° C; X H NMR (300 MHz, CD3OD): d 7. 35 (s, 2H), 6.61 (m, 2H), 6.33 (m, ÍH), 4.36 (d, J = 15.0 Hz, 2H), 415 (m, 4H), 3.80 (m, 4H), 3.20 (m, ÍH), 2.17 (s, 6H), 1.28 (m, 6H), 1.15 (d, J = 7.0 Hz, 2H); LC-MS m / z = 667 [C24H3? Br2N208P + H] +; Analysis Calculated for (C24H3? Br2N208P + 0.1 CH3COCH3): C, 43.43; H, 4.74; N, 4.17. Found: C, 44. 05; H, 4.47; N, 4.02; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = methanol-dichloromethane (1:24); Rf = 0.22.
Example 15-33: Di-N- (i-1-ethoxycarbonyl-ethylamino) [3, 5-dibromo-4- (4'-hydroxy-3'-iso-propylphenoxy) phenoxy] methylphosphonamide The title compound was prepared from [3,5-dibromo-4- ('-hydroxy-3' -isopropylphenoxy)] phenoxymethylphosphonic acid (compound 8-1) in accordance with the procedures described by the synthesis of compound 15-17. mp 62-65 ° C; lH NMR (300 MHz, CD3OD): d 7.35 (s, 2H), 6.61 (m, 2H), 6.33 (m, ÍH), 4.36 (d, J = 15.0 Hz, 2H), 4.15 (m, 4H), 3.80 (m, 4H), 3.20 (m, ÍH), 2.17 (s, 6H), 1.28 (m, 6H), 1.15 (d, J = 7.0 Hz, 2H); LCMS m / z = 695 [C24H3? Br2N2? 8P + H] +; Analysis Calculated for (C24H3? Br2N208P): C, 44.98; H, 5.08; N, 4.03. Found: C, 45.16; H, 5.07; N, 4.04; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = methanol-dichloromethane (1:24); Rf = 0.26.
Example 15-34: Di-N- (1-1-ethoxycarbonyl-1-methyl-ethylamino) [3, 5-dibromo-4- (4'-hydroxy-3'-isopropylphenoxy) phenoxy] methyl-p-osphonamide The title compound was prepared from [3,5-dibromo-4- (4'-hydroxy-3'-isopropylphenoxy)] phenoxymethylphosphonic acid (compound 8-1) in accordance with the procedures described by the synthesis of compound 15 -1. MP 62-65 ° C; XH RM? (300 MHz, CD3OD): d 7.41 (s, 2H), 6.63 (m, 2H), 6.36 (m, ÍH), 4.31 (d, J = 15.0 Hz, 2H), 4.15 (m, 5H), 3.20 ( m, HH), 1.61 (d, J = 25.0 Hz, 12H), 1.29 (m, 9H), 1.15 (d, J = 7.5 Hz, 6H); LC-MS m / z = 723 [C28H39Br2N208P + H] +; Analysis Calculated for (C28H39Br2N208P): C, 46.55; H, 5.44; N, 3.88. Found: C, 46.71; H, 5.42; N, 3.90; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = methanol-dichloromethane (1:24); Rf = 0.41.
Compound 15-35: Di-N- (ethoxycarbonyl-methylamino) [3, 5-dimethyl-4- (4 '-hydroxy-3'-isopropylbenzyl) phenoxymethyl] phosphonamide To a stirred solution of [3,5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl)] - phenoxymethylphosphonic acid (Example 7) (0.41 g, 1.11 mmol) and DMF (0.1 mL, 1.11 mmol) in dichloromethane (5.6 mL) at 0 ° C was added oxalyl chloride (0.38 mL, 4.4 mmol). The reaction mixture was heated at 50 ° C for 3 h, cooling to room temperature and concentrated under reduced pressure. To the residue at -78 ° C was added a solution of glycine ethyl ester chlorhydrate (0.65 g, 4.44 mmol) and triethylamine (1.25 L, 8.88 mmol) in dichloromethane (5.3 mL). The reaction mixture was stirred for 14 h at room temperature, filtered to remove the salts, and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (50 mL) and solution? AHC03 aqueous (100 mL). The organic layer was separated, 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 CH2Cl2 ~ MeOH (95: 5) to give the title compound as an opaque white foam (41.3 mg, 20.2%). 1H NMR (300 MHz, DMSO-de): d 8.97 (s, ÍH), 6.81 (s, ÍH), 6.63 (s, 2H), 6.57 (d, J = 8.4 Hz, ÍH), 6.43 (d, J = 7.8 Hz, ÍH), 4.76 (m, 2H), 4.07 (m, 2H), 4.00 (d, J = 6.6 Hz, 2H), 3.78 (s, ÍH), 3.66 (m, 4H), 3.08 (m, ÍH), 2.15 (s, 6H), 1.16 (t, 6H), 1.07 (d, J = 6.6 Hz, 6H); LC-MS m / z = 535.3 [C27H39N2? 7P + H] +; Analysis Calculated for (C27H39N207P): C, 60.66; H, 7.35; N, 5.24. Found: C, 60.51; H, 7.12; N, 4.93.
Compound 15-36: Di-N- (isopropyloxycarbonyl-methylamino) [3, 5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) phenoxymethyl] phosphonamide The title compound was prepared from [3,5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl]] - phenoxymethylphosphonic acid (Example 7) and glycine hydrochloride iso-propylester in accordance with the described procedure by the synthesis of compound 15-35. X H NMR (300 MHz, DMSOde): d 8.97 (s, ÍH), 6.81 (s, ÍH), 6.63 (s, 2H), 6.57 (d, J = 8.4 Hz, ÍH), 6.43 (d, J = 7.8 Hz, ÍH), 4.86 (m, 2H), 4.72 (m, 2H), 4.10 (d, J = 9.3 Hz, 2H), 3.78 (s, 2H), 3.61 (m, 4H), 3.12 (m, ÍH ), 2.14 (s, 6H), 1.14 (d, J = 6.0 Hz, 12H), 1.08 (d, J = 6.6 Hz, 6H); LC-MS m / z = 563.3 [C29H43N2? 7P + H] +; Analysis Calculated for (C29H43N207P): C, 61.91; H, 7.70; N, 4.98. Found: C, 61.81; H, 7.69; N, 5.11.
Compound 15-39: Di-N- (propyloxycarbonyl-methylamino) [3,5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) phenoxymethyl] phosphonamide The title compound was prepared from [3,5-dimethy1-4- (4'-hydroxy-3'-isopropylbenzyl)] - phenoxymethylphosphonic acid (example 7) and glycine hydrochloride n-propylester according to the procedure described for the synthesis of compound 15-35: XH RM? (300 MHz, DMSO-d6): d 8.96 (s, ÍH), 6.81 (s, ÍH), 6.62 (s, 2H), 6.57 (d, J = 8.4 Hz, ÍH), 6.43 (d, J = 10.2 Hz, ÍH), 4.78 (m, 2H), 4.08 (d, J = 9.0 Hz, 2H), 3.94 (t, 4H), 3.78 (s, 2H), 3.65 (m, 4H), 3.10 (m, ÍH) ), 2.14 (s, 6H), 1.56 (m, 4H), 1.08 (d, J = 6.6 Hz, 6H), 0.87 (t, 6H); LC-MS m / z = 563.6 [C 29 H 43 N 207 P + H] +; Analysis Calculated for (C29H43N 07P + 0.1 eq C3H60): C, 61.91; H, 7.73; N, 4.93. Found: C, 61.87; H, 8.12; N, 4.77.
Compound 15-40: Acetic acid salt of di-N- (1-1-propyloxycarbonyl-1- (5-pentylamino)) [3,5-dimethyl-4- (4'-hydroxy-3'-iso-propyl -benzyl) phenoxy] methylphosphonamide To a stirred suspension of 3,5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) phenoxymethyl) phosphonic acid (compound 7, 0.25 g, 0.68 mmol) in 1,2-dichloroethane (10 mL) at rt were added oxalylchloride (0.34 g, 2.7 mmol) and DMF (0.1 mL, 0.68 mmol). The reaction mixture was heated at 50 ° C for 3 h, and cooled to rt. The reaction mixture was concentrated under reduced pressure and azeotroped with toluene (2x10 mL). The crude compound was treated with lysine propilester (free base form) (0.1.0 g, 2.72 mmol) and N, N-diisopropylethylamine (0.8 mL, 2.72 mmol) in CH2Cl2 at 0 ° C. The reaction mixture was stirred for 14 h at rt and the reaction mixture was concentrated under reduced pressure. The residue is It was partitioned between EtOAc (50 mL) and aqueous NaHCO3 solution (50 mL). The organic layer was separated, washed with brine, dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel, eluting with ethyl acetate: hexanes (3: 2), treated with acetic acid and filtered to give the title compound as a white solid (78 mg, 92%). %, PF: 65-68 ° C, 98% pure). ? ti NMR (300 MHz, CDC13): d 6.81 (s, ÍH), 6.69 (s, 2H), 6.61-6.55 (m, 2H), 4.25 (dd, J = 2.0, 6.4 Hz, 4H), 4.18- 4.0 (m, 6H), 3.92 (s, 2H), 3.31-3.20 (m, ÍH), 2.91 (q, J = 5.7 Hz, 4H), 2.24 (s, 2H), 1.93 (s, 3H), 1.80 -1.50 (m, 14H), 1.14 (d, J = 6.6 Hz, 6H), 0.99 (t, J = 7.5 Hz, 3H), 0.91 (t, J = 7.5 Hz, 3H); LC-MS m / z = 705 [C37H6? N407P + H] +; CLAR conditions: column YMC packODS-Aql2S051546W; mobile phase = CH30H: TFA 5% (7: 3) flow ratio = 1.0 mL / min; detection = UV 220, 254, 280 nm retention time in min: 13.20; Anal. Calculated: (MF: C37H5? N407P + 2.0 AcOH + 1.5 H20) Calculated: C: 57.80, H: 8.52, N: 6.58; Found: C: 57.53, H: 8.67, N: 6.25.
Compound 15-41: Acetic acid salt of di-N- (1-1-isopropyloxycarbonyl-1- (5-pentylamino)) [3,5-dimethyl-4- (4'-hydroxy-3'-iso-propyl -benzyl) phenoxymethylphosphonamide The title compound was prepared from 3,5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) phenoxymethyl) phosphonic acid (compound 7) in accordance with the procedure described by the synthesis of compound 15-40 as a white solid: (100 mg, 95%, PF: 62-64 ° C, 98% pure). X H NMR (300 MHz, CDC13): d 6.82 (s, ÍH), 6.70 (s, 2H), 6.62-6.56 (m, 2H), 4.25 (m, 2H), 4.05-4.0 (m, 2H), 3.92 (s, 2H), 3.30-3.20 (m, ÍH), 2.98-2.38 (m, 4H), 2.24 (s, 2H), 2.02-1.40 (m, 16H), 1.30 (d, J = 6.6 Hz, 6H ), 1.22 (d, J = 6.9 Hz, 6H), 1.14 (d, J = 6.9 Hz, 6H); LC-MS m / z = 705 [C37H61N07P + H] +; CLAR conditions: column YMCpackSB- Aql2S051546W; mobile phase = CH30H: TFA 5% (7: 3) flow ratio = 1.0 mL / min; detection = UV 220, 254, 280 nm retention time in min: 5.79; Anal. Calculated: (MF: C37H6? N407P + 2.0 AcOH + 2.1 H20) Calculated: C: 57.07, H: 8.55, N: 6.49; Found: C: 56.79, H: 8.52, N: 6.31. Compound 15-42: Di-N- (1-ethoxycarbonyl-l-methylethylamino) [3,5-dichloro-4- (4'-hydroxy-3'-isopropylbenzyl) -phenoxymethyl] phosphonamide The title compound was prepared from [3,5-dichloro-4- (4'-hydroxy-3'-isopropylbenzyl) -phenoxymethyl] -phosphonic acid (Example 7-5) in accordance with the procedure described by the synthesis of example 15-1. mp 43-45 ° C; X H NMR (300 MHz, DMSO-d 6): d 9.10 (s, ÍH), 7.18 (s, 2H), 6.98 (s, ÍH), 6.67 (m, 2H), 4.46 (d, J = 10.8 Hz, 2H ), 4.06-4.63 (m, 9H), 3.14 (m, ÍH), 1.43 (d, J = 11.4 Hz, 12H), 1.22 (t, 6H), 1.10 (d, J = 6.6 Hz, 6H); LC-MS m / z = 632 [C29H4? Cl2N207P + H] +; Analysis Calculated for (C29H4? Cl2N207P + 0.1 TFA): C, 54.55; H, 6.44; N, 4.36. Found: C, 54.44; H, 6.74; N, 4.48.
Compound 15-43: Di-N- (-l-l-propyloxycarbonyl-2-phenylethylamino) [3, 5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy] methylphosphonamide The title compound was prepared from acid 3,5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) phenoxymethyl) phosphonic acid (compound 7) according to the procedure described by the synthesis of compound 15-1 to provide a white foam. 1 H NMR (300 MHz, DMSO-de): d 8.99 (s, ÍH), 7.30-7.13 (m, 10H), 6.83 (s, ÍH), 6.62-6.45 (m, 3H), 4.73 (t, J = 11.7 Hz, ÍH), 4.36 (t, J = 11.7 Hz, ÍH), 4.06-3.80 (m, 6H), 3.80 (s, 2H), 3.63 (d, J = 9.3 Hz, 2H), 3.17-3.08 ( m, ÍH), 2.95-2.75 (m, 4H), 2.17 (s, 6H), 1.55-1.42 (m, 4H), 1.09 (d, J = 6.9 Hz, 6H), 0.85-0.74 (m, 6H); 31P NMR (DMSO-de) d 18.87 (s); LC-MS m / z = 743 [C43H55N207P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate / dichloromethane (2: 1); Rf = 0.58; Analysis Calculated for (C43H55N207P + 0.3 H20): C, 69.02; H, 7.49; N, 3.74. Found: C, 69.01, H, 7.60; N, 3.65.
Compound 15-44: Di-N- (-I-l-isopropyloxycarbonyl-2-phenylethylamino) - [3,5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) phenoxy] -methylphosphonamide The title compound was prepared from acid 3,5-dimethyl-4- (4 '-hydroxy-3'-isopropylbenzyl) phenoxymethyl) phosphonic acid (compound 7) according to the procedure described by the synthesis of compound 15-1 to provide a white foam. X H NMR (300 MHz, DMSO-de): d 8.99 (s, ÍH), 7.30-7.13 (m, 10H), 6.83 (s, ÍH), 6.62-6.45 (m, 3H), 4.85-4.73 (m, 2H), 4.66 (t, J = 11.4 Hz, ÍH), 4.34 (t, J = 11.4 Hz, ÍH), 4.06-3.88 (m, 2H), 3.80 (s, 2H), 3.65 (d, J = 9.6 Hz, 2H), 3.17-3.08 (m, ÍH), 2.95-2.75 (m, 4H), 2.17 (s, 6H), 1.17-1.00 (m, 18H); 31P NMR (DMSO-de) d 18.89 (s); LC-MS m / z = 743 [C43H55N2? 7P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate / dichloromethane (2: 1); Rf = 0.56; Analysis Calculated for (C43H55N2? 7P): C, 69.56; H, 7.46; N, 3.77. Found: C, 69.30, H, 7.59; N, 3.72.
Example 16 Compound 16: 3,5-dichloro-4- (4'-hydroxy-3'-iso-propylphenoxy) benzylphosphonic acid Alternative synthesis for the compound of Example 16 Step a: To a solution of 3,5-dichloro-4- (4'-hydroxy-3'-iso-propylphenoxy) benzyl alcohol in CH2Cl2 (5.0 mL) at -78 ° C is added BBr3. The reaction mixture is stirred at room temperature for 16 h, draining in ice water and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is 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: Diethyl 3,5-dichloro-4- (4'-hydroxy-3'-iso-propylphenoxy) benzyl phosphonate is prepared from 3,5-dichloro-4- (4'-hydroxy-3'- bromide) iso-propylphenoxy) benzyl following the procedure described in example 9, step g.
Step c: 3,5-Dichloro-4- (4'-hydroxy-3'-isopropylphenoxy) benzylphosphonic acid is prepared from 3,5-dichloro-4- (4'-hydroxy-3'-iso-propylphenoxy) benzylphosphonate of diethyl following the procedure described in example 9, step h.
Example 17 Compound 17: [3,5-Dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) phenoxy] acetic acid Compound 17 was synthesized by a method in the literature (G. Chiellini et al., Bioorg, Med. Chem. Lett., 2000, 10, 2607).
Example 18 Compound 18: 3,5-Dichloro-4- ['-hydroxy-3'-iso-propylphenoxy] benzenacetic 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) iodonium tetrafluoroborate (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 methyl 3,5-dichloro-4-hydroxybenzoate (1.65 g, 6.90 mmol). in dichloromethane (20.0 mL). 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 methoxyphenoxybenzoate as an orange oil (2.02 g, 80%): 1 H NMR (300 MHz, DMSO-de): d 8.10 (m, 1 H), 6. 85 (m, 2 H), 6.50 (m, 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 3,5-dichloro-4- (3'-iso-propyl-4'-methoxyphenoxy) -benzoic acid methyl ester (1.40 g, 3.37 mmol) in THF (10.0 mL) at 0 ° C was added a solution of DIBAL-H (8.12 mL, 8.12 mmol, 1.0 M solution in THF). The reaction mixture is stirred at room temperature for 16 h, quenched with cold 1 N HV1 and diluted with ethyl acetate. The organic layer was washed with 1 N HCl and brine, dried over MgSO 4, filtered and concentrated under reduced pressure to provide 4- (3 '-iso-propyl-4'-methoxyphenoxy) -3,5-dichlorobenzyl alcohol as an opaque white solid (0.94 g, 100%): 1 H NMR (300 MHz, DMSO-d 6): 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 CBr (0.534 g, 1.61 mmol) in diethyl ether (15.0 mL) at room temperature was added 4- (3'-iso-propyl alcohol. -4'-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) benzylbromide (0.320). g, 54%): XH 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). '-methoxyphenoxy) diethyl benzylphosphonate as an oil (0.59 g, 85%): 1 H NMR (300 MHz, DMSO-de): 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 he 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), cooling down 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 h. 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 mLx2), dried over MgSO4 and filtered. The solvent was removed under reduced pressure to provide 3,5-dichloro-4- (3'-iso-propyl- '-hydroxyphenoxy) benzylphosphonic acid as a brown solid (0.20 g, 40%): mp: 178-181 ° C; LCMS m / z = 391 [C 16 H 17 Cl 2 O 5 P-H] "; X H NMR (300 MHz, DMSO-de): 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); Calculated Analysis for (C? 6H? 7Cl205P + 0.2 C4H802 + 0.5 H20): C, 48.30; H, 4.73. Found: C, 48.69, H, 5.16.With the appropriate starting material, compounds 19-1 through 19 -3 were prepared in a manner analogous to that described by the synthesis of compound 19.
Compound 19-1: [3, 5-Dibromo-4- (4'-hydroxy-3'-iso-propylphenoxy)] benzylphosphonate diethyl It is prepared from methyl 3, 5-dibromo-4-hydroxybenzoate (J. Med. Chem. 2003, 46, 1580) according to the procedure described by the synthesis of compound 19. pf: 145 ° C; LCMS m / z = 536 [C2oH25Br2? 5P + H] +; 1 H NMR (300 MHz, CD 3 OD): d 7.53 (s, 2 H), 6.50 (m, 2 H), 6.23 (m, 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); Analysis Calculated for (C2oH25Br205P): C, 44.80; H, 4.70. Found: C, 45.19, H, 4.80.
Compound 19-2: Acid [3,5-dibromo-4- (4'-hydroxy-3'-iso-propyl-enoxy)] benzylphosphonic acid It is prepared from compound 19-1 in accordance with the procedure described by the synthesis of compound 19 step e. mp: 76-79 ° C; LC-MS m / z = 480 [C? 6H? 7Br2? 5P + H] +; X H NMR (300 MHz, CD 3 OD): d 7.52 (s, 2 H), 6.55 (m, 2 H), 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, 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 NH-4H2PO4 / 0.002 M (NH4) 2HP04) with 5% acetonitrile. Flow ratio = 4 mL / min; UV @ 255 nm. Retention time in minutes, (tr = 5.80, 96% purity).
Compound 19-3: Acid [3,5-dimethyl-4- (4'-hydroxy-3'-iso- propylphenoxy)] benzylphosphonic It is prepared from methyl 3, 5-dimethyl-4-hydroxybenzoate in accordance with the procedure described by the synthesis of compound 19. mp: 79-82 ° C; LC-MS m / z = 351 [C? 8H2305P + H] +; X H NMR (300 MHz, CD 3 OD): 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); Analysis Calculated for (C18H2305P + 1.2 H20): C, 58.12; H, 6.88. Found: C, 58.01; H, 7.00.
Example 20 Compound 20 [3,5-Dimethyl-4-N- (4'-hydroxy-3-iso-propylphenylamino) phenoxy] methylphosphonic acid Step a: A solution of 4-amino-3,5-dimethylphenol (5.0 g, 36.46 mmol, Fieser, LF Organic Syn theses, 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 brine. 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 ethyl acetate-hexanes (1:19) to provide 2,6-dimethyl-4-triisopropylsilanyloxyphenylamine. (8.46 g, 79%): XH 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 g). mmol) and potassium tert-butoxide (2.18 g, 22.72 mmol). The reaction mixture was heated at 110 ° C in the sealed tube for 16 h, cooling 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-triisopro-ylsilyloxyphenyl) - (3-iso-propyl-4-methoxymethoxyphenyl) amine as a yellow solid (4.8 g, 58%):? RM? (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-iso-propyl-4-methoxymethoxyphenyl) amine (800 mg, 1.70 mmol) in THF (10.0 mL) at 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 RM? (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: A solution of 3,5-dimethyl-4-N- (3-iso-propyl-4'-methoxymethoxyphenylamino) was added to a solution of sodium hydride (22 mg, 0.86 mmol) in DMF at 0 ° C. ) phenol (270 mg, 0.86 mmol) in DMF (2.0 mL). The reaction mixture was stirred at room temperature for 1 h and thereto was added a solution of diethyl tosyloxymethylphosphonate (0.34 g, 1.03 mmol) in DMF (1.0 mL). 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? AHC03 (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 MgSO4, 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] methylphosphonate diethyl (160 mg, 52%): XH RM? (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) phenoxymethylphosphonate (150 mg, 0.32 mmol) in CH 2 Cl 2 (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%). : XH RM? (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, ÍH), 2.10 (s, 6 H), 1.10 (d, J = 6.9 Hz, 6 H). pf > 200 ° C; LC-MS m / z = 366 [C? 8H24? 05P + H] +; Analysis Calculated for (C18H24? 05P + 0.5 H20 + 0.2 HCl): C, 56.65; H, 6.66; ?, 3.67. Found: C, 56.45; H, 6.73; ?, 3.71.
Using the appropriate starting material, compound 20-1 was prepared in a manner analogous to tdescribed by the synthesis of compound 20.
Compound 20-1 Acid [3,5-dimethyl-4- (4'-hydroxy-3-iso-propylphenylethylamino) phenoxy] methylphosphonic acid Prepared by standard reductive amination (J. Org. Chem. 1972, 31, 1673) of N, N- (2,6-dimethyl-4-triisopropylsilanyloxyphenyl) - (3-iso-propyl-4-methoxymethoxyphenyl) amine with formaldehyde followed by the same procedure described for the synthesis of compound 20. 1H RM? (300 MHz, CDC13): 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? 9H26? 05P + H] "Analysis Calculated for (C? 9H26? 05P + 0.3 HBr + 0.1 CH2C12): C, 55.41; H, 6.46;?, 3.38. C, 55.35; H, 6.55;?, 3.43.
Example 21 Compound 21: 2- [3,5-dichloro-4- (4'-hydroxy-3'-iso-) acid propylphenoxy) phenyl] -2-oxoethylphosphonic Step a: To a stirred solution of diethyl methylphosphonate (0.4 g, 2.6 mmol) in anhydrous THF (15 mL) at -78 ° C was added n-BuLi (1.95 mL, 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 g. 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 mL) and H20 (50 mL) and extracted with ethyl acetate (50 mL × 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 was added TMSBr (0.83 g, 0.8 mL, 5.4 mmol). 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 CH30H (3 mL). 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% ): 1 NMR (300 MHz, CD3OD): 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 CH 2 Cl 12 (5%). mL) at -78 ° C was added BBr3 (1.0 mL, 1.0 mmol, 1.0 M in CH2CI2). The reaction mixture was stirred at room temperature for 14 h, draining in ice water (25 mL) and stirred for 1 h. The reaction mixture was extracted with ethyl acetate (50 mLx2). 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- (4'-hydroxy-3'-isopropylphenoxy) phenyl] -2-oxoethylphosphonic acid as a yellow solid (0.14 g. , 92%, MP: 83-85 ° C, 98% pure): XH NMR (300 MHz, CD30D): 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 m / z = 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; Calculated Analysis: (C? 7H? 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 opaque white solid (5.80 g. , 93%):? Ti NMR (300 MHz, DMSO-de): 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 was added 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). 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 opaque 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, 6 H); 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 mL) a 0 ° C was added sodium hydride (0.064 g, 1.22 mmol, 60% dispersion in oil). The reaction mixture was stirred at room temperature for 1 h and cooled to 0 ° C. Diethyl trifluoromethanesulfonyloxymethylphosphonate (0.18 g, 0.94 mmol) was added to the stirred mixture. The reaction mixture is 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-ert-butoxycarbonyl- [3, 5-dichloro-4- (3-iso-propyl) 4'-methoxyphenoxy) phenylamino] methylphosphonate diethyl as an oil (0.34 g, 63%): XH NMR (300 MHz, DMSO-de): 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; Mobile phase = ethyl acetate-hexanes (2: 3); Rf = 0.15 Step d: To a solution of diethyl N-ert-butoxycarbonyl- [3,5-dichloro-4- (3-iso-propyl-4'-methoxy-phenoxy) phenylamino] methyl) phosphonate (0.25 g, 0.43 mmol) 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 mL, 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 MgSO4 and concentrated under reduced pressure to provide [3,5-dichloro-4- (4'-hydroxy-3-iso-propylphenoxy) phenylamino] methylphosphonic acid as an opaque white solid (0.15 g, 85%). % during two stages): mp: 97-100 ° C; LCMS m / z = 405, 407 [C? 6H? 8Cl2? 05P + H] +; XH RM? (300 MHz, DMSO-de): 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); Analysis Calculated for (C? 6H? 8Cl2N05P + 0.1 C4H802 + 0.3H20): C, 46.85; H, 4.65; N, 3.33. Found: C, 47.09; H, 4.94; N, 3.50.
Compound 22-1: [3,5-dibromo-4- ('-hydroxy-3' -iso-propylphenoxy) phenylamino] methylphosphonic acid The title compound was prepared from 4-amino-2,6-dibromophenol according to the procedure described by the synthesis of Example 22, steps a-d; 1 H NMR (200 MHz, DMS0-d 6): d 8.95 (m, HH), 7.02 (s, 2H), 6.63 (m, 2H), 6.23 (m, HH), 3.31 (d, J = 12.0 Hz, 2H ), 3.14 (m, ÍH), 1.12 (d, J = 6.0 Hz, 6H); LC-MS m / z = 496 [C? 6H? 8Br2N05P + H] +; CLAR conditions: Column = Agilent zorbax RP18, 150x3.0 mm; Mobile phase = Solvent B (Acetonitrile) = acetonitrile grade CLAR; Solvent A (buffer) = 20 mM potassium phosphate buffer (pH 4.7). Flow ratio = 0.75 mL / min; UV @ 254 nm. Retention time in minutes, (tr = 8.70 / 20 min, 92% purity).
Example 23 Compound 23: N- [3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylphenoxy) benzamido] methyl phosphonic acid Step a: To a solution of methyl 3,5-dimethyl-4- (3'-iso-propyl-4'-methoxyphenoxy) benzoate (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? AOH 1? (28.15 mL, 28.15 mmol). The reaction mixture was stirred at room temperature for 16 h and acidified with conc. Cold 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'-i so-propyl-4'-methoxyphenoxy) -3,5-dimethylbenzoic acid as a pink solid (1.38 g, 78%): XH RM? (300 MHz, DMSO-de): 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 l-hydroxy-7-azabenzotriazole (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 mL x 3) and brine, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by preparative CCD to give N- [3,5-dimethyl-1,4- (3'-iso-propyl-4'-methoxyphenoxy) -benzamido] methylphosphonate diethyl as an oil (0.20 g, 68%) : 1H RM? (300 MHz, DMSO-de): 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 (m, 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 (0.56 mL, 4.31 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 dissolved in dichloromethane (5.0 L), 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 MgSO4, 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? 9H24? 06P + H] +; XH RM? (300 MHz, CD3OD): 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); Analysis Calculated for (C? 9H24? 06P + 1.0 H20): C, 55.47; H, 6.37; ?, 3.40. Found: C, 55.30; H, 6.32; ?, 3.12.
Example 24 Compound 24: 2- [3,5-Dimethoxy-4- (4'-hydroxy-3 '-isopropylbenzyl) 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 by the synthesis of Example 7-2) and DMAP (0.85). g, 6.92 mmol) in CH 2 Cl 2 (20 mL) at 0 ° C was slowly added 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 4, 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%):? H NMR (300 MHz, DMSO-de): 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 mL, 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 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-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%): XH 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-CH2Cl (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). The deprotection with TMSBr as described by the synthesis of compound 7, step b provided 2- [3,5-dimethoxy-4- (4'-hydroxy-3'-isopropylbenzyl) phenyl] ethylphosphonic acid as a light pink foam (73 mg, 91% ). 1 H NMR (200 MHz, DMSO-de): 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 [C2oH2706P + H] +; Analysis Calculated for (C2oH27? 6P + 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 a manner analogous to that described for the synthesis of compound 24.
Compound 24-1: 2- [3,5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) phenyl] ethylphosphonic acid It is prepared from 3, 5-dimethyl-4- (3'-iso-propyl-1-methoxymethoxybenzyl) phenol (Chiellini et al., Bioorg, Med Chem. Lett, 1 0: 2601 (2000)). mp: 65-68 ° C; X H NMR (300 MHz, CD 3 OD): 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 ] +; Analysis Calculated for (C 20 H 27 O 4 P + 0.6 H 20 + 0.4 CH 3 OH): C, 63.47; H, 7.78. Found: C, 63.39; H, 8.06.
Compound 24-2: Trans-2- [3,5-dimethyl-4- ('-hydroxy-3'-iso-propylbenzyl) phenyl] vinylphosphonic acid It is prepared from 3,5-dimethyl-4- (3'-iso-propyl-4'-methoxymethoxybenzyl) phenol (Chiellini et al., Bioorg, Med Chem. Lett 10: 2601 (2000)). mp: 82-84 ° C; X H NMR (300 MHz, CD 3 OD): 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] +; Analysis Calculated for (C2oH25? 4P + 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] -ethyl-phosphonic acid The title compound was prepared from the intermediate 4- (3 '-sec-butyl-4' -methoxymethoxy-benzyl) -3,5-dimethyl-phenol, is prepared from 4-bromo-2-methyl-phenol in accordance with the procedure described in Chiellini et al. , Bioorg. Med. Chem. Let t. 10: 2601 (2000), and transformed into the title compound by the procedure used for the synthesis of compound 24 as a light yellow foam.; X 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? H29? 4P + H] +; Analysis Calculated for (C21H29O4P + 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'-hydroxy-benzyl) phenyl] ethylphosphonic acid The intermediate 4- (3'-ethyl-4'-methoxybenzyl) -3,5- dimethylphenol, is prepared according to the procedure described in Chiellini et al. , Bioorg. Med. Chem. Lett. 10: 2601 (2000), 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, DMSO-d 6): d 8.98 (s, ÍH), 6.86 (d, ÍH, J = 3 Hz), 6.72 (d, ÍH, J = 1.8 Hz), 6.60 (s, 2H), 6.49 (dd, ÍH, 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; Analysis Calculated for (Ci9H2504P +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) phenoxy] methylphosphonic 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), (Chiellini et al. al , Bioorg. Med. Chem. Let t. 10: 2601 (2000)) in THF (10.0 mL) at 0 ° C was added tetrabutylammonium fluoride (1.91 L, 1.91 mmol, 1.0 M solution in THF). The reaction mixture was stirred at room temperature for 20 min, diluted with diethyl ether and washed with water (20 mL × 2) and brine. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting 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%): X H NMR (300 MHz, DMS0-d 6): 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- '-methoxymethoxy-benzylhydroxy) phenol (0.380 g, 1.15 mmol) in DMF (10.0 mL) at 0 ° C was added Cs2C03 (1.87 g, 5.75 mmol). After 5 min, diethyl trifluoromethane-sulfonyloxymethyl phosphonate (0.24 g, 1.15 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 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, eluting with acetone-hexanes (1: 4) as mobile phase to provide [3,5-dimethyl-4- (3 ' diethyl-iso-propyl-4'-methoxymethoxybenzylhydroxy) phenoxy] methylphosphonate as an oil (0.41 g, 74%): X H NMR (300 MHz, DMSO-d 6): 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 diethyl [3,5-dimethyl-4- (3'-iso-propyl-4'-methoxymethoxybenzylhydroxy) phenoxy] methylphosphonate (0.32 g, 0.66 mmol) in dichloromethane (8.0 mL) at 0 ° C Dess-Martin periodinone (2.08 mL, 0.99 mmol, 0.48 M solution in CH2C12) was added. The reaction mixture was stirred at room temperature for 16 h, concentrated, diluted with diethyl ether (10.0 mL). To the solution was added a solution of 580 mg of Na S03 pentahydrate in 60 mL saturated NaHCO 3). After 15 min, the reaction mixture was diluted with ethyl acetate and water and washed with saturated NaHCO3 and brine. The organic layer was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1: 1) to give [3,5-dimethyl-4- (3'-isopropyl-1,4'-methoxymethoxybenzoyl) phenoxy] methylphosphonate diethyl as an oil (0.285 g, 89 %): 1 H NMR (300 MHz, DMSO-de): d 7.22 (m, 1 H), 7.43 (m, 1 H), 7.13 (m, 1 H), 6.85 (s, 2 H), 5.35 (s) , 2H), 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- '-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 1 N NaOH and extracted with dichloromethane and ethyl acetate. The aqueous layer was made acidic with 2 N HCl and extracted with ethyl acetate. The organic layer was dried over MgSO 4, 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] +; 1ti 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 solution (pH 6.1, 0.018 M NH-4H2PO4 / O.OO2 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, Chiellini et al. , Bioorg. Med. Chem. Let t. 10: 2601 (2000)) in DMF (30.0 mL) was added Cs2C03 (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 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 give l- (2-bromoethoxy) -4- (3'-iso-propyl-4'-methoxymethoxybenzyl) ) -3,5-dimethylbenzene as an oil (0.26 g, 16%): XH 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 rt, diluted with ethyl acetate and extracted with water (10 mLx4) and brine. The organic layer was dried over MgSO 4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with acetone-hexanes (1: 1) to give 2- [3,5-dimethyl-4- (3'-iso-propyl-4'-methoxymethoxybenzyl) phenoxy] ] diethyl ethylphosphonate as an oil (0.085 g, 50%): X H NMR (300 MHz, DMSO-de): 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 gave 2- [3,5-dimethyl-4-acid] ('-hydroxy-3' -isopropylbenzyl) phenoxy] ethylphosphonic acid as a brown oil (0.055 g, 87%): mp: 58-61 ° C; LC-MS m / z = 379, [C20H27O5P + H] +; ? ti 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'-isopropylbenzyl) phenoxy] methylphosphonic 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 MgSO4, filtered and concentrated to give the crude product as a colorless oil which was used for 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 mL) 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, cooling to room temperature and filtered through a stopper.
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 (1:19) to provide 4-fluoro-3-isopropenylbenzaldehyde (500 mg, 50%). : X H NMR (300 MHz, CDC13): d 7.89 (m, 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, Chiellini et al., Bioorg, Med.Chem.Let t.10: 2601 (2000)) in THF a- 78 ° C was added n-butyllithium (1.58 mL, 3.96 mmol, 2.5 M in THF). 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 MgSO4, filtered and concentrated to provide crude l- (2,6-dimethyl-4-triisopropylsilanyloxyphenyl) -1- (4'-fluoro-3'-isopropenylphenyl) methanol as an oil: 1H 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-triisopropylsilanyloxy-phenyl) -l- (4'-fluoro-3'-isopropenylphenyl) methanol (1.2 g, 2.71 mmol) and Pd / C (0.1 g , 10%) in EtOH / HOAc (9: 1, 10 mL) was stirred under an atmosphere of H2 for 16 h. The reaction mixture was filtered through a plug of Celite and concentrated to provide crude 3,5-dimethyl-4- (4'-fluoro-3'-isopropylbenzyl) triisopropylsilane-benzene which was used for the next step without further purification. .
Step e: To a solution of 3,5-dimethyl-4- (4'-fluoro-3'-isopropylbenzyl) triisopropylsilane-benzene in THF (10 mL) at 0 ° C was added TBAF (1 M, 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 MgSO, 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-dimethyl-4- (4'-fluoro-3'-isopropylbenzyl) phenol (450 mg, 61% over two steps): 1 H 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 = acetate of ethylhexanes (1: 9); Rf = 0.50.
Step f: [3,5-Dimethyl-4- (4'-fluoro-3'-iso-propylbenzyl) phenoxy] methylphosphonic 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: XH NMR (300 MHz, DMSO-d6): d 7.03 (m, 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: [3,5-dichloro-4- (4'-fluoro-3'-isopropyl-benzyl) -phenoxy] methylphosphonic acid The intermediate (2,6-dichloro-4-triisopropylsilanyloxy-phenyl) - (4-fluoro-3-isopropyl-phenyl) -methanol was prepared by the procedure described for the synthesis of compound 27, steps a, b, c, d as an oil (520 mg, 98%): XH NMR (300 MHz, CDC13): d 7.24 (m, HH), 6.98 (m, 2H), 6.91 (s, 2H), 6.52 (s, ÍH), 4.48 (s, ÍH), 3.24 (m, ÍH), 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 TFA (1.53 M, 0.7 mL) was added followed by triethylsilane (0.6 mL, 3.77 mmol) at RT After stirring 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, HH), 6.91 (m, 4H), 4.21 (s, 2H), 3.19 (m, HH), 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-propylbenzyl) -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-de): d 7.22 (s, 2H), 7.18 (m, HH), 7.04 (m, HH), 6.87 (m, ÍH), 4.22 (d, J = 9.6 Hz, 2H), 6.60 (s, 2H), 3.12 (m, ÍH), 1.19 (d, J = 6.9 Hz, 6H). mp = 132-135, LC-MS m / z = 408 [C 17 H 18 Cl 2 FO 4 P + H] +; Analysis Calculated for (C? 7H? 8Cl2F04P + 0.2H20): 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-3-iso-propylphenyl) iodonium tetrafluoroborate (4.80 g, 9.38 mmol) and copper powder (0.79 g, 12.52 mmol) in CH2C12 (15.0 mL) at 0 ° C 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) was added. The reaction mixture was stirred at room temperature for 3 d and filtered through a Celite plug. 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-dimethyl-4- (3'-iso-propyl-4). '-methoxyphenoxy) benzaldehyde as an oil (2.00 g, 100%): 1H 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 min 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 cold aqueous NH 4 Cl solution, 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, eluting with acetone-hexanes (1: 4) to give trans-2- [3,5-dimethyl-4- (3 '-iso. -propyl-4 '-methoxyphenoxy) phenyl] vinylphosphonate diethyl as an oil (0.21 g, 74%): 1ti NMR (300 MHz, DMSO-de): 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 mL x 3), dried over MgSO 4 and filtered. The 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 [C? 9H2305P + 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 mM ammonium phosphate buffer solution (pH 6.1, 0.018 M NH4H2PO4 / 0.002 M (NH) 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- ('-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 min and thereto was added 3,5-dimethyl-4- (3-iso-propyl-4-methoxyphenoxy) benzaldehyde (0.20 g, 0.67 mmol, Example 28, stage a). The reaction mixture was stirred at room temperature for 1 h, quenched with cold saturated NH 4 Cl, 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, eluting with acetone-hexanes (3:17) to give trans-3- [3,5-dimethyl-4- (3 '-iso. ethyl-propyl-4'-methoxyphenoxy) phenyl] acrylate as an oil (0.24 g, 97%): * H NMR (300 MHz, DMSO-de): 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 (m, 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 1N 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, eluting 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%): XH 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 mL) 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. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting 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 mL) 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, eluting with acetone-hexanes (1: 9) to provide 1-bromo-3- [3,5-dimethyl-4- (3'-iso-propyl-4 ' -methoxyphenoxy) phenyl] propane as an oil (0.30 g, 72%): X H NMR (300 MHz, DMSO-de): 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 (m, 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 chromatography of column on silica gel, eluting with acetone-hexanes (1: 3) to give diethyl 3- [3,5-dimethyl-4- (3'-iso-propyl-4'-methoxyphenoxy) phenyl] propylphosphonate as an oil ( 0.11 g, 32%): X 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 CHC12 (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 mLx2) and water (20 mLx2), dried over MgSO4, 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% during two stages): mp: 60-63 ° C; LC-MS m / z = 379 [C2oH27? 5P + H] +; X H NMR (200 MHz, DMSO-d 6): 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 diethyl trans-2- [3,5-dimethyl-4- (3'-iso-propyl-4'-methoxyphenoxy) phenyl] vinylphosphonate (1.77 g, 4.10 mmol, Example 28, step b) and Pd / C (177 mg) in EtOH / HOAc (10 mL, 9: 1)) was stirred under an atmosphere of H2 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, eluting with ethyl acetate-hexanes (1: 1) to give 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: XH 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 [C 20 H 27 O 5 P + 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) phenoxy] methylphosphonic 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. l-chloroperoxybenzoic acid (0.22 g, 0.905 mmol) was added. 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. The 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 eluting with acetone-hexanes (1: 4) to provide 3,5-dimethyl-4- (3'-iso-propyl-1-methoxyphenoxy) phenol as an oil (0.08). g, 47%):? NMR (200 MHz, DMSO-de): d 9.17 (s, 1 H), 6.82 (m, 1 H), 6.70 (m, 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 m / z = 367 [C? 8H2306P + H] +; XH 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); Calculated Analysis 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'-bis-propyl-4'-methoxyphenoxy) benzaldehyde (4.1 g, 15.2 mmol, Example 28, step a) in methanol (35 L) a 0 ° C was slowly added NaBH 4 (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 acetate 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, eluting with ethyl acetate-hexanes (2: 4) to provide 3,5-dimethyl-4- (3'-iso-propyl-4'-methoxyphenoxy) alcohol. ) benzyl as a white solid (3.4 g, 83%, PF: 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 mL). The organic layer was washed with brine, dried over Na 2 SO 4, filtered and concentrated under reduced pressure to provide crude 3,5-dimethyl-4- (3'-iso-propyl-4'-methoxyphenoxy) benzyl bromide as an 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 (m, 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 mL) at room temperature was added a solution of 3,5-dimethyl-4- (3'-iso-propyl bromide. -4'-methoxyphenoxy) encyl (0.85 g, 2.34 mmol) in ethanol (5 mL). The reaction mixture was heated at 80 ° C for 2 h, cooling to room temperature, and draining in 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 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-dimethyl-4- (3'-iso-propyl-4'-methoxyphenoxy) phenylacetonitrile. as a brown solid (0.64 g, 85%, P.F .: 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 a 50% solution. % H2S04 (14 mL). The reaction mixture was heated at 105 ° C, for 3 h, cooling to room temperature and pouring into ice water (100 mL). The mixture was stirred for 1 h and extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with water and brine, dried over Na 2 SO 4, filtered and concentrated under reduced pressure to give 3,5-dimethyl-4- (3'-iso-propyl-4'-methoxyphenoxy) phenylacetic acid as a solid brown (0.62 g, 85%, PF: 118-120 ° C): H 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 chloride of acetyl (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 provide methyl 3,5-dimethyl-4- (3'-iso-propyl-4'-methoxyphenoxy) phenylacetate as a yellow solid. (0.69 g, 95%): XH 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 (d, 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'-isopropylphenoxy) 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; 1R 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 m / z = 393 [C2oH25? 6P + H] +; CLAR conditions: ODSAQ column AQ-303-5; mobile phase = CH3OH: TFA 5% (7: 3) flow ratio = 1.0 mL / min; detection = UV @ 254 nm retention time in min: 11.19; Analysis Calculated for (C20H25? 6P + 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, Chiellini et al., Bioorg. Med. Chem. Let t.10: 2601 (2000)) in THF (30.0 mL) at 0 ° C was added TBAF (4.93 mL, 4.93 mmol, 1.0 M solution in THF). The reaction mixture was stirred at room temperature for 60 min, diluted with diethyl (10.0 mL) 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, eluting 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%): X 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 (, 1 H), 2.10 (s, 6 H), 1.16 (m, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (4: 1); Rf = 0.17. 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 Cs2CO3 (1.87 g, 5.75 mmol) was added. After 5 min, the trifluoromethanesulfonic acid diethoxyphosphorylmethyl ester (0.24 g, 1.15 mmol) was added. The reaction mixture was stirred at room temperature for 16 h, quenched with 1N 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, eluting with acetone-hexanes (1: 4) to provide [3, 5-dimethyl-4- [(3'-iso-propyl-4'-methoxymethoxyphenyl) -hydroxymethyl] phenoxy] methylphosphonate diethyl ester as an oil (0.41 g, 74%): XH 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, 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 L, 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, eluting with acetone-hexanes (1: 1) to provide [3,5-dimethyl-4- [(4'-hydroxy-3'-iso-propylphenyl) methoxymethyl) ] phenoxy] methylphosphonate diethyl as an oil (0.125 g, 69%): X H NMR (300 MHz, DMSO-de): 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 (m, 4 H) 3.20 (s, 3 H), 2.17 (s, 6 H), 1.21 (m, 6 H), 1.11 (m, 6 H); CCD conditions: 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) methoxymethyl] 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 (5 mLx2) and acidified with 2M HCl. The mixture was diluted with ethyl acetate and washed several times with water. The organic layer was dried over MgSO 4 and concentrated under reduced pressure to provide the title compound as a red powder (0.035 g, 62%): X H NMR (300 MHz, D 20): 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) CLAR grade acetonitrile; Solvent B (buffer) = 20 mM ammonium phosphate buffer solution (pH 6.1, 0.018 M NH-4H2PO4 / O.OO2 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) phenoxymethylphosphonate (0.26 g, 0.61 mmol, is 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 4, filtered and concentrated under reduced pressure to provide [3, 5-dimethyl-4- (4'-hydroxybenzyl) phenoxy] methylphosphonate diethyl ester (0.22 g, 95%) as a colorless oil: 1R NMR (300 MHz, DMSO-de): d 9.11 (s, 1 H), 6.60-6.80 (m, 6 H), 4.35 (d, J = 14.7 Hz, 2 H), 4.11 (m, 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] methylphosphonate] according to the procedure described in compound 2 steps f and g: X NMR (300 MHz, CD3OD): 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); LCMS m / z = 449 [C16H? 8I05P + H] +; Analysis Calculated for (C16H18I05P + 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) was added 4-hydroxy-benzaldehyde (15.0 g, 0.123 mol) in DMF (10 mL) at 0 ° C, 5 min. later the reaction mixture became a cake. The heterogeneous mixture was stirred at 0 ° C for 30 min. The MOMC1 (9.96 g, 0.123 mol) was added slowly and the reaction mixture was allowed to warm until t.a .. After stirring at t.a. for 16 h, the volatiles were removed under vacuum. The residue was partitioned between ethyl acetate and water and the aqueous 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%): X H NMR (300 MHz, CDC13): d 9.94 (s, ÍH), 7.88 (m, 2H), 7.18 (m, 2H), 5.29 (s, 2H), 3.53 (s, 2H); 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 warmed to t.a .. The reaction was diluted then 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 give 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 atm) at RT 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) : ""? NMR (300 MHz, CDC13): d 6.93 (s, 4H), 6.63 (s, 2H), 5.16 (s, 2H), 3. 94 (s, 2H), 3.50 (m, 3H), 1.58 (s, 6H), 1.29 (m, 3H), 1.13 (m, 18H). 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) was then added and after stirring at 0 ° C for 2 h, the reaction mixture was quenched with a saturated solution of NH4C1 and diluted with EtOAc. The aqueous 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%): XH NMR (300 MHz, d6-DMS0): d 10.33 (s, ÍH), 7.24 (m, 3H), 6.58 (s, 2H), 5.31 (s, 2H), 3.91 ( s, 2H), 3.33 (s, 6H), 1.23 (m, 3H), 1.06 (m, 18H). 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 mL) was added TBAF (1 M, 3.68 mL) at 0 ° C. After stirring at t.a. for 2 h, the reaction mixture was diluted with EtOAc and water. The layer aqueous was extracted with EtOAc and the combined organic extracts were dried (MgSO.sub.4), 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). stages): 1 H NMR (200 MHz, CDC13): d 10.45 (s, ÍH), 7.54 (s, ÍH), 7.27 (m, ÍH), 7.09 (m, ÍH), 6.56 (s, 2H), 5.25 (s, 2H), 3.92 (s, 2H), 3.50 (s, 3H), 2.16 (s, 6H). 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 Cs2CO3 (3.2 g, 9.83 mmol), followed by by diethyl phosphorylmethyl ester of trifluoromethanesulfonic acid (649 mg, 2.16 mmol) at RT After stirring at for 16 h, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic extracts were dried (MgSO 4), filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate-hexanes: 1: 1) to give [diethyl 4- (3'-formyl-4'-methoxymethoxybenzyl) -3,5-dimethylphenoxy] methylphosphonate ( 650 mg, 72%): XH NMR (300 MHz, CDC13): d 10.42 (s, ÍH), 7.51 (s, ÍH), 7.09 (m, 2H), 6.67 (s, 2H), 5.25 (s, 2H), 4.26 (m, 6H), 3.94 (s, 2H), 3.50 (s, 3H) ), 2.19 (s, 6H), 1.37 (m, 6H). 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 t.a. a solution of NaH2PÜ4 (52 mg, 0.43 mmol) in water (0.2 mL), 30% H202 (30%, 0.16 mL) was added followed by a solution of sodium chlorite (245 mg, 2.17 mmol) in water (1.0 mL). After stirring at a.t. for 30 min., the reaction mixture was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water, brine, dried (MgSO 4), filtered and concentrated to provide [3,5-dimethyl-4- (3'-carboxy-4'-hydroxybenzyl) diethyl phenoxy] methylphosphonate as yellow solid (585 mg, 86.9%): XH NMR (300 MHz, CDC13): d 7.91 (m, HH), 7.11 (m, 2H), 6.68 (s, 2H), 4.25 ( m, 6H), 3.96 (s, 2H), 3.54 (s, 3H), 2.19 (s, 6H), 1.37 (m, 6H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = MeOH-ethyl acetate (1: 9); Rf = 0.2.
Step h: To the solution of [3,5-dimethyl-4- (3'-carboxyl-4'-hydroxy) diethyl benzyl) phenoxymethylphosphonate (100 mg, 0.21 mmol) in CH2C12 (10 mL) was added TMSBr (0.28 mL, 2.10 mmol) at t.a. After stirring at t.a. 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 CHC12 twice to give [3,5-dimethyl-4- (3'-carboxy-4 '-hydroxybenzyl) phenoxy] methylphosphonic acid as a solid white (48 mg, 61.5%): mp. > 200 ° C; 1 H NMR (200 MHz, DMSO-d 6): d 7.38 (d, J = 2.1 Hz, HH), 7.17 (m, HH), 6.87 (d, J = 8.4 Hz, HH), 6.74. (s, 2H), 4.06 (d, J = 10.2 Hz, 2H), 3.89 (s, 2H), 2.18 (s, 6H). pf > 200, LC-MS m / z = 367 [C? 7H? 907P + H] +; Analysis Calculated for (d7H? 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- (4'-hydroxy-3'-iso-propylcarbamoylbenzyl) -phenoxy] methylphosphonic acid Step a: To a solution of [3,5-dimethyl-4- (3'-carboxy-4 '-hydroxy-benzyl) phenoxymethylphosphonate diethyl ester (compound 35, stage 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 stirring at t.a. 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 provide [3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylcarbamoylbenzyl) -phenoxy] methylphosphonic acid diethyl acid as yellow 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 for the synthesis of compound 35, step f as an opaque white solid (30 mg, 93.7%); mp .: 90 ° C, dec; X H NMR (300 MHz, DMSO-de): d 8.52 (d, J = 7.5 Hz, HH), 7.77 (d, J = 1.5 Hz, HH), 6.73 (m, 4H), 4.14 (m, HH), 4.06 (d, J = 10.2 Hz, 2H), 3.88 (s, 2H), 2.18 (s, 6H), 1.21 (d, J = 6.9 Hz, 6H). pf: decomposed to 90, LC-MS m / z = 408 [C2oH26N06P + H] +; Analysis Calculated for (C20H26NO6P + 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) phenoxy] methylphosphonic acid Step a: 5- (2,6-dimethyl-4-triisopropylsilanyloxybenzyl) -2-methoxymethoxy benzaldehyde (example 35, step e) was transformed into 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%); 1 H NMR (200 MHz, CDC13): d 7.94 (s, ÍH), 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 p = MeOH-ethyl acetate (1: 9); Rf = 0.45.
Step b: N-phenethyl-5- (2,6-dimethyl-4-triisopropylsilanyl- oxybenzyl) -2-methoxymethoxybenzamide was prepared by the procedure used for the synthesis of compound 36, step a: colorless liquid (330 mg, 75%); X H NMR (300 MHz, CDC13): d 8.05 (d, J = 2.4 Hz, HH), 7.84 (m, HH), 7.82 (m, 5H), 6.97 (d, J = 9.0 Hz, HH), 6.64 ( m, ÍH), 6.61 (s, 2H), 5.01 (s, 2H), 3.97 (s, 2H), 3.82 (m, 2H), 3.30 (s, 3H), 2.97 (m, 2H), 2.18 (s) , 6H), 1.28 (m, 3H), 1.14 (m, 18H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile p = ethyl acetate-hexanes (1: 1); Rf = 0.55.
Step c: N-phenethyl-5- (2,6-dimethyl-4-hidoxybenzyl) -2-methoxymethoxy benzamide 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 p = ethyl acetate-hexanes (1: 1); Rf = 0.45.
Step d: Diethyl [3, 5-dimethyl-4- (4'-methoxymethoxy-3'-phenethylcarbamoyl benzyl) phenoxy] methylphosphonate was prepared by the procedure used for the synthesis of compound 35, step f: (185 mg, 80 %); XH RM? (300 MHz, CDC13): d 7.98 (d, J = 2.1 Hz, ÍH), 7.85 (m, ÍH), 7.32 (m, 5H), 7.01 (d, J = 5.4 Hz, ÍH), 6.91 (m, ÍH), 6.69 (s, 2H), 4.29 (m, 4H), 3.98 (s, 2H), 3.81 (m, 2H), 3.31 (s, 3H), 2.96 (m, 2H), 2.22 (s, 6H) ), 1. 41 (m, 6H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile p = 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: a white solid (40 mg, 48.8%): mp .: 100 ° C, dec; ? ti NMR (300 MHz, DMSO-de): d 8.85 (m, ÍH), 7.67 (d, J = 2.1 Hz, ÍH), 7.32 (m, 5H), 6.86 (m, 2H), 6.78 (s, 2H), 4.10 (d, J = 10.5 Hz, 2H), 3.91 (s, 2H), 3.57 (m, 2H), 2.92 (m, 2H), 2.24 (s, 6H). mp: decomposed to 100, LC-MS m / z = 470 [C25H8 06P + H] +; Analysis Calculated for (C25H28N06P + 0.9 HBr): C, 55.37; H, 5.37; N, Example 38: Compound 38: [4- (3'-benzyl-4 '-hydroxy-benzyl) -3,5-dimethylphenoxy] methylphosphonic acid Step a: To a stirred solution of bromobenzene (0.45 g, 2.89 mmol) in THF (20 mL) at -78 ° C was added n-BuLi (1.16 mL, 2.5 M in hexanes). 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 NH 4 Cl and diluted with diethyl ether. The organic layer was dried over Na S0, 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%): 1 H NMR (200 MHz, DMSO-d 6): 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 (m, 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 atmosphere of H2 for 16 h. The mixture was filtered through a plug of Celite. The solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2 (26 mL), ethyl-diisopropyl-amine (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 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 [4- (3'-benzyl-4'-methoxymethoxy-benzyl) -3,5-dimethyl. -phenoxy] -triisopropylsilane as an oil (0.9 g, 66%): X H NMR (200 MHz, DMSO-de): 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) , 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 '-methoxymethoxy-benzyl) -3,5-dimethyl-phenoxy] -triisopropylsilane (0.9 g, 1.73 mmol) in THF (20 mL) at room temperature environment, tetrabutylammonium fluoride (2.3 mL, 1.0 M in THF) was added. 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 raw product was purified by column chromatography on silica gel, eluting 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%): X H 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%): XH NMR (200 MHz, DMSO-de): d 7.22 (m, 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 = 1 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 NMR (200 MHz, DMSO-d6): 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 [C23H25? 5P + H] +; Analysis Calculated for (C23H2505P +0.2 Et2O + 0.6 H20): C, 65.26; H, 6.49. Found: C, 65.07; H, 6.38.
Example 39: Compound 39: [3,5-dimethyl-4- [3 '- (4-f-luoro-benzoyl) -4'-hydroxy-benzyl] phenoxy] -methylphosphonic acid Step a: [5- (2,6-Dimethyl-4-triisopropylsilanyloxy-benzyl) -2-methoxymethoxy-phenyl] - (4-fluoro-phenyl) -methanol was prepared by the procedure used for the synthesis of Example 38, step a as an oil (0.68 g, 56%): H 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 was added Dess-Martin Periodinano (3.9 mL, 0.48 M solution in CH2C12). The reaction mixture was stirred at room temperature for 4 h, concentrated, diluted with ethyl acetate. To the solution was added a solution of pentahydrate Na2S203 (50 mg) in 60 mL saturated NaHCO3. After 15 min, the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give crude 5- (2,6-dimethyl-4-triisopropylsilanyloxy-benzyl) - (4-fluorobenzoyl) -2-methoxymethoxy-phenyl as an oil (0.68 g, 100%): 1H NMR (200 MHz, DMSO-de): 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: 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; X H NMR (300 MHz, DMSO-de): d 9.05 (s, 1 H), 7.78 (m, 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'-hydroxy-benzyl] phenoxymethylphosphonate was prepared by the procedure used by the synthesis of Example 35 step f as a light yellow oil (0.054 g, 19%): XH NMR (300 MHz, DMSO-de): d 7.76 (m, 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 e: The title compound was prepared by the procedure used for the synthesis of Example 35 step h as a foam yellow (22 mg, 50%): X H NMR (200 MHz, DMSO-d 6): 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 Et2O + 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-f luoro-benzyl) -' -hydroxy-benzyl] phenoxymethylphosphonic acid Step a: To a stirred solution of diethyl [3, 5-dimethyl-4- [3 '- (4-fluoro-benzyl) -4' -hydroxy-benzyl] phenoxymethylphosphonic acid (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 Na 2 SO 4, filtered and concentrated under reduced pressure to provide diethyl [3,5-dimethyl-4- [3 '- (4-fluorophenyl-hydroxymethyl) -4'- acid. hydroxy-benzyl] phenoxy] methylphosphonic acid as an oil (0.13 g, 100%). This crude product was dissolved in CH2CI2 (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 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 [3,5-dimethyl-4- [3 '- (4-fluoro-benzyl) -4'-hydroxybenzyl] phenoxy] methylphosphonate diethyl as an oil (80 mg, 69%): X H NMR (200 MHz, DMSO-de): 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 = 1 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%): 1 H NMR (200 MHz, DMSO-d 6): 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 Na2SO4, filtered and concentrated under reduced pressure to provide 4- (3'-benzyl-4'-methoxymethoxy-benzyl) -3,5-dimethyl-phenyl trifluoromethanesulfonate as an oil (0.5 g, 73%). : 1 H 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); CCD conditions: 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 (0.82 mL, 20 mmol), Pd (OAc) 2 (23 mg, 0.1 mmol), bis- (diphenphosphino) propane (42 mg, 0.1 mmol) and TEA (0.28 mL, 2 mmol) were added. 60 psi (4.218 kg / cm2) of CO was then emptied and the reaction mixture was stirred at 90 ° C for 16 h. The cold bomb was vented and the reaction mixture was emptied into cold IN HCl, extracted with EtOAc twice, the combined EtOAc washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (15:75) to give 4- (3'-benzyl- '-methoxymethoxy-benzyl) -3,5-dimethyl-benzoate. methyl as a yellow oil (360 mg, 88%): 1ti NMR (300 MHz, DMSO-de): 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, 6H). 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 (2.5M 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 at 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 NH 4 Cl and diluted with diethyl ether. The organic layer was dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate to provide [3, 5-dimethyl-4- [3'-benzyl-4'-hydroxybenzyl] benzoyl] methylphosphonate diethyl ester as a light yellow oil (350 mg, 75%): X H NMR (300 MHz, DMS0-d 6): 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, 6H), 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%): X H NMR (200 MHz, DMSO-de): 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 25 O 5 P + H] +; Analysis Calculated for (C24H25? 5P +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 for 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 3,5-dimethyl-4- (4'-fluoro-3'-iso-propyl-benzyl) -phenol (compound 27, step e) by the procedure described by the synthesis of the compound 41 as a white solid (106 mg, 81.5%): 1 H NMR (300 MHz, DMSO-de): d 7.70 (s, 2H), 7.10 (m, ÍH), 6.98 (m, ÍH), 6.65 (m, ÍH), 4.00 (s, 2H), 3.48 (d, J = 22.4 Hz, 2H), 3.09 (m, ÍH), 2.26 (s, 6H), 1.17 (d, J = 7.0 Hz, 6H). 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-ethylphosphonic acid 3, 5-Dichloro-4- (4-fluoro-3-iso-propyl-benzyl) -phenol, intermediate for the synthesis of compound 27-2, was transformed into the title compound by the procedure described by the synthesis of the compound 41 to give a white solid (65 mg, 82%): X 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, ÍH), 4.32 (s, 2H), 3.60 (d, J = 22.5 Hz, 2H), 3.12 (m, ÍH), 1.20 (d, J = 6.9 Hz, 6H). mp = 132-134, LC-MS m / z = 417 [C? 8H? 8Cl2F? P + 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-4- [3'-benzyl-4 '-hydroxy-benzyl] phenyl] -ethylphosphonic acid Step a: To a stirred solution of diethyl [3, 5-dimethyl-4- [3'-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 NaBH4 (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-ethyl- Diethyl phosphonate as an oil (0.27 g, 100%): 1H NMR (300 MHz, DMSO-de): 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 4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (3: 1) to provide 2- [4- (3'-benzyl-4 '-hydroxy-benzyl) -3.5 -dimethyl-phenyl] ethylphosphonate as an oil (55 mg, 26%): 1 H NMR (300 MHz, DMSO-de): 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, 6H), 2.06 (m, 2H), 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; X H 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: Intermediate 2- [3,5-dimethyl-4- (4'-fluoro-3'-iso-propyl-benzyl) phenyl] -2-oxo-ethylphosphonate diethyl by the synthesis of compound 41-1 is transformed into diethyl 2- [3,5-dimethyl-4- (4'-fluoro-3'-iso-propyl-benzyl) phenyl] -2-hydroxyethylphosphonate by the process described by the synthesis of compound 42, step a to give a yellow liquid (580 mg, 96.2%): XH NMR (300 MHz, CDC13): d 7.12 (s, 2H), 6.99 (m, HH), 6.84 (m, HH), 6.66 (m, HH) ), 5.09 (s, ÍH), 4.19 (m, 4H), 4.01 (s, ÍH), 3.18 (m, ÍH), 2.22 (s, 6H), 2.20 (m, 2H), 1.36 (m, 6H) , 1.25 (d, J = 6.4 Hz, 6H). 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-hydroxy-ethylphosphonate (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 is purified by column chromatography (silica gel, ethyl acetate-hexanes: 9: 1) to give 2- [3,5-dimethyl-4- (4'-fluoro-3 '-iso-propyl-benzyl) phenyl] diethyl ethylphosphonate (450 mg, 93.5%): XH NMR (300 MHz, CDC13): d 6.99 (s, ÍH), 6.98 (s, 2H), 6.88 (m, ÍH), 6.66 (m, ÍH), 4.65 (m, 4H), 3.99 (s, 2H), 3.19 (m, ÍH), 2.88 (m, 2H), 2.24 (s, 6H), 2.10 (m, 2H), 1.51 (m, 6H), 1.25 ( d, J = 6.9 Hz, 6H). 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%): X H NMR (300 MHz, DMSO-d 6): d 7.09 (m, ÍH), 6.98 (m, ÍH), 6.92 (s, 2H), 6.66 (m, ÍH), 3.94 (s, 2H), 3. 95 (s, 2H), 3.11 (m, ÍH), 2.70 (m, 2H), 2.18 (s, 6H), 1.80 (m, 2H), 1.19 (d, J = 7.2 Hz, 6H). mp = 116-118, LC-MS m / z = 365 [C 20 H 26 FO 3 P + 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%); NMR (300 MHz, DMSO-de): d 6.79 (s, 2H), 3.72 (s, 3H), 2.37 (s, 6H); 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. -isopropyl thiophenol (US 6,747,048 B2, 600mg, 2.3 mmol) and 3,5-dimethyl-4-iodoanisole (678 mg, 3.72 mmol) in toluene (10mL). After refluxing overnight, the mixture of The cold reaction was emptied 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'-methoxyphenylsulfanyl) anisole (0.358 g, 49%); X H NMR (200 MHz, DMSO-de): d 6.87-6.80 (m, 4 H), 6.56 (m, H H), 3.76 (s, 3 H), 3.71 (s, 3 H), 3.15 (m, H H), 2.34 (s, 6H), 1.06 (d, 6H, J = 7Hz); 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-phenylsulfanyl) phenol was prepared from 2,5-dimethyl-4- (3'-iso-propyl-4) '-methoxy-phenylsulfanyl) anisole according to the procedure described in example 8, step d. 1 H NMR (300 MHz, DMSO-de): d 9.58 (bs, ÍH), 9.21 (bs, ÍH), 6.77 (m, ÍH), 6.63 (m, 3H), 6.46 (dd, ÍH, J = 2.7 Hz and J = 8.1 Hz), 3.09 (m, ÍH), 2.28 (s, 6H), 1.06 (d, 6H, J = 7.2 Hz); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 25% ethyl acetate in hexane; Rf = 0.12 Step d: Diethyl [3, 5-Dimethyl-4- (4'-hydroxy-3'-iso-) phosphonate propyl-phenylsulfanyl) -phenoxy] methyl was prepared according to the procedure described in compound 8, step e: 1 H NMR (300 MHz, DMSO-de): d 9.26 (s, ÍH), 6.92 (s, 2H), 6.81 (d, 1H, J = 2.4 Hz), 6.65 (d, ÍH, J = 8.4 Hz), 6.47 (dd, ÍH, J = 2.1 Hz and J = 8 Hz), 4.42 (d, 2H, J = 10 Hz), 4.11 (m, 4H), 3.10 (m, ÍH), 2.35 (s, 6H), 1.25 (m, 6H), 1.06 (d, 6H, J = 2.9 Hz); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 50% ethyl acetate in hexane; Rf = 0.12 Step e: 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, ÍH), 6.88 (s, 2H), 6.81 (d, J = 2.1 Hz, ÍH), 6.64 (d, J = 8.4 Hz, ÍH), 6.46 ( dd, J = 2 Hz and J = 8.2 Hz, ÍH), 4.08 (d, J = 10.2 Hz, 2H), 3.10 (m, ÍH), 2.34 (s, 6H), 1.07 (d, J = 6.6 H, 6H z); LC-MS m / z = 381 [? SH2? 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 until 70% B in 13min - maintained 1 min to 70% B - Gradient up to 100% B in 6 min. T.R. = 10.23 min.
Example 44: Compound 44: [3,5-dimethyl-4- [4 '-hydroxy-3' - (isopropylsulfonyl) benzyl] phenoxy] methylphosphonic acid 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 disulphide di-iso-propyl as the electrophilic. The product of this reaction was carried out in the next step as a mixture of the desired product and starting material triisopropyl- [3,5-dimethyl-4- (4'-methoxymethoxybenzyl) -phenoxy] silane: XH NMR (200 MHz , DMSO-de): d 1.15 (d, J = 6.4 Hz, 6H); 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'-isopropylsulfanylbenzyl) 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 product desired and 3,5-dimethyl-4- (4'-methoxymethoxybenzyl) phenol: 1 H NMR (200 MHz, DMSO-de): d 1.16 (d, J = 9.9 Hz, 6H); 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) phenoxy] methylphosphonate was prepared according to the procedure described in example 8, step e and was carried out a mixture of the desired product and [3, 5-dimethyl-4- (4'-methoxymethoxybenzyl) phenoxymethylphosphonate diethyl ester: * H NMR (200 MHz, DMSO-d6): d 4.36 (d, 2H, J = 15Hz), 4.11 ( m, 4H), 1.26 (t, 6H, J = 10.8 Hz), 1.16 (d, 6H, J = 9.9 Hz); LC-MS m / z = 465 [C23H3606PS + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 50% ethyl acetate in hexane; Rf = 0.12 Step d: A mixture of [3,5-dimethyl-4- (4'-methoxymethoxy-3'-iso-propylsulfanylbenzyl) phenoxymethylphosphonate diethyl ester (0.200g, 0.402mmol), saturated sodium bicarbonate (1Ml) and mCPBA 50% -60% (0.173g, 1.01mmol) in dichloromethane (5mL) 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 '- (isopropylsulfonyl) benzyl] phenoxy] methylphosphonate diethyl ester ( 0.090 g, 42%); l H NMR (200 MHz, DMSO-d 6): d 7.42 (s, ÍH), 7.24 (s, 2H), 6.77 (s, 2H), 5.32 (s, 2H), 4.36 (d, J = 10 Hz, 2H ), 4.11 (m, 4H), 3.96 (s, 2H), 3.69 (m, ÍH), 3.39 (s, 3H), 2.16 (s, 6H), 1.26 (t, J = 1 Hz, 6H), 1.12 (d, J = 1 Hz, 6H); 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, ÍH), 7.31 (s, ÍH), 7.12 (dd, J = 5.8, 2.2 Hz, HH z), 6.93 (d, J = 8 H, ÍH z), 6.72 (s, 2H), 4.04 (d, J = 10.2 H, 2H z), 3.89 (s, 2H), 3.64 (m, ÍH), 2.15 (s, 6H), 1.11 (d, J = 1 Hz, 6H); LC-MS m / z = 427 [C? 9H2507PS-H] "; CCD conditions: Silica gel uniplaca, 250 microns; Mobile phase = Isopropyl alcohol / NH40H / H20 [7: 1: 2]; Rf = 0.53; Calculated Analysis for (C? 8H2305PS + 1 M H20 + 0.1 M 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'-isopropyl) benzyl] benzofuran-2-phosphonic acid Step a: To a mixture of 3,5-dimethyl-4- (4 '-methoxymethoxy-3'-iso-propylbenzyl) phenol (1.0 g, 3.18 mmol, Chiellini et al., Bioorg, Med. Chem. Let t. 10: 2601 (2000)) in C2H5OH (30.0 mL) and 40% aqueous methylamine (6.20 mL) at 0 ° C was added a solution of potassium iodide (2.5 g, 15.0 mmol) and iodine (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 column chromatography on silica gel, eluting with 20% ethyl acetate in hexanes to provide 3,5-dimethyl-2-iodo-4- (4 '-methoxymethoxy-3'-iso-propylbenzyl) phenol as a white solid: X H NMR (300 MHz, CD30D): d 6.93 (m, 2 H), 6.65 (m, 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: To a mixture of Cu20 (0.08 g, 0.57 mmol) in DMF (2.0 mL) was added a solution of diethyl ethynylphosphonate (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, cooling 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. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel, eluting with 50% ethyl acetate in hexanes to give [, 6-Dimethyl-5- (4 '-hydroxy-3' - isopropyl) benzyl] benzofuran-2-diethyl phosphonate (0.07 g, 26%) as a colorless oil: * H 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 (m, 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 = acetate of ethylhexanes (1: 1] Rf 0.50 Step c: [4,6-Dimethyl-5- (4'-hydroxy-3'-isopropyl) benzyl] benzofuran-2-phosphonic acid was prepared from [4,6-Dimethyl-5- (4 '- hydroxy-3'-i so-propyl) benzyl] benzofuran-2-diethyl phosphonate according to the procedure described in example 7, step b: mp: 180-182 ° C; XH NMR (300 MHz, CD3OD): 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 [C2oH2305P + H] +; Analysis Calculated for (C20H23O5P + 0.7 H2O + 0.1 CH3OH): C, 61.87; H, 6.41. Found: C, 61.80; H, 6.60.
Example 46 Compound 46: [3,5-Dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) -2-iodophene] methylphosphonic acid The title compound was prepared from 3,5-dimethy1-4- (3 '-iso-propyl-4' -methoxymethoxy) benzyl-2-iodophenol (compound 45, step) according to the procedure described in example 7: X 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? 9H2 l05P + 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'-isopropylbenzyl) -phenylamino] methylphosphonic acid Step a: A solution of 3,5-dimethyl-4- (4'-methoxymethoxy-3'-isopropylbenzyl) -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 mL, 91.40 mmol), and Pd (OAc) 2 (0.102 g, 0.46 mmol) in DMF (25 mL) were added. heated to 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, eluting with ethyl acetate-hexanes (1: 4) to provide 3,5-dimethyl-4- (4'-methoxymethoxy-3'-isopropylbenzyl) benzoate methyl as an oil (1.52 g, 93%): 1 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 1 M NaOH (12.64 mL, 12.64 mmol). The reaction mixture was heated at 50 ° C for 16 h, cooling to 0 ° C and acidified with 2 N HCl. The mixture was extracted with ethyl acetate (20 mL) and washed with H2O (10 mLx2.). The solvent was removed under reduced pressure to provide 3,5-dimethyl-4- (4'-methoxymethoxy-3'-iso-propylbenzyl) benzoic acid as a white solid (0.71 g, 98%): XH NMR (300 MHz , DMSO-de): 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, 2H), 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 emptied 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 reduced pressure. The crude product was purified by column chromatography on silica gel, eluting 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%): XH RM? (300 MHz, DMSO-de): d 9.16 (s, 1 H), 7.16 (s, 2 H), 6.96 (m, 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- ('-methoxymethoxy-3'-iso-propylbenzyl) carbamate (0.315 g, 0.76 mmol) in THF (8.0 mL) at -78 ° C lithium diisopropylamide (0.46 g, 0.91 mmol, 2.0 M solution in THF / heptane / ethylbenzene) was added. The reaction mixture was stirred at -78 ° C for 20 min and the 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 reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1: 1) to give N-t-butoxycarbonyl- [3,5-dimethyl-4- (4 '-methoxymethoxy-3 '-isopropylbenzyl) phenylamino] methylphosphonate diethyl as an oil (0.21 g, 49%): XH RM? (300 MHz, DMSO-de): d 7.00 (s, 2 H), 6.94 (m, 1 H), 6.90 (m, 1 H), 6.64 (m, 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 (m, 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 N- t -butoxycarbonyl- [3,5-dimethyl-4- (4'-methoxymethoxy-3'-isopropylbenzyl) 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 α to HCO3, diluted with ethyl acetate (20 mL) and washed with H20 (10 mL × 2). The organic solution was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting 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%): 1H NMR? (300 MHz, DMSO-de): d 8.95 (s, 1 H), 6.84 (m, 1 H), 6.63 (s, 2 H), 6.63 (m, 1 H), 6.50 (m, 1 H), 5.39 (m, ÍH), 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 de gel de silica, 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'-isopropylbenzyl) phenylamino] methylphosphonate (0.070 g, 0.17 mmol) in CH2C12 (3.0 mL) at -30 ° C bromotrimethylsilane (0.28 mL, 2.08 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 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 H2O. 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; H NMR (300 MHz, DMSO-de): 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 [C? 9H26N04P-H] +; Analysis Calculated for (C19H26N04P + 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-dimethylphenoxy] methylphosphonic acid Step a: To a suspension of methyltrifosphonium bromide (4.81 g, 13.46 mmol) in THF (10.0 mL) at 0 ° C was added n-butyllithium. (4.30 g, 10.76 mmol, 2.5 M solution in hexane). 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 synthesis) was added thereto. from Example 35, step d) in THF (5.0 mL). The reaction mixture was stirred at room temperature during 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, eluting 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%): 1 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 (s, 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 iodine (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 ( 0.053mL, 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. The solvent was removed under reduced pressure to provide triisopropyl- [4- (3'-cyclopropyl-4'-methoxymethoxybenzyl) -3,5-dimethylphenoxy] silane as an oil (0.14 g, 91%): 1 H NMR (300 MHz, DMSO -de): 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 ( m, 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, eluting with ethyl acetate-hexanes (1: 9) to give 4- (3'-cyclopropyl-4'-methoxymethoxybenzyl) -3,5-dimethylphenol as an oil. (0.18 g, 71%): t 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. Mix The reaction mixture was cooled to 0 ° C, quenched with cold IN HCl and extracted with ethyl acetate (8.0 mL). The organic solution was 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: 1) to provide [4- (3'-cyclopropyl-4'-methoxymethoxybenzyl) -3,5-dimethylphenoxy] methylphosphonate diethyl as oil (0.10 g, 28%): X H NMR (300 MHz, DMSO-d 5): 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 min and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with H0. The solution organic 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; 1ti NMR (300 MHz, DMSO-de): 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 (m, 1 H), 0.81 (m, 2 H), 0.47 (m, 2 H); LC-MS m / z = 362 [C? 9H2305P-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 Na 2 S 2 γ 4 (29 g, 165.13 mmol). The mixture was stirred at room temperature for 3 h, filtered and concentrated. The residue was partitioned between EtOAc and water. The organic layer was collected and dried over Na 2 SO 4, filtered and concentrated under reduced pressure to provide the 2-amino-4-bromo- Crude phenol as a yellow solid (3.9 g, 75%): X H NMR (200 MHz, DMSO-de): 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 mL) 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. The 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 4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting 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 CH2Cl2 (100 mL) at room temperature was added ethyl-diisopropyl-amine (4.47 mL, 25.7 mmol) and chloro-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 Na2SO4, filtered and concentrated under reduced pressure to give crude N- (5-bromo-2-methoxymethoxyphenyl) dimethylamine as a red oil (4.4 g, 99%):? RM? (200 MHz, DMSO-de): 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-methoxymethoxy-phenyl) 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? H 4 Cl and was diluted with diethyl ether. The organic layer was dried over? A2S04, filtered and concentrated under reduced pressure.
The crude product was purified by column chromatography on silica gel, eluting 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%):? H NMR (300 MHz, DMSO-d6): 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. 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 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 give N- [5- (2 ', 6'-dimethyl-4'- triisopropylsilyloxybenzyl) -2-methoxymethoxyphenyl] dimethylamine as a yellow oil (3 g, 91%): X 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 mL, 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, eluting with ethyl acetate-hexanes (1: 1) to give 4- (3'-dimethylamino-4'-methoxymethoxybenzyl) -3,5-dimethylphenol as an oil light yellow (1.8 g, 90%): * H RM? (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: Uniplaca of silica gel, 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. The solvent was removed under reduced pressure, and the residue was partitioned between EtOAc and saturated NaHCO 3. 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, eluted with ethyl acetate-hexanes (8: 2) to provide [diethyl 4- (3'-dimethylamino-4'-methoxymethoxybenzyl) -3,5-dimethylphenoxy] methylphosphonate as a light yellow oil (0.5 g, 65%): 1 H NMR (300 MHz, DMSO-de): 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 min 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 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-CH 2 Cl 2 (3: 1) to give [4- (3 '- diethyl dimethylamino-4'-hydroxybenzyl) -3,5-dimethyl-phenoxy] methylphosphonate as a light yellow oil (0.29 g, 67%): X H NMR (200 MHz, DMSO-de): d 8.77 (s, 1 H ), d 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; = ethyl acetate-CH2Cl (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. H NMR (300 MHz, DMSO-de): 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: degasses at 90 ° C; LC-MS m / z = 366 [C18H24N05P + H] +; Analysis Calculated for (C18H24N05P + 1.4HBr + 0.4H2O + O.lMeOH): 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 diethyl [3, 5-dimethyl-4- (3'-carboxy-4'-methoxymethoxybenzyl) phenoxymethylphosphonate (0.36 g, 0.77 mmol) in toluene (20 mL) at room temperature was added azide. of diphenylphosphoryl (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 is dried over Na2SO4, filtered and concentrated under reduced pressure.
The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate to give [diethyl 4- (3'-benzyloxycarbonylamino-4'-methoxymethoxybenzyl) -3,5-dimethylphenoxy] methylphosphonate as a light yellow oil (0.4 g, 91%): 1 H 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. Four. Five.
Step b: To a stirred solution of diethyl [4- (3'-benzyloxycarbonylamino-4'-methoxymethoxy-benzyl) -3,5-dimethylphenoxy] methylphosphonic 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 min by microwave. The solvent was removed under reduced pressure, and the residue was partitioned between EtOAc 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, eluting with ethyl acetate to provide [diethyl 4- (3 '-benzyloxycarbonylamino-4' -hydroxybenzyl) -3,5-dimethylphenoxy] methylphosphonate as a light yellow oil (0.076 g, 82%): * H NMR (300 MHz, DMSO-d6): 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 Na 2 SO 4, 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, DMSO-de): 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: shrink a 180 ° C. LC-MS m / z = 472 [C 24 H 26 N 0 7 P + 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 diethyl [4- (3'-benzyloxycarbonylamino-4'-methoxymethoxybenzyl) -3,5-dimethylphenoxy] methylphosphonic acid (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%): 1 H 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, J = 7 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] methylphosphonic acid (0.13 g, 0.3 mmol) in CHC12 (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 it was divided between CH2CI2 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 [3,5-dimethyl-4- (3'-methanesulfonylamino-4'-methoxymethoxybenzyl) phenoxymethylphosphonate diethyl ester as a light yellow oil ( 0.12 g, 77%): X H 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) phenoxymethylphosphonate (0.12 g, 0.23 mmol) in MeOH (2 mL) at room temperature was added HCl (1.2 mL, 2 N), and the reaction mixture was heated at 100 ° C for 5 min 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 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 [3, 5-dimethyl-4- (4'-hydroxy-3'-methanesulfonylaminobenzyl) phenoxymethylphosphonate diethyl ester as a white solid (0.08 g, 74%): 1 H NMR (300 MHz, DMSO-de): d 6.85 (d, J = 1.8 Hz, 1 H), 6.76 (m, 3 H), 6.63 (m, 1 H), 4. 37 (d, J = 9.9 Hz, 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-de): 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: reduced to 200 ° C; LC-MS m / z = 416 [C17H22N07PS + H] +; Calculated Analysis for (C17H22N07PS + 0. lMeOH + 0.8H2O): C, 47.43; H, 5.59; N, 3.23. Found: C, 47.57; H, 5.68; N, 3.10. Using the appropriate starting material, compounds 51-2 were prepared in a manner analogous to that described by the synthesis of compound 51-1.
Compound 51-2: [3,5-Dimethyl-4- (4'-hydroxy-3'-trifluoroacetylaminobenzyl) phenoxy] methylphosphonic acid X H NMR (200 MHz, DMSO-de): 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 + 0.4H2O): 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: Diethyl (3 '-amino-4' -hydroxybenzyl) -3,5-dimethylphenoxy] methylphosphonate was prepared according to the procedure described by the synthesis of example 51-1, step c: 1 H NMR (200 MHz , DMSO-de): 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. EtOAc and water were added. 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 to provide [3, 5-dimethyl-4- (4'-hydroxy-3'-isobutyrylaminobenzyl) phenoxymethylphosphonate diethyl ester as a yellow oil (0.046 g, 83%): 1 H NMR (300 MHz, DMSO- de): d 9.55 (s, 1 H), 9.22 (s, 1 H), 7.36 (s, 1 H), 6.73 (m, 3 H), 6.58 (m, 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: X H NMR (200 MHz, DMSO-de): 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 + 0.9H2O + 0.45HBr): 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- ('-hydroxy-3' -isopropylbenzyl) benzenesulfonyl] methylphosphonic acid Step a: To a stirred solution of 3,5-dimethyl-4- (4'-methoxymethoxy-3'-iso-propylbenzyl) 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, eluting 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 (m, 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) methylsulfanylbenzene (0.24 g, 0.7 mmol) at room temperature in CH2Cl2 (10 mL) was added m-CPBA (0.42 g, 2.45 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 NaSO 4, filtered and concentrated under reduced pressure to provide 3,5-dimethyl-4- (4'-methoxymethoxy-3'-iso-propylbenzyl) methylsulfonylbenzene as a light yellow oil ( 0.23 g, 87%): X H NMR (200 MHz, CDCl 3 -d 2): 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 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 diethylphosphorocloridate (0.11 mL, 0.73 mmol) was added at 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 4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate to give [3, 5-dimethyl-4- (4'-methoxymethoxy-3'-iso-propylbenzyl) phenylsulfonyl] methylphosphonate diethyl ester as a light yellow oil (130 mg, 42%): 1 H NMR (200 MHz , DMSO-de): 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, 6H), 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: 1 H NMR (200 MHz, DMSO-d 6): 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, H 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 + 1.0H2O + 0.15HBr + 0.2Et2O): 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 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: 9) to give (4-bromo-2,6-dimethylphenoxy) triisopropylsilane as a colorless oil (1.6 g, 15% ): 1 H NMR (300 MHz, DMSO-de): 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 The reaction mixture was stirred at -78 ° C for 1 hr, then dimethyldisulfide (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 NHC1 and diluted with diethyl ether. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give crude (2,6-dimethyl-4-methylsulfanylphenoxy) triisopropyl-silane as an oil. (0.46 g, 100%):? H NMR (300 MHz, DMSO-de): 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 with 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%): * H NMR ( 200 MHz, DMSO-d6): 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 de 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 diethyl phosphorochloridate (0.25 mL, 1.72 mmol) was added 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, eluting with ethyl acetate-hexanes (1: 1) to provide (3,5-dimethyl-4-triisopropylsilanyloxy-benzenesulfonyl) methylphosphonate diethyl ester as a colorless oil (0.1 g , 15%): X 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 (3, 5-dimethyl-4- triisopropylsilanyloxy-benzenesulfonyl) methylphosphonate from diethyl 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 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 (5: 1) to provide (3,5-dimethyl-4-hydroxybenzenesulfonyl) methylphosphonate diethyl as a light yellow oil (70 mg , 100%): 1 H NMR (300 MHz, CDC13-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) iodonium tetrafluoroborate (0.15 g, 0.3 mmol) and copper powder (16 mg, 0.26 mmol) in CH 2 Cl 2 (5 mL) at 0 ° C was added a solution of triethylamine (0.031 mL, 0.22 mmol) and diethyl (3,5-dimethyl-4-hydroxybenzenesulfonyl) methylphosphonate (70 mg, 0.2 mmol) in CH2Cl2 (2 mL). The reaction mixture was stirred at room temperature for 16 hrs and filtered through a plug of Celite. The solvent was removed under pressure reduced and the crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (5: 1) to provide [3,5-dimethyl-4- (4'-methoxy-3'-iso- diethyl propylphenoxy) benzenesulfonyl] methylphosphonate as a light yellow oil (40 mg, 41%): 1 H NMR (200 MHz, DMSO-de): 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, 1 H), 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): X H NMR (200 MHz, DMSO-de): 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 + 1.3H20 + O.lEtOAc): 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-propylphenoxy) benzenesulfanyl] methylphosphonic 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 plug of Celite. 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 min by microwaves. 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-dimethyl-4-triisopropylsilanyloxy-phenylsulfanyl) methylphosphonate. diethyl as a yellow oil (1.6 g, 52%): XH RM? (200 MHz, DMSO-de): d 7.09 (s, 2 H), 4.98 (m, 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. Four. Five.
Step b: The title compound was prepared according to the procedure described by the synthesis of example 53, steps e, f and g: X 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 m / z = 383 [C18H2305PS + H] +; Analysis Calculated for (C18H2305PS + 0.15TFA + 0.2Et2O): 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 diethyl [3, 5-dimethyl-4- (3'-amino-4'-methoxymethoxybenzyl) phenoxy] methylphosphonate (Example 51, step a, 0.29g, 0.66 mmol) at 80 ° C. in dimethyldisulfide (3 mL), isoamyl nitrite (0.4 mL, 2.64 mmol) was added. The reaction mixture was stirred at 80 ° C for 1 h. The solvent it was removed under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1: 1) to give [3,5-dimethyl-4- (3'-methylsulfanyl-4'-methoxymethoxybenzyl) phenoxymethylphosphonate diethyl ester as a red oil (0.12 g, 39%):? H NMR (200 MHz, DMSO-de): 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, DMSOde): 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); LC-MS m / z = 369 [C? 7H2? 05PS + H] +; Analysis Calculated for (C? 7H2? 05PS + O.lEtOAc + 0.1TFA): C, 54.40; H, 5.68. Found: C, 54.65; H, 5.33.
Example 56: Compound 56: 3, 5-Dichiane-4- (4'-hydroxy-3'-iso-propylphenoxy) phenoxymethylphosphonate 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) iodonium 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, eluting 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-d 6): 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 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, eluting with acetone-hexanes (1: 9) to give 3,5-diiodo-4- (4'-methoxy-3-benzoate. '-iso-propylphenoxy) phenyl as an opaque white solid (0.61 g, 98%): 1 NMR (300 MHz, DMSO-d6): 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, ÍH), 6.73 (d, J = 3.0 Hz, ÍH), 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: To a stirred solution of 3,5-diiodo-4- (4'-methoxy-3'-iso-propylphenoxy) phenylbenzoate (0.4 g, 0.76 mmol) in DMF (5.0 mL) at t.a. CuCN (0.27 g, 3.0 mmol) was added. The reaction mixture was heated at 160 ° C for 5 min under microwave irradiation, the reaction mixture was cooled to room temperature and emptied into IN HCl (50 mL) and extracted with ethyl acetate (100 mL x 2). The layers Organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (3: 7) to provide 3,5-dicyano-4- (4'-methoxy-3'-iso-propylphenoxy) phenol as a viscous oil (105 mg, 35%): XH 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%) : 1H NMR (300 MHz, CD3OD) d 7.38 (s, 2H), 6.81 (d, J = 3.0 Hz, ÍH), 6. 70 (d, J = 9.0 Hz, ÍH), 6.52 (dd, J = 9.0, 3.0 Hz, ÍH), 3. 26 (heptet, J = 7.0 Hz, ÍH), 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.
Step 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 t.a. After stirring at a.t. 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) phenoxymethylphosphonate diethyl (44 mg, 22%): H NMR (300 MHz, CDC13) d 7.42 (s, 2H), 6.73 (d, J = 3.0 Hz, ÍH), 6.68 (d, J = 9.0 Hz, ÍH), 6.57 (dd, J = 9.0, 3.0 Hz, ÍH), 4.35-4.20 (m, 6H), 3.23 (heptet, J = 7.0 Hz, ÍH), 1.38 (t, J = 7.0 Hz, 6H), 1.18 (d , J = 7.0 Hz, 6H); CCD conditions: Merck silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (1: 1), R = 0.2.
Step f: The title compound was prepared by the procedure described for the synthesis of compound 8, step f (18 mg, 47%): X H NMR (300 MHz, CD 3 OD) d 7.74 (s, 2 H), 6.85 (d, J = 3.0 Hz, HH), 6.72 (d, J = 9.0 Hz, HH), 6.56 (dd, J = 9.0, 3.0 Hz, HH), 4.35 (d, J = 6.8 Hz 2H), 3.27 (heptet, J = 7.0 Hz, ÍH), 1.18 (d, J = 7.0 Hz, 6H); Analysis Calculated for (C? 8H? 7N2? 6P + 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-yloxy] methylphosphonic 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 hydroxymethyl phosphonate of diethyl (0.045 mL, 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, eluting with ethyl acetate-hexanes (2: 1) to provide [4,6-dichloro-3-fluoro-5- (4'-hydroxy-3 '- iso-propylphenoxy) -pyrid-2-yloxy] diethyl methylphosphonate as a yellow oil (43 mg, 28%): X H NMR (300 MHz, DMSO-de): 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; 1 H 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); LCMS m / z = 427 [C? 5H15C? 2FN06P + H] +; Analysis Calculated for (C? 5H? 5C? 2FN06P + 0.5H2O): 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-dimethylphenoxy] methylphosphonic acid: A mixture of [3,5-Dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl]] phenoxy] methylphosphonic acid (5.0 g, 13.7 mmol) and acetic anhydride (5.0 g, 48.9 mmol) in toluene (70 mL) ) HE 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 and evaporation of toluene 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 boiled isopropyl ether, cooled to 20 ° C, collecting the solid by filtration and drying under vacuum, mp: 169-172 ° C; 1 H NMR (300 MHz, DMSO-d 6): d 7.06 (d, J = 2.1 Hz, HH), 6.85 (d, J = 8.4 Hz, HH), 6.70 (s, 2H), 6.65 (dd, J = 9.0 and 2.4 Hz, HH), 4.02 (d, J = 10.2 Hz, 2H), 3.90 (s, 2H), 2.94-2.84 (m, HH), 2.25 (s, 3H), 2.15 (s, 6H), 1.07 (d, J = 6.9 Hz, 6H). Analysis Calculated for (C2? H2706P): C, 62.06; H, 6.70. Found: C, 62.22; H, 6.82.
Example 59 Cis and Trans (S) -2- [(4- (4'-Acetoxy-3'-iso-propylbenzyl) -3,5-dimethylphenoxy) methyl] -4- (3-chlorophenyl) -2-oxo- 2? 5- [1,3,2] -dioxaphosphonane: 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 [4- (4'-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 it was 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, eluting with ethyl acetate-hexanes (50% -100%) to provide: Compound 59-trans: (610 mg, 14%): XH NMR (300 MHz, DMSO- of): d 7.48-7.36 (m, 4H), 7.07 (d, J = 2.1 Hz, ÍH), 6.85 (d, J = 8.4 Hz, ÍH), 6.83 (s, 2H), 6.64 (dd, J = 9.0 and 2.0 Hz, ÍH), 5.85-5.82, (m, ÍH), 4.74-4.68 (m, 1H), 4.61 (d, J = 9. 3 Hz, 2H), 4.52-4.42 (m, ÍH), 3.92 (s, 2H), 2.94-2.85 (m, ÍH), 2.25 (s, 3H), 2.24-2.20 (m, 2H), 2.17 (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 = 0.5 Compound 59-cis: (2.5g, 57%): XH NMR (300 MHz, DMSO-de): d 7.47 (m, ÍH), 7.38-7.26 (m, 3H), 7.06 (d, J = 2.1 Hz, ÍH), 6.85 (d, J = 8.7 Hz, ÍH), 6.76 (s, 2H), 6.67 (dd, J = 8.1 and 2.1 Hz, ÍH), 5.76-5.72 (m, ÍH), 4.61-4.36 (m , 4H), 3.92 (s, 2H), 2.94-2.85 (m, ÍH), 2.25 (s, 3H), 2.20-2.19 (m, 2H), 2.16 (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 = 0.35; Analysis Calculated for (C 30 H 34 ClO 6 P + 0.13 H 20): 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-methylphenoxy] methylphosphonic acid Step a: To a stirred solution of l-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 NHC1 and diluted with diethyl ether. The organic layer was dried over Na 2 SO 4, filtered and concentrated under reduced pressure to provide 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 stirring at a.t. for 6 hours, the reaction mixture was filtered through Celite and concentrated under reduced pressure to give crude 4- (4'-methoxy-2'-methyl-3'-iso-propylbenzyl) -3-methyl-anisole as a yellow oil (0.8 g, 93%): X H NMR (300 MHz, DMSO-de): 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, IM in CH2C12). The reaction mixture was stirred at room temperature for 16 hrs. Ice was added and the mixture was diluted with CH2C1. The organic layer was dried over NaSO4, 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 4- (4'-hydroxy-2'-methyl-3'-iso-propylbenzyl) -3 -methylphenol as a yellow solid (0.54 g, 75%): 1 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.
Step 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 Cs2C03 (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. 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 raw product is purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (4: 1) to provide [4- (4'-Hydroxy-3'-iso-propyl-2'-methylbenzyl) -3-methylphenoxy] methylphosphonate diethyl ester as a colorless oil (0.14 g, 17%): XH NMR (300 MHz, DMSO-de ): 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 (m, 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%): X H NMR (300 MHz, DMSOde): 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 + 0.13HBr): 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) -2,5,5-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 mL) 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, eluting with 10% ethyl acetate in hexanes to provide 2,4-dimethyl-6-hydroxy-3- (4'-methoxymethoxy). Methyl -3 '-iso-propylbenzyl) benzoate (0.32 g, 38%): 1 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 MgSO 4, 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 2,4-dimethyl-6-hydroxy-3- ('-methoxymethoxy-3'-iso-propylbenzyl) benzyl alcohol: 1 HOUR 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.
Step 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 a H 2 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: XH 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 (s, 1 H), 2.19 (s, 3 H), 2.16 (s, 3 H), 2.11 (s, 3 H), 1.17 (d, J = 10.8 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 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; H 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 [C20H27? 5P + 1.1 H20]: C, 60.32; H, 7.39. Found: C, 60.05; H, 7.14.
Example 62 Compound 62 [6-iodo-4- (4'-hydroxy-3'-isopropylbenzyl) -2,5,5-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 transformed into the title compound according to the procedure described by synthesis of compound 7-1: mp: 185-187 ° C; X 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 (m, 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 [C 20 H 27 O 5 P] +; Analysis Calculated for (C20H26IO5P + 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 Stage 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) in accordance with the procedure described by the synthesis of compound 4 , step a: XH NMR (200 MHz, DMSO-de): 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 (0Ac) 2 (0.031 g, 0.14 mmol) in toluene (40 mL) at t.a. 2, 2'-bis (diphenylphosphino) -1, 1'-biphenyl (0.13 mL, 0.21 mmol) was added (+/-). The reaction mixture was stirred at t.a. for several minutes and CS2C03 (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 toluene), and diethyl aminoethyl phosphonate 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 t.a., diluted with diethyl ether (25 mL), filtered and concentrated. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1: 1) to provide [3-bromo-4- (4'-methoxy-3'-iso-propylphenoxy) -5 diethyltrifluoromethylphenylamino] methylphosphonate as an oil (0.28 g, 18%): 1 H NMR (300 MHz, DMS0-d 6): d 7. 33 (m, 1 H), 7.16 (m, 1 H), 6.85 (m, 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; X H NMR (300 MHz, CD 3 OD): 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 [C? 7H? 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: Omin: 20% B; 13 min: 70% B; 16min: 100% B; 18min: 20% B. Flow ratio = 2.0 mL / min; UV @ 254 nm. tr = 9.16min.
Example 64 Compound 64: [3,5-Dimethyl-4- [4 '-hydroxy-3' - (3-trifluoromethylphenoxy) benzyl] phenoxy] methylphosphonic acid Step a: To 5- (2,6-dimethyl-4-triisopropylsilanyloxybenzyl) -2-methoxymethoxy-benzaldehyde (compound 15, step e; 0.460 g, 1 mmol) in dichloromethane 30 mL was added mCPBA (0.870 g, 2.52 mmol ) and saturated sodium bicarbonate solution (2 mL). After stirring at t.a. overnight, the reaction mixture was poured into dichloromethane 50 mL and washed 3 x with 10 mL of 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 IN NaOH and stirred for 1.5 hours at room temperature. The reaction was made acidic with 12 N HCl (pH <3) and it was emptied into 50 mL ethyl acetate. The layers were separated and the 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%): X H NMR (300 MHz, DMSO-dg): d 8.95 (s, 1 H), 6.86 (d, H, J = 8.1 Hz), 6.56 (s, 2 H), 6.41 (d, ÍH, J = 2.1 Hz), 6.34 (dd, ÍH, J = 2.1 Hz and J = 8.7 Hz), 5.05 (s, 2H), 3.78 (s, 2H), 3.38 (s, 3H), 2.13 (s, 6H), l.ll (m, 3H), 1.00 ( m, 18H); 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%). t H NMR (300 MHz, DMSO-d 6): d 7.53 (t, H, J = 7.8 Hz), 7.35 (d, H, J = 7.8 Hz), 7.21-7.10 (m, 2 H), 6.98 (s, H) ), 6.89 (m, ÍH), 6.59 (m, ÍH), 6.64 (s, 2H), 5.09 (s, 2H), 3.89 (s, 2H), 3.18 (s, 3H), 2.11 (s, 6H) , 1.16 (m, 3H), 1.01 (m, 18H); 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, ÍH), 7.55 (t, ÍH, J = 7.8 Hz), 7.38 (1H, d, J = 8.4 Hz), 7.14 (m, 2H), 7.02 (s, ÍH), 6.88 (dd, ÍH, J = 1.5 Hz and J = 6. 6 Hz), 6.72 (d, ÍH, 2.1 Hz), 6.44 (s, 2H), 5.08 (s, 2H), 3.85 (s, 2H), 3.18 (s, 3H), 2.08 (s, 6H); (Silica gel uniplaca, 250 microns; Mobile phase = 25% ethyl acetate in hexane: Rf = 0.28.
Step d: Diethyl [3,5-dimethyl-4- [4 '-methoxymethoxy-3' - (3-trifluoromethyl-phenoxy) benzyl] phenoxymethylphosphonate was prepared according to the procedure described by the synthesis of compound 8, steps e (0.015 g, 15%); X H NMR (300 MHz, DMSOde): d 7.55 (t, H, J = 8.4 Hz), 7.37 (d, H, J = 7.5 Hz), 7.14 (m, 2 H), 7.02 (s, H), 6.86 ( dd, ÍH, J = 1.7Hz and J = 7 Hz), 6.73 (s, 2H), 5.08 (s, 2H), 4.34 (d, 2H, J = 9.9 Hz), 4.09 (m, 4H), 3.91 ( s, 2H), 3.18 (s, 3H), 2.18 (s, 6H), 1.24 (t, 6H, J = 1 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%); X H NMR (300 MHz, DMSO-d 6): d 9.48 (s, HH), 7.53 (t, HH, J = 7.8 Hz), 7.34 (d, HH, J = 7.2 Hz), 7.07 (d, HH, J = 9 Hz), 7.01 (s, ÍH), 6.90 (d, ÍH, J = 8.4 Hz), 6.71 (m, 4H), 4.00 (d, 2H, J = 10.2 Hz), 3.84 (s, 2H), 2.15 (s, 6H); LC-MS m / z = 481 [C23H22F306P-H] "; Uniplaca gel silica, 250 microns; Mobile phase = isopropyl alcohol / water / ammonium hydroxide [7: 2: 1]: Rf = 0.47; CLAR, zorbax, XDB-C8, 150mm x 4.6 mm, 5um, flow 1 mL / min, Solvent A: 0.05 M KH2P04 aqueous pH 6.2, Solvent B: acetonitrile, Gradient 40% B up to 60% B for llmin then 60% B . Total run time 12 min. T.A. 1.87 min; Analysis Calculated for (C 23 H 22 F 306P + 0.3 M H 20 + 0.1 M 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), (Chiellini et al., Bioorg, Med. Chem. Lett.10: 2601 (2000)) in EtOH (6.2 mL) and CH3NH2 40% in water (2.5 mL) was added iodine (0.39 g, 1.54 mmol) and Kl (0.25 g 1.54 mmol) in H2O (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 mLx2). The combined organic layers were 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 2,6-diiodo-3,5-dimethyl-4- (4 '-methoxymethoxy-3' -isopropylbenzyl) phenol as a colorless oil (198 mg, 50%): 1 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) a 0 ° C Cs2CO3 (0.34 g, 1.05 mmol) was added. After 10-min, diethyl trifluoromethanesulfonyloxymethylphosphonate (0.1 g, 0.35 pmol) 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 IN HCl, diluted with ethyl acetate, and washed with water (10 mLx4) and brine. The organic layer is 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-3,5-dimethyl-4 - (3'-Isopropyl-4'-methoxymethoxybenzyl) phenoxymethylphosphonate diethyl ester as an oil (0.21 g, 85%): XH 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) , 2H), 3.50 (s, 3H), 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 the acid 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; 1 H NMR (300 MHz, CD 3 OD): 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 / z = 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 = UV @ 280 nm retention time in min: 13.82; Analysis Calculated for (C20H25O6P + 0.9 H20): C, 36.09; H, 3.95. Found: C, 35.80; H, 4.22. Using the appropriate starting material, 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'-isopropylbenzyl) phenoxy] methylphosphonic acid Step A: A stirred solution of 3,5-dimethyl-4- (4 '-methoxymethoxy-3'-iso-propylbenzyl) phenol (0.2 g, 0.63 mmol), (Chiellini et al., Bioorg, Med.Chem.Lett.10: 2601 (2000)) in EtOH (6.0 mL) and CH3NH2 40% in water (2.5 mL) was added bromine (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, eluting 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%): 1ti 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; XH NMR (300 MHz, CD3OD): 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 [C19H2.3I2O5P + H] At CLAR conditions: ODSAQ column AQ-12S05146W; mobile phase = 0.05% TFA / CH3CN: 0.05% TFA / H2O. (1: 1) flow ratio = 1.0 mL / min; detection = UV @ 254 nm retention time in min: 10.45; Analysis Calculated for (C2oH23Br205P): 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. 38: 695 (1995), 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 turned into a clear orange solution. After stirring 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 orange solution turned green and was formed a precipitate. 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- ( 4'-methoxy-3 '-iso-propylphenoxy) -phenyl hydrazine (305 mg, 45%): tH NMR (300 MHz, CDC13) d 6.77 (d, J = 3.0 Hz, ÍH), 6.67 (d, J = 9.0 Hz, HH) 6.58 (s, 2H), 6.37 (dd, J = 9.0, 3.0 Hz, HH), 3.77 (s, 3H), 3.27 (heptet, J = 6.9 Hz, HH), 2.09 (s, 3H ), 1.18 (d, J = 6.9 Hz, 6H); CCD conditions: Merck silica gel, 250 microns; Mobile phase = dichloromethane-methanol (9: 1), Rf = 0.6.
Step b: The 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 divided between ethyl acetate and water and the layer organic 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 , 6-dimethyl-4- (4'-methoxy-3'-diiso-propylphenoxy) indolephosphonate diethyl ester (276 mg, 61%): 1 H NMR (300 MHz, CDC13) d (s, 1H, exchangeable with D20), 7.17 (s, ÍH), 7.07 (m, ÍH), 6.83 (d, J = 3.0 Hz, ÍH), 6.65 (d, J = 9.0 Hz, ÍH), 6.34 (dd, J = 9.0, 3.0 Hz, ÍH) ), 4.30-4.08 (m, 4H), 3.77 (s, 3H), 3.28 (heptet, J = 6.9 Hz, ÍH), 2.35 (s, 3H), 2.24 (s, 3H), 1.37 (t, J = 7.1 Hz, 6H), 1.18 (d, J = 6.9 Hz, 6H); 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) indolophosphonic acid was prepared according to the procedure described by the synthesis of example 8, step f (100 mg, 51% ): XH NMR (300 MHz, CD3OD) d 7.14 (s, ÍH), 6.97 (s, ÍH), 6.75 (d, J = 9.0 Hz, ÍH), 6.68 (d, J = 3.0 Hz, ÍH), 6.35 (dd, J = 9.0, 3.0 Hz, HH), 3.75 (s, 3H), 3.25 (heptet, J = 6.9 Hz, HH), 2.27 (s, 3H), 2.16 (s, 3H), 1.11 (d, J = 6.9 Hz, 6H); LCMS m / z = 390.4 [C20H24 O5P + H] A 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 acid (100 mg, 0.26 mmol) in dichloromethane (10 mL) at -78 ° C. The ice bath was stirred and the reaction mixture was heated to t.a. After stirring at a.t. 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 (86.3 mg, 80%). %): * H NMR (300 MHz, CD3OD) d 7.18 (s, ÍH), 6.97 (d, J = 3.0 Hz, ÍH), 6.60 (s, ÍH), 6.57 (d, J = 9.0 Hz, ÍH) , 6.26 (dd, J = 9.0, 3.0 Hz, ÍH), 3.22 (heptet, J = 6.9 Hz, ÍH), 2.28 (s, 3H), 2.18 (s, 3H), 1.12 (d, J = 6.9 Hz, 6H); Analysis Calculated for (C19H22N05P + 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. Example 67 Compound 67: 2- [3,5-dibromo-4- (4'-hydroxy-3'-isopropylphenoxy) phenyl] ethylphosphonic acid Step a: To a solution of dimethyl methylphosphonate (0.06 g, 0.48 mmol) in THF (3.0 mL) at -78 ° C was slowly added LDA (0.25 mL, 2 M in THF). After 30 min, a solution of 3,5-dibromo-4- (3'-isopropyl-4'-methoxylphenoxy) benzyl bromide (0.20 g, 0.40 mmol, intermediate for the synthesis of compound 19-1) in THF is he added. The reaction mixture was stirred at -78 ° C for 5 min, allowed to warm to room temperature and stirred for 2 h. The reaction mixture was quenched with aqueous NH4C1 (10.0 mL) and extracted with ether (10.0 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 50% acetone in hexanes to provide dimethyl 2- [3,5-dibromo-4- (4'-methoxy-3'-isopropylphenoxy) phenyl] ethylphosphonate (0.09 g, 43%) as a colorless oil: XH NMR (300 MHz, CD3OD): d 7.64 (s, 2H), 6.82 (d, J = 10.0 Hz, ÍH), 6.75 (d, J = 4.2 Hz, ÍH), 6.44 (dd, J = 2.8, 10.2 Hz, ÍH), 3.79 (d, J = 2.8 Hz, 6H), 3.76 (s, 3H), 3.30 (m, ÍH), 2.94 (m, 2H), 2.23 (m, 2H), 1.17 (d, J = 7.0 Hz, 6H); LC-MS m / z = 537 [C2oH25 Br205P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (1: 1); Rf = 0.50.
Step b: The title compound was prepared from dimethyl 2- [3,5-dibromo-4- (4 '-methoxy-3'-isopropylphenoxy) phenyl] ethylphosphonate in accordance with the procedure described by the synthesis of compound 4 , step b: mp: 56-59 ° C; X H NMR (200 MHz, DMSO-de): d 9.02 (s, ÍH), 7.65 (s, 2H), 6.64 (m, 2H), 6.21 (dd, J = 2.8, 10.2 Hz, ÍH), 3.14 (m , HH), 2.79 (m, 2H), 1.87 (m, 2H), 1.11 (d, J = 7.0 Hz, 6H); LCMS m / z = 495 [C17H19 Br205P + H] +; Analysis Calculated for (C? 7H19 Br205P +0.5 H20): C, 40.58; H, 4.01. Found: C, 40.26; H, 4.22.
Example 68 Compound 68: [3,5-Dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) benzyl] phosphonic acid Step a: To a solution of methyl 3,5-methyl-4- (3'-isopropyl-4'-methoxymethoxybenzyl) benzoate 1.80 g, 5.0 mmol, Example 47, step a) in THF (30.0 mL) at 0 ° C DIBAL (12.6 mL, 12.6 mmol) was slowly added. The reaction mixture was stirred at 0 ° C for 2 h and quenched with potassium tartrate of sodium. The reaction mixture was diluted with hexanes and stirred at room temperature for 2 h. The organic layer was separated, dried over MgSO 4, filtered and concentrated under reduced pressure. The crude product was dissolved in ether (95.0 mL) and slowly added to a solution of carbon tetrabromide and PPh3 in ether (20.0 mL). The reaction mixture was stirred at room temperature for 16 h 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 10% ethyl acetate in hexanes to provide 3,5-dimethyl-4- (3'-isopropyl-4-bromide. '-methoxymethoxybenzyl) benzyl (1.82 g, 93%) as a white solid: XH NMR (300 MHz, CD3OD): d 7.13 (s, 2H), 6.93 (m, 2H), 6.67 (d, J = 7.2 Hz, ÍH), 5.17 (s, 2H), 4.54 (s, 2H), 4.02 (s, 2H), 3.48 (s, 3H), 3.31 (m, ÍH), 2.25 (s, 6H), 1.17 (d, J = 7.0 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 9); Rf = 0.8.
Step b: To a solution of 3,5-dimethyl-4- (3'-isopropyl-4'-methoxymethoxybenzyl) benzyl bromide (0.60 g, 1.53 mmol) in DMF (5.0 mL) at room temperature was slowly added a solution of trimethylphosphite (0.57 g, 4.60 mmol) in DMF (1.0 mL). The reaction mixture was stirred at 140 ° C for 3 h and cooled to room temperature. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 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 50% acetone in hexanes to give dimethyl 2- [3,5-dibromo-4- (4'-methoxymethoxy-3'-isopropylphenoxy)] benzylphosphonate ( 0.20 g, 31%) as a colorless oil: XH NMR (300 MHz, CD3OD): d 7.04 (d, J = 2.4 Hz, 2H), 6.93 (m, 2H), 6.69 (d, J = 7.2 Hz, ÍH) , 5.17 (s, 2H), 4.01 (s, 2H), 3.72 (d, J = 10.2 Hz, 6H), 3.28 (m, ÍH), 3.22 (d, J = 21.3 Hz, 2H), 2.25 (s, 6H), 1.17 (d, J = 7.0 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (1: 1); Rf = 0.5 Step c: The title compound was prepared from dimethyl [3,5-dibromo-4- (4'-hydroxy-3'-isopropylphenoxy) benzyl] phosphonate according to the procedure described by the synthesis of compound 7, stage b: mp: 60-63; 1 H NMR (300 MHz, CD3OD): d 7.03 (s, 2H), 6.93 (m, 2H), 6.09 (s, ÍH), 6.58 (m, 2H), 3.95 (s, 2H), 3.23 (m, ÍH), 3.08 (d, J = 21.0 Hz, 2H), 2.24 (s, 6H), 1.17 (d, J = 7.0 Hz, 6H); LC-MS m / z = 349 [C? 9H2504P + H] +; Analysis Calculated for (C? 9H25? 4P + 0.6H2O): C, 63.47; H, 7.55. Found: C, 63.53; H, 7.35.
Example 69 Compound 69: [3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy] methylphosphonic acid monomethyl ester Step a: A solution of [3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy] methylphosphonic acid (compound 7, 105 mg, 0.29 mmol), oxalyl chloride (0.5 mL) and DMF (2 drops) in dichloromethane was refluxed for 2 hours then concentrated under reduced pressure and azeotroped twice with dichloromethane. The residue was taken in dichloromethane and triethylamine (0.16 mL, 1.2 mmol) followed by methanol (1 mL) were added at t.a. After stirring at a.t. for 2 hours, the reaction mixture was quenched with brine, diluted with ethyl acetate, washed with 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 96/4 to 92/8) to give [3,5-dimethyl-4- (4'-Hydroxy-3'-iso-propylbenzyl) phenoxymethylphosphonate dimethyl (75 mg, 70%):? H NMR (200 MHz, CDC13) d 6.92 (d, J = 3.0 Hz, ÍH), 6.68 (s, 2H), 6.66 (d, J = 9.0 Hz, ÍH), 6.52 (dd, J = 9.0, 3.0 Hz, ÍH), 4.31 (d, J = 10.2 Hz, 2H), 3.89 (d, J = 11.0 Hz, 6H), 3.15 (heptet, J = 7.0 Hz, ÍH), 2.19 (s, 6H), 1.21 (d, J = 7.0 Hz, 6H); CCD conditions: Merck silica gel, 250 microns; Mobile phase = dichloromethane-methanol (9: 1); Rf = 0.65.
Step b: An IN solution of sodium hydroxide (1 mL, 1 mmol) was added to a solution of dimethyl 3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxymethylphosphonate (75 mg, 0.19 mmol) in THF at rt The biphasic solution was stirred at t.a. for 24 hours then it was diluted with ethyl acetate and extracted twice with IN sodium hydroxide. The combined aqueous extracts were acidified to pH 1 with concentrated hydrochloric acid and extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give the title compound (55 mg, 76%): XH NMR (200 MHz, CDC13) d 6.92 (d, J = 3.0 Hz, 1H) , 6.68 (s, 2H), 6.60-6.4 (m, 2H), 4.31 (d, J = 10.2 Hz, 2H), 3.89 (d, J = 11.0 Hz, 3H), 3.15 (heptet, J = 7.0 Hz, ÍH), 2.19 (s, 6H), 1.21 (d, J = 7.0 Hz, 6H); LC-MS m / z = 379.4 [C 20 H 27 O 5 P + H] +; Analysis Calculated for (C2oH27? 5P + 0.4 H20): C, 62.30; H, 7.27. Found: C, 62.20; H, 7.51.
Compound 69-1: [3,5-dimethyl-4- (4'-hydroxy-3'-iso-propylbenzyl) phenoxy] methylphosphonic acid monoethyl ester Step a: Diethyl [3,5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) phenoxymethylphosphonate was prepared from [3,5-dimethyl-4- (4'-methoxymethoxy-3 '- iso-propylbenzyl) phenoxymethylphosphonate diethyl ester (Example 7, step a) according to the procedure described by the synthesis of compound 7-14, step a: XH NMR (300 MHz, DMSO-d6): d 9.00 (s, ÍH) , 6.85 (m, ÍH), 6.74 (s, 2H), 6.63 (m, ÍH), 6.48 (m, ÍH), 4.36 (d, J = 9.0 Hz, 2H), 4.13 (m, 4H), 3.81 ( s, 2H), 3.14 (m, ÍH), 2.18 (s, 6H), 1.27 (m, 6H), 1.12 (d, J = 6.0 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (1: 4); Rf = 0.40.
Step b: The title compound was prepared according to the procedure described by the synthesis of compound 69, step b: 1 H NMR (300 MHz, DMSO-d 6): d 9.00 (s, ÍH), 6.85 (m, ÍH), 6.73 (s, 2H), 6.61 (m, ÍH), 6.48 (m, ÍH), 4.21 (d, J = 9.0 Hz, 2H), 4.06 (m, 2H), 3.81 (s, 2H), 3.14 (m, ÍH), 2.18 (s, 6H), 1.24 (m, 3H), 1.12 (d, J = 6.0 Hz, 6H); LC-MS m / z = 393 [C 21 H 29 O 5 P-H] +; Analysis Calculated for (C 21 H 29 O 5 P + 0.1 H 20): C, 63.98; H, 7.47. Found: C, 63.93, H, 7.07. CLAR conditions: Column = Agilent zorbax RP18, 150x3.0 mm; Mobile phase = Solvent B (Acetonitrile) = acetonitrile grade CLAR; Solvent A (buffer) = 20 mM potassium phosphate buffer (pH 4.7). Flow ratio = 0.75 mL / min; UV @ 254 nm. tr = 13.98 min).
Compound 69-2: [3,5-dibromo-4- (4'-hydroxy-3'-isopropylphenoxy) benzyl] phosphonic acid monomethyl ester Step a: To a solution of [3,5-dimethyl-4- (3'-isopropyl-4'-methoxyphenoxy)] benzyl bromide (intermediate for the synthesis of compound 19-1, 0.20 g, 0.40 mmol) in DMF (2.5 mL) at room temperature was slowly added a solution of trimethylphosphite (0.57 g, 4.60 mmol) in DMF (0.5 mL). The reaction mixture was stirred at 140 ° C for 3 h and cooled up to room temperature. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 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 50% acetone in hexanes to provide dimethyl 3,5-dibromo-4- (3'-isopropyl-4'-methoxyphenoxy) benzyl] phosphonate (0.10. g, 49%) as a colorless oil: XH NMR (300 MHz, CD3OD): d 7.68 (s, 2H), 6.83 (d, J = 7.2 Hz, ÍH), 6.72 (s, ÍH), 6.45 (d, J = 7.2 Hz, ÍH), 3.81 (s, 6H), 3.77 (s, 3H), 3.38 (d, J = 10.2 Hz, 2H), 3.28 (m, ÍH), 1.17 (d, J = 7.0 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (1: 1); Rf = 0.5 Step b: To a solution of dimethyl [3,5-dibromo-4- (3'-isopropyl-4'-methoxyphenoxy) benzyl] phosphonate (0.22 g, 0.42 mmol) in CH 2 Cl (3.0 mL) at -78 ° C. slowly added BBr3 (0.63 mL, 0.63 mmol). After 5 min, the reaction mixture was allowed to warm to room temperature and was stirred for 3 h. The reaction mixture was quenched with ice-water and extracted with ethyl acetate (10 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 50% acetone in hexanes to provide dimethyl 3,5-dibromo-4- (4'-hydroxy-3'-isopropylphenoxy) benzyl] phosphonate (0.06 g, 28%) as a white solid: XH NMR (200 MHz, DMSO-de): d 9.07 (s, ÍH), 7.67 (d, J = 2.2 Hz, ÍH), 6.65 (m, 2H), 6.22 (dd, J = 2.8, 10.2 Hz, ÍH), 3.64 (d, J = 11.0 Hz, 6H ), 3.40 (d, J = 15.0, 2H), 3.18 (m, ÍH), 1.10 (d, J = 7.0 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (1: 1); Rf = 0.3.
Step c The title compound was prepared according to the procedure described by the synthesis of compound 69, step b: mp: 56-59 ° C; X H NMR (200 MHz, DMSO-de): d 9.05 (s, ÍH), 6.75 (s, 2H), 7.66 (d, J = 2.2 Hz, ÍH), 6.66 (m, 2H), 6.22 (dd, J = 2.8, 10.2 Hz, ÍH), 3.57 (d, J = 11.0 Hz, 3H), 3.12-3.23 (m, 3H), 1.10 (d, J = 7.0 Hz, 6H); LC-MS m / z = 495 [C? 7H19 Br205P + H] +; Analysis Calculated for (C17H19 Br205P): C, 41.32; H, 3.88. Found: C, 41.55; H, 4.02. Compound 69-3: [3,5-Dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) benzyl] phosphonic acid monomethyl ester or The title compound was prepared from dimethyl 2- [3,5-dibromo-4- (4'-methoxymethoxy-3'-isopropylphenoxy)] benzylphosphonate (compound 68, step b) in accordance with the procedure described by synthesis of compound 7-14, step a followed by compound 69, step b: mp: 72-75; X H NMR (300 MHz, CD 3 OD): d 7.01 (d, J = 2.1 Hz, 2 H), 6.84 (d, J = 2.1 Hz, 1 H), 6.54 (m, 2 H), 3.94 (s, 2 H) ), 3.65 (d, J = 10.8 Hz, 3 H), 3.21 (m, 1 H), 3.09 (d, J = 21.0 Hz, 2 H), 2.23 (s, 6 H), 1.13 (d, J = 7.0 Hz, 6 H); LC-MS m / z = 361 [C 20 H 27 O 4 P-H] +; Analysis Calculated for (C20H27O4P + 0.2H2O): C, 65.63; H, 7.55. Found: C, 65.70; H, 7.44.
Compound 69-4: [3,5-dibromo-4- (4'-hydroxy-3'-iso-propylphenoxy) phenylamino] -methylphosphonic acid monomethyl ester Step a: To a stirred mixture of t-butyl [3,5-dibromo-4- (3'-isopropyl-4'-methoxymethoxyphenoxy) phenyl] carbamate (compound 84, step f, 0.15 g, 0.28 mmol) and acetonitrile (4.0 mL) was added CS2C03 (0.179 g, 0.55 mmol) followed by 4-chloro- dimethyl benzenesulfonyloxymethylphosphonate (0.087 g0.28 pmol). The reaction mixture was stirred at 40 ° C for 16 h and the solvent was evaporated. The reaction mixture was partitioned with ethyl acetate and H20, the organic layer was concentrated and the crude was purified by preparative thin layer chromatography on silica gel, eluting with ethyl acetate-hexanes (3: 2) to give N- dimethyl tert-butoxycarbonyl- [3,5-dibromo-4- (3'-isopropyl- '-methoxymethoxyphenoxy) phenylamino] methylphosphonate as an oil (0.040 g, 22%): XH RM? (300 MHz, DMSO-d6): d 7.88 (s, 2 H), 7.03 (m, 1 H), 6.72 (m, 1 H), 6.46 (m, 1 H), 5.18 (s, 2 H), 4.25 (m, 2 H), 3.64 (d, J = 9.0 Hz, 6 H), 3.41 (s, 3 H), 3.27 (m, 1 H), 1.44 (s, 9 H), 1.15 (d, J = 6.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (4: 1); Rf = 0.42.
Step b: To a mixture of N-ert-butoxycarbonyl- [3, 5-dibromo-4- (3'-isopropyl-4 '-methoxymethoxyphenoxy) phenylamino] methylphosphonate (0.27 g, 0.41 mmol) in methanol (6.0 mL) was added 3? HCl (0.68 mL, 2.03 mmol). The reaction mixture was heated with microwave radiation at 100 ° C in a sealed vial for 5 minutes. The solvent was removed and the residue was partitioned with ethyl acetate and water. The organic layer was co-evaporated with methanol and concentrated under reduced pressure to provide N-ert-butoxycarbonyl- [3,5-dibromo-4- (4'-hydroxy-3'-isopropyl-phenoxy) phenylamino] methylphosphonate (0.075 g, 87%) as a solid. : 1H RM? (300 MHz, DMSO-de): d 8.90 (s, 1 H), 7.09 (s, 2 H), 6.65 (m, 2 H), 6.28 (m, 2 H), 3.70 (m, 6 H), 3.66 (m, 2 H), 3.19 (m, 1 H), 1.14 (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: To a stirred solution of N-ert-butoxycarbonyl- [3,5-dibromo-4- (4'-hydroxy-3'-isopropylphenoxy) phenylamino] methylphosphonate (0.075 g, 0.14 mmol) in THF (2.0 mL) 1 M? aOH (0.70 mL, 0.86 mmol) was added. The reaction mixture was stirred at t.a. for 16 h, then heated at 40 ° C for 5 hrs. The reaction mixture was cooled to 0 ° C, treated 2? HCl (pH-1) was diluted with ethyl acetate and H0, partitioned, and the organic layer was extracted with H20. The organic layer was filtered and concentrated to give the title compound as a gray solid (0.070 g, 96%): 1 H RM? (300 MHz, DMSO-d6): d 8.97 (s, 1 H), 7.07 (s, 2 H), 6.65 (m, 2 H), 6.25 (m, 1 H), 3.64 (m, 2 H), 3.42 (s, 3 H), 3.16 (m, 1 H), 1.14 (d, J = 6.0 Hz, 6 H); LCMS m / z = 510 [C17H2oBr2? 05P-H] +; CLAR conditions: Column = Shimadzu LC-A8, SPD-10A; YMC Pack RP-18 filter, 150x4.6; Mobile phase = Solvent Acetonitrile / O .05% TFA; Solvent B = H2O / 0.05% TFA. Flow ratio = 2.0 mL / min; UV @ 254 nm. Retention time in minutes, (tr = 8.81 / 20.00, 93% purity).
Compound 69-5: [(3, 5-Dimethyl-4- [3 '- (4-fluorobenzyl) -4' -hydroxybenzyl] -phenylamino) methyl] methylphosphonic acid monomethyl ester Prepared from benzyl N- [3, 5-dimethyl-4- (3 '- (4-fluorobenzyl) -4'-methoxymethoxybenzyl) phenyl] carbamate (compound 79, step b) in accordance with the procedure described by Synthesis of compound 69-4: 1H RM? (300 MHz, DMSO-d6): d 9.15 (s, 1 H), 7.01 - 7.22 (m, 4 H), 6.76 (s, 1 H), 6.67 (d, J = 8.1 Hz, 1 H), 6.58 (d, J = 8.1 Hz, 1 H), 6.40 (s, 2 H), 3.79 (s, 2 H), 3.71 (s, 2 H), 3.58 (d, J = 10.5 Hz, 3 H), 3.29 (m, 2 H), 2.07 (s, 6 H); LC-MS m / z = 444 [C 24 H 27 F? 04 P + H] +; Analysis Calculated for (C24H27F? 04P + 2.2H20): C, 59.67; H, 6.55; ?, 2.90. Found: C, 59.40; H, 6.24; ?, 3.31.
Compound 69-6: [3,5-dibromo-4- (4'-hydroxy-3'-iso-propylphenoxy) -phenoxy] methylphosphonic acid monomethyl ester Step a: To a stirred mixture of DMF (20.0 mL) and NaH (0.074 g, 1.86 mmol) at 0 ° C was added 3,5-dibromo-4- (3-isopropyl-4-hydroxy-phenoxy) phenol (Intermediate for the synthesis of compound 8-1, 0.75 g, 1.86 mmol) was dissolved in DMF (2.0 mL). The reaction mixture was allowed to stir at t.a. for 1 hr and cooled to 0 ° C. The dimethyl 4-chloro-benzenesulfonyloxymethylphosphonate (0.11 g, 0.36 mmol) was added and the reaction mixture was stirred at r.t. for 16 h. The reaction was quenched with ice H20, the pH was adjusted to 1 with 2 M HCl, and the mixture was partitioned with ethyl acetate and H20. The organic layer was concentrated and co-evaporated with acetone (2X). The residue was treated with a mixture of hexane / ethyl acetate and sonic to give dimethyl 3,5-dibromo-4- (4-hydroxy-3-iso-propyl-phenoxy) phenoxymethylphosphonate as a precipitated white solid (0.070) g, 34%): X H NMR (200 MHz, DMSO-d 6): d 9.00 (s, ÍH), 7.47 (s, 2H), 6.65 (m, 2H), 6.23 (m, ÍH), 4. 60 (d, J = 10.0 Hz, 2H), 3.75 (d, J = 10.0 Hz, 6H), 3.12 (m, ÍH), 1.09 (d, J = 6.0 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate; Rf = 0.60.
Step b: To a stirred solution of dimethyl 3,5-dibromo-4- (4-hydroxy-3-iso-propyl-phenoxy) phenoxymethylphosphonate (0.155 g, 0.30 mmol) in THF (4.0 mL) was added 2M NaOH. (0.89 mL, 1.77 mmol). The reaction mixture was stirred at t.a. for 48 h, cooling to 0 ° C, treated with concentrated HCl (pH-1), and partitioned with ethyl acetate and H2O. The organic layer was extracted with H20 (IX). The organic layer was concentrated, dissolved in acetone, filtered and concentrated to provide the title compound as an opaque white solid (0.110 g, 73%):? H NMR (300 MHz, DMSO-d6): d 9.03 (s, ÍH), 7.47 (s, 2H), 6.66 (m, 2H), 6.27 (m, ÍH), 4.41 (d, J = 9.0 Hz, 2H), 3.69 (d, J = 9.0 Hz, 3H), 3.17 ( m, ÍH), 1.14 (d, J = 6.0 Hz, 6H); LC-MS m / z = 510 [C? 7Hi9Br206P-H] A Compound 69-7: monomethyl ester of 2- [3,5-Dibromo-4- (4'-hydroxy-3'-isopropylphenoxy) -phenyl ester ] ethylphosphonic The title compound was prepared from dimethyl-2- [3,5-dibromo-4- (4'-methoxy-3'-isopropylphenoxy) phenyl] ethylphosphonate (Example 67) according to the procedures described by the synthesis of example 69-2. PF: 65-68 ° C; X H NMR (300 MHz, CD30D): d 7.62 (s, 2H), 6.65 (m, 2H), 6.34 (dd, J = 11.2, 2.1 Hz, ÍH), 3.73 (d, J = 10.5 Hz, ÍH), 3.25 (m, HH), 2.95 (m, 2H), 2.16 (m, 2H), 1.18 (d, J = 7.0 Hz, 6H); LC-MS m / z = 509 [C? 8H2? Br205P + H] +; Analysis Calculated for (C? 8H2? Br205P): C, 42.55; H, 4.17. Found: C, 42.72; H, 3.90.
Example 70 Compound 70: [3,5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) phenoxymethyl] methylphosphinic acid Step a: The solid sodium hydroxide (400 mg, 10 mmol) was added to a solution of diethyl [3,5-dimethyl-4- (4'-methoxymethoxy-3'-isopropylbenzyl) phenoxymethylphosphonate (compound 7, step a). , 500 mg, 1.08 mmol) in THF (6 mL) and water (2 mL). The biphasic mixture was stirred at t.a. for 2 days, then diluted with ethyl acetate and washed with brine then IN hydrochloric acid, dried (Na2SO4) and concentrated under reduced pressure. The crude material was carried out without purification:? Ti NMR (300 MHz, CDC13) d 6.96 (d, J = 2.1 Hz, ÍH), 6.91 (d, J = 8.1 Hz, ÍH), 6.71 (s, 2H) , 6.66 (dd, J = 8.1, 2.1 Hz, ÍH), 5.12 (s, 2H), 4.4-4.2 (m, 4H), 3.94 (s, 2H), 3.51 (s, 3H), 3.31 (heptet, J = 7.0 Hz, ÍH), 2.23 (s, 6H), 1.41 (t, J = 7.0 Hz, 3H), 1.21 (d, J = 7.0 Hz, 6H).
Step b: Thionyl chloride (120 μL, 1.62 mmol) was added to a solution of [3,5-dimethyl-4- (4'-methoxymethoxy-3'-iso-propylbenzyl) phenoxy] methylphosphonic acid monoethyl ester solution. crude (1.08 mmol) and pyridine (510 μL, 6.48 mmol) in dichloromethane at rt After stirring at t.a. for 18 hours, the yellow solution was concentrated under reduced pressure. The yellow oil was dissolved in THF (10 mL) and the solution was cooled to -78 ° C. A solution of MeMgBr in THF (3M, 1.1 mL, 3.3 mmol) was added to the hydrochloride solution at -78 ° C. After stirring at -78 ° C for 15 min, the reaction mixture was quenched at -78 ° C with acetic acid (324 μL, 5.4 mmol), diluted with ethyl acetate and washed successively with saturated bicarbonate solution of sodium, 10% of a copper sulfate solution, brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate / methanol 99/1 to 95/5) to give ethyl [3,5-dimethyl-4- (4'-methoxymethoxy-3'-isopropylbenzyl) phenoxymethyl] methylphosphinate (318 mg, 68%). %): 1tt NMR (300 MHz, CDC13) d 6.98 (s, ÍH), 6.92 (d, J = 8.4 Hz, ÍH), 6.70 (s, 2H), 6.66 (d, J = 8.4 Hz, ÍH), 5.19 (s, 2H), 4.4-4.2 (m, 4H), 3.96 (s, 2H), 3.51 (s, 3H), 3.33 (heptet, J = 7.0 Hz, ÍH), 2.26 (s, 6H), 1.68 (d, J = 15 Hz, 3H), 1.4 (t, J = 7.0 Hz, 3H), 1.22 (d, J = 7.0 Hz, 6H); CCD conditions: Merck silica gel, 250 microns; Mobile phase = dichloromethane-methanol (9: 1); Rf = 0.5 Step c: The title compound was prepared according to the procedure described by the synthesis of compound 7, step b, (225.8 mg): X H NMR (300 MHz, DMSO d 6) d 9.00 (s, ÍH), 6.86 (d , J = 1.8 Hz, HH), 6.73 (,, 2H), 6.63 (d, J = 8.4 Hz, 2H), 6.46 (d, J = 8.4, 1.8 Hz, HH), 4.11 (d, J = 8.4 Hz , 4H), 3.82 (s, 2H), 3.51 (s, 3H), 3.14 (heptet, J = 7.0 Hz, 1H), 2.19 (s, 6H), 1.43 (d, J = 14.7 Hz, 3H), 1.12 (d, J = 7.0 Hz, 6H); LC-MS m / z = 363.1 [C2oH270 P + H] +; Analysis Calculated for (C20H27? 4P + 0.2 H20): C, 65.63; H, 7.55. Found: C, 65.47; H, 7.57.
EXAMPLE 71 Compound 71: [3,5-Dibromo-4- (4'-hydroxy-3'-isopropyl-) acid phenoxy) benzyl] methylphosphinic Step a: To a solution of 3,5-dibromo-4- (3'-isopropyl-4'-methoxylphenoxy) benzyl bromide (intermediate for the synthesis of compound 19-1, 0.30 g, 0.60 mmol) in DMF (4.0 mL) at room temperature was slowly added a solution of diethyl methylphosphonite (0.25 g, 1.8 mmol) in DMF (0.5 mL). The reaction mixture was stirred at 100 ° C for 3 h and cooled to room temperature. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 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 50% acetone in hexanes to provide [ethyl 3, 5-dibromo-4- (3'-isopropyl-4'-methoxyphenoxy) benzyl] methylphosphinate (0.29. g, 92%) as a colorless oil: XH NMR (200 MHz, DMSOde): d 7.69 (d, J = 2.8 Hz, ÍH), 6.84 (d, J = 10 Hz, ÍH), 6.73 (d, J = 4.2 Hz, HH), 6.40 (dd, J = 2.8, 10.2 Hz, HH), 3.98 (m, 2H), 3.73 (s, 3H), 3.20 (m, HH), 1.38 (d, J = 10.2 Hz, 3H), 1.19 (t, J = 7.8 Hz, 3H), 1.11 (d, J = 7.0 Hz, 6H); LC-MS m / z = 521 [C20H25 Br204P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; Acetone-hexanes mobile phase (1: 1); Rf = 0.50.
Step b: The title compound was prepared according to the procedure described by the synthesis of compound 4, step b: mp: 61-63 ° C; X H NMR (200 MHz, DMSO-de): d 9.05 (s, ÍH), 7.65 (d, J = 2.4 Hz, 2H), 6.67 (m, 2H), 6.23 (dd, J = 2.8, 10.2 Hz, ), 3.36 (d, J = 10.2 Hz, 3H), 3.14 (m, HH), 1.28 (d, J = 10.2 Hz, 3H), 1.11 (d, J = 7.0 Hz, 6H); LC-MS m / z = 479 [C17H19 Br204P + H] +; Analysis Calculated for (C17H19 Br204P): C, 42.71; H, 4.01. Found: C, 42.45; H, 4.40.
Example 72 Compound 72: [3,5-Dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) benzyl] methylphosphinic acid Step a: To a solution of [3,5-dimethyl-4- (3'-isopropyl-4'-methoxymethoxybenzyl)] benzyl bromide (compound 68, step a, 0.25 g, 0.64 mmol) in DMF (4.0 mL) At room temperature, a solution of diethyl methyl phosphite was slowly added (0.26 g, 1.92 mmol) in DMF (1.0 mL). The reaction mixture was stirred at 110 ° C for 2 h and cooled to room temperature. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 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 80% acetone in hexanes to provide ethyl [3,5-dimethyl-4- (3'-isopropyl-4'-methoxymethoxybenzyl) benzyl] methylphosphinate (0.18. g, 70%) as a colorless oil: 1ti NMR (300 MHz, CD3OD): d 7.04 (d, J = 2.4 Hz, 2H), 6.91 (m, 2H), 6.72 (d, J = 7.2 Hz, ÍH), 5.18 (s, 2H), 4.07 (m, 2H), 4.01 (s, 2H), 3.47 (s, 3H), 3.28 (m, ÍH), 3.22 (d, J = 21.3 Hz, 2H), 2.25 (s) , 6H), 1.45 (d, J = 14.1 Hz, 3H), 1.17 (d, J = 7.0 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (1: 1); Rf = 0.3.
Step b: The title compound was prepared according to the procedure described by the synthesis of compound 7, step b: mp: 170-173; lW NMR (300 MHz, CD30D): d 6.97 (s, 2H), 6.79 (s, ÍH), 6.52 (m, 2H), 3.91 (s, 2H), 3.20 (m, ÍH), 3.09 (d, J = 17.7 Hz, 2H), 2.20 (s, 6H), 1.37 (d, J = 14.1 Hz, 3H), 1.10 (d, J = 7. 0 Hz, 6H); LC-MS m / z = 347 [C 20 H 27 O 3 P + H] +; Analysis Calculated for (C20H27O3P + 0 .3 H20): C, 68. 28; H, 7 91 Found: C, 68.33; H, 9.11 Example 73 Compound 73: acid [3, 5-Dibromo-4- (4 '-hydroxy-3' -isopropylphenoxy) benzyl] ethylphosphinic Step a: To a solution of 3,5-dibromo-4- (3'-isopropyl-4'-methoxylphenoxy) benzyl bromide (intermediate for the synthesis of compound 19-1, 0.19 g, 0.39 mmol) in DMF (3.0 mL) at room temperature was slowly added a solution of diethyl ethyl phosphite (0.17 g, 1.17 mmol) in DMF. The reaction mixture was stirred at 100 ° C for 2 h and cooled to room temperature. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 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 50% acetone in hexanes to provide [3, 5-dibromo-4- (4'-hydroxy-3'-isopropylphenoxy) benzyl] ethylphosphinate diethyl ester (0.19. g, 93%) as a colorless oil: XH NMR (300 MHz, CD3OD): d 7.70 (d, J = 2. 8 Hz, 2H), 6.84 (d, J = 10 Hz, ÍH), 6.71 (d, J = 4.2 Hz, ÍH), 6.48 (dd, J = 2.8, 10.2 Hz, ÍH), 4.09 (m, 2H) , 3.81 (s, 3H), 3.30 (m, 3H), 1.84 (m, 2H), 1.13-1.40 (m, 12H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (1: 1); Rf = 0.50.
Step b: The title compound was prepared according to the procedure described by the synthesis of compound 4, step b: mp: 80-83 ° C; XH NMR (300 MHz, CD3OD): d 7.68 (d, J = 2.8 Hz, 2H), 6.64 (m, 2H), 6.36 (dd, J = 2.8, 10.2 Hz, ÍH), 3.33 (m, ÍH), 3.24 (d, J = 15.6 Hz, 2H), 1.76 (m, 2H), 1.19 (m, 9H); LC-MS m / z = 493 [C18H2? Br204P + H] +; Analysis Calculated for (C18H2? Br20 P): C, 43.93; H, 4.30. Found: C, 43.56; H, 4.26.
Example 74 Compound 74: Ethyl [(4-methylphenyl) sulfonyloxymethyl] methylphosphinate Step a: To a stirred solution of diethyl (4-methylphenyl) sulfonyloxymethylphosphonate (intermediate for the synthesis of compound 7, 2.00 g, 6.21 mmol) in benzene (20.0 mL) was added phosphorus pentachloride (1.55 mL, 7.45 mmol) and the reaction mixture was refluxed until homogeneous, then stirred at r.t. overnight. The solvents were removed and the residue coevaporated with toluene (2X). The crude was used as it is in the next stage.
Step b: To crude ethyl (4-methylphenyl) sulfonyloxymethylphosphinate monochlorohydrate (2.00 g, 6.39 mmol) in dry THF (30.0 mL) at -78 ° C was added MeMgBr (2.20 mL, 6.97 mmol, 3.0 M in diethyl ether). The reaction was quenched immediately after the addition of MeMgBr with 1 mL of acetic acid. The reaction mixture was diluted with ethyl acetate and H20 and the organic layer was washed twice with saturated aqueous NaHCO3 and once with H2O. The organic layer was concentrated and co-evaporated with MeOH. The product was obtained by precipitation from hexanes to give the title compound as a white solid (1.40 g, 77% over two steps): X H NMR (200 MHz, DMS0-d 6): d 7.85 (m, 2H), 7.52 (m, 2H), 4.30 (d, J = 12.0 Hz, 2H), 3.90 (m, 2H), 2.40 (s, 3H), 1.45 (d, J = 21.0 Hz, 3H), 1.15 (m, 3H) ); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-methanol (9: 1); Rf = 0.27.
Example 75 Compound 75: [3,5-Dimethyl-4- (4'-hydroxy-3'-methylsulfanylbenzyl) phenoxy] methylphosphonic acid monomethyl ester Step a: To a stirred solution of triisopropyl- [3,5-dimethyl-4- (4'-methoxymethoxybenzyl) phenoxy] silane (1.2 g, 2.8 mmol) and TMEDA (0.51 mL, 3.42 mmol) in ether (25 mL) n-BuLi (1.37 mL, 2.5 M in hexanes) was added at -20 ° C. The mixture was stirred at -20 ° C for 1 h and methyldisulfanylmethane (0.5 mL, 5.6 mmol) was added. The reaction mixture was stirred at -20 ° C for 1 h, allowed to warm to room temperature and stirred for 4 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 give triisopropyl- [3,5-dimethyl-4- (4 '-methoxymethoxy-3'-methylsulfanylbenzyl) phenoxy] silane as a yellow oil (1.3 g, 98 g). %): X H NMR (300 MHz, DMSO-de): d 6.95 (d, J = 8.1 Hz, HH), 6.78 (d, - = 2.1 Hz, HH), 6.4 (dd, J = 2.1, 8.1 Hz, ÍH), 6.60 (s, 2H), 5.19 (s, 2H), 3.90 (s, 2H), 3.35 (s, 3H), 2.27 (s, 3H), 2.14 (s, 6H), 1.25 (m, 3H) ), 71 1. 09 (d, J = 6.9 Hz, 18H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 15% ethyl acetate in hexanes; Rf = 0.46.
Step b: To a stirred solution of triisopropyl- [3,5-dimethyl-4- (4'-methoxymethoxy-3'-methylsulfanylbenzyl) phenoxy] silane (1.3 g, 2.74 mmol) in THF (20 mL) at room temperature added tetrabutylammonium fluoride (3.4 mL, 1.0 M in THF). The reaction mixture was stirred at room temperature for 2 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, eluting with ethyl acetate-hexanes (4: 6) to provide 3,5-dimethyl-4- (4 '-methoxymethoxy-3'-methylsulfanylbenzyl) phenol as a solid white (0.75 g, 86%): X H NMR (300 MHz, DMSOde): d 9.04 (s, ÍH), 6.93 (d, J = 8.4 Hz), 6.86 (d, J = 1.2 Hz), 6.61 (dd, J = 1.2, 8.4 Hz, ÍH), 6.49 (s, 2H), 5.19 (s, 2H), 3.86 (s, 2H), 3.40 (s, 3H), 2.32 (s, 3H), 2.12 ( s, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 30% ethyl acetate in hexanes; Rf = 0.45.
Step c: To a solution of 3,5-dimethyl-4- (4 '-methoxymethoxy-3' - methylsulfanylbenzyl) phenol (0.54 g, 1.7 pmol) in CH3CN (20 mL) at room temperature was added CS2C03 (0.82 g, 2.54 mmol) and dimethyl (4-chlorophenylsulfonyloxy) methylphosphonate (0.54 g, 1.7 mmol). The reaction mixture was refluxed 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 4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (4: 1) to provide [3,5-dimethyl-4- (4'-methoxymethoxy-3'-methylsulfanylbenzyl) phenoxymethylphosphonate dimethyl as a colorless oil (0.3 g, 40%): 1ti NMR (200 MHz, DMSO-de): d 6.89 (m, 2H), 6.75 (s, 2H), 6.58 (m, ÍH), 5.16 (s, 2H), 4.42 (d, J = 10.0 Hz, 2H), 3.89 (s, 2H), 3.73 (d, J = 10.6 Hz, 6H), 3.37 (s, 3H), 2.30 (s, 3H), 2.17 ( s, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 80% ethyl acetate in hexanes; Rf = 0.31.
Step d: To a stirred solution of dimethyl [3,5-dimethyl-4- (4'-methoxymethoxy-3'-methylsulfanylbenzyl) phenoxymethylphosphonate (0.051 g, 0.12 mmol) in MeOH (1.5 mL) at room temperature was added HCl (0.93 mL, 1 N), and heated at 100 ° C for 5 min by microwave. The solvent was removed under reduced pressure, and the residue was partitioned between EtOAc and saturated NaHCO 3. 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 dimethyl [3,5-dimethyl-4- (4'-hydroxy-3-methylsulfanylbenzyl) phenoxymethylphosphonate as a colorless oil (0.037 g. , 80%):? H NMR (200 MHz, DMSO-de): d 9.57 (s, ÍH), d 6.74 (m, 3H), 6.63 (d, J = 8.0 Hz, ÍH), 6.49 (m, ÍH ), 4.42 (d, J = 9.8 Hz, 2H), 3.83 (s, 2H), 3.72 (d, J = 10.3 Hz, 6H), 2.26 (s, 3H), 2.16 (s, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate; Rf = 0.45.
Step e: To a stirred solution of dimethyl [3,5-dimethyl-4- (4'-hydroxy-3-methylsulfanylbenzyl) phenoxy] methylphosphonate (0.037 g, 0.093 mmol) in THF (3 mL) at room temperature was added NaOH (0.37 mL, 1 N), and stirred for 48 h at room temperature. This was made acidic by IN HCl until pH = 2, and the mixture was partitioned between EtOAc and saturated NaHCO 3. The organic layer was dried over Na 2 SO 4, filtered and concentrated under reduced pressure to provide the title compound as a light brown foam (0.030g, 84%): X H NMR (200 MHz, DMSO-de): d 9.61 (s, ), 6.78 (s, ÍH), 6.64 (m, 3H), 6.46 (d, J = 8.0 Hz, ÍH), 3.96 (d, J = 9.2 Hz, 2H), 3.81 (s, 2H), 3.51 (d) , J = 9. 8 Hz, 3H), 2.26 (s, 3H), 2.14 (s, 6H); LC-MS m / z = 383 [C? 8H2305PS + H] +; Analysis Calculated for (C? 8H2305PS + 0.1H2O + 0.4CH2C12): C, 52.85; H, 5.78. Found: C, 52.68; H, 5.45.
Example 76 Compound 76: [3,5-Dimethyl-4- (4'-hydroxy-3'-methanesulfonylbenzyl) -phenoxy] methylphosphonic acid monomethyl ester Stage a; a stirred solution of dimethyl [3,5-dimethyl-4- (4'-methoxymethoxy-3'-methylsulfanylbenzyl) phenoxymethylphosphonate (compound 75, step c, 0.25 g, 0.57 mmol) in CH2C12 (15 mL) at room temperature added m-CPBA (0.34 g, 2 mmol). The mixture was stirred for 16 h at room temperature, quenched with saturated Na 2 SO 3 and diluted with CH 2 C 12. The organic layer was collected and 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 dimethyl 3,5-dimethyl-4- (3'-methansulfoni-1,4-dimethoxy-benzyl) phenoxymethylphosphonate as a colorless oil. (0.14 g, 53%): 1 H NMR (200 MHz, DMSO-de): d 7.43 (s, ÍH), 7.25 (s, 2H), 6.77 (s, 2H), 5.35 (s, 2H), 4.43 (d, J = 10.0 Hz, 2H), 3.95 (s, 2H), 3.73 (d, J = 10.6 Hz, 6H), 3.41 (s, 3H) , 3.25 (s, 3H), 2.17 (s, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate; Rf = 0.31.
Step b: To a stirred solution of dimethyl [3,5-dimethyl-4- (3'-methanesulfonyl-4'-methoxymethoxybenzyl) phenoxymethylphosphonate (0.14 g, 0.3 mmol) in MeOH (2 mL) at room temperature was added HCl (0.3 mL, 10 N), and heated at 100 ° C for 5 min by microwave. The solvent was removed under reduced pressure, and the residue was partitioned between EtOAc and saturated NaHCO 3. 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 methanol-ethyl acetate (5:95) to provide [3,5-dimethyl-4- (4'-hydroxy-3'-methanesulfonylbenzyl) phenoxymethylphosphonate dimethyl as a colorless oil (0.042 g, 33%): XH NMR (200 MHz, DMS0-d6): d 10.87 (s, HH), 7.30 (d, J = 1.8 Hz, HH), 7.13 (dd, J = 1.8, 8.4 Hz, ÍH), 6.92 (d, J = 8.4 Hz, ÍH), 6.76 (s, 2H), 4.42 (d, J = 10.0 Hz, 2 Hz), 3.89 (s, 2H), 3.74 (d , J = 10.6 Hz, 6H), 3.19 (s, 3H), 2.16 (s, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 5% methanol in ethyl acetate; Rf = 0.42.
Step c: To a stirred solution of dimethyl [3,5-dimethyl-4- (4'-hydroxy-3'-methansulfonylbenzyl) phenoxymethylphosphonate (0.042 g, 0.098 mmol) in THF (3 mL) at room temperature was added NaOH (0.39 mL, 1 N), and stirred for 48 h at room temperature. This was made acidic by IN HCl until pH = 2, and the mixture was partitioned between EtOAc and saturated NaHCO 3. The organic layer was dried over Na 2 SO 4, filtered and concentrated under reduced pressure to provide the title compound as a light yellow foam (0.016 g, 39%): X H NMR (200 MHz, DMSOde): d 10.96 (s, 1 H), 7.34 (d, J = 1.8 Hz, HH), 7.11 (dd, J = 1.8, 8.4 Hz, HH), 6.95 (d, J = 8.4 Hz, HH), 6.71 (s, 2H), 4.07 (d, J) = 9.6 Hz, 2H), 3.88 (s, 2H), 3.58 (d, J = 10.4 Hz, 3H), 3.19 (s, 3H), 2.15 (s, 6H); LC-MS m / z = 415 [C? 8H2307PS + H] +; Analysis Calculated for (C? 8H2307PS + 1.1H20): C, 49.79; H, 5.86. Found: C, 49.47; H, 5.73.
Example 77 Compound 77: [(3,5-dimethyl-4- (4-hydroxy-3-methanesulfonylbenzyl) phenoxy) methyl] methylphosphinic acid Step a: To a solution of 3,5-dimethyl-4- (4 '-methoxymethoxy-3'-methylsulfanylbenzyl) phenol (compound 75, step b, 0.11 g, 0.35 mmol) in CH 3 CN (5 mL) at room temperature was added Cs2C03 (0.17 g, 0.52 mmol) and ethyl [(4-methylphenyl) sulfonyloxymethyl] ethylphosphinate (compound 74, 0.1 g, 0.35 mmol). The reaction mixture was refluxed 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 4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate to provide ethyl [(3,5-dimethyl-4- (4'-methoxymethoxy-3'-methylsulfanylbenzyl) phenoxy) methyl] methylphosphinate as a colorless oil (0.3 g, 91%):? H NMR (200 MHz, DMSO-de): d 6.89 (m, 2H), 6.76 (s, 2H), 6.56 (dd, J = 1.8, 8.4 Hz, ), 5.16 (s, 2H), 4.27 (m, 2H), 4.04 (m, 2H), 3.89 (s, 2H), 3.37 (s, 3H), 2.30 (s, 3H), 2.17 (s, 6H) , 1.51 (d, J = 14.6 Hz, 3H), 1.23 (t, J = 7.0 Hz, 3H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate; Rf = 0.32.
Step b: To a stirred solution of [(3,5-dimethyl-4- (4 '- ethyl methoxymethoxy-3 '-methylsulfanylbenzyl) phenoxy) methyl] methylphosphinate (0.14 g, 0.32 mmol) in CH2C1 (10 mL) at room temperature was added m-CPBA (0.19 g, 1.12 mmol). The mixture was stirred for 16 h at room temperature, quenched with saturated Na 2 SO 3 and diluted with CH 2 Cl 2. The organic layer was collected and 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 ethyl [(3,5-dimethyl-4- (3'-methanesulfonyl-4'-methoxymethoxybenzyl) phenoxy) methyl] methylphosphinate as a colorless oil (0.07 g, 47%): 1 H NMR (200 MHz, DMSO-de): d 7. 42 (s, ÍH), 7.25 (s, 2H), 6.78 (s, 2H), 5.35 (s, 2H), 4.27 (m, 2H), 4.04 (m, 2H), 3.95 (s, 2H), 3.41 (s, 3H), 3.25 (s, 3H), 2.17 (s, 6H), 1.51 (d, J = 14.6 Hz, 3H), 1.23 (t, J = 7.0 Hz, 3H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 5% methanol in ethyl acetate; Rf = 0.32.
Step c: To a stirred solution of ethyl [(3, 5-dimethyl-4- (3'-methanesulfonyl-4'-methoxymethoxybenzyl) phenoxy) methyl] methylphosphinate (0.07 g, 0.15 mmol) in CH2C12 (6 mL) a -20 ° C TMSBr (0.2 mL, 1.5 mmol) was added. The mixture was stirred for 16 h at temperature environment and concentrated under reduced pressure. The residue was added MeOH and stirred for 1 h at room temperature. The solution was concentrated under reduced pressure to provide the title compound as a light pink foam (0.04 g, 67%): X H NMR (200 MHz, DMSO-de): d 10.84 (s, ÍH), 7.31 (d, J = 1.8 Hz, ÍH), 7.17 (dd, J = 1.8, 8.4 Hz, ÍH), 6.95 (d, J = 8.4 Hz, ÍH), 6.74 (s, 2H), 4.08 (d, J = 8.4 Hz, 2H ), 3.89 (s, 2H), 3.19 (s, 3H), 2.16 (s, 6H), 1.39 (d, J = 14.6 Hz, 3H); LC-MS m / z = 399 [C18H2306PS + H] +; Analysis Calculated for (C18H2306PS + 0.2CH2C12 + 1.8H20): C, 48.81; H, 6.08. Found: C, 48.52; H, 6.22.
Example 78 Compound 78: 2- [3,5-Dimethyl-4- (3 '- (4-fluorobenzyl) -4'-hydroxybenzyl) phenyl] ethylphosphonic acid monomethyl ester Step a: To a solution of 4-bromophenol (13.84 gm, 0.08 Mol), benzylic 4-fluoroalcohol (8.68 gm, 0.08 Mol), and 120 mL of dichloroethane was added zinc bromide (21 gm, 0.09 Mol). The reaction mixture was stirred at 60 ° C for 24 h, filtered and concentrated under reduced pressure. The pure product was obtained by flash chromatography using SiO2, dichloromethane / hexane [1: 1] as eluent to give 4-bromo-2- (4-fluorobenzyl) phenol (9.25 g, 41%) as a colorless oil: XH NMR ( 200 MHz, DMSO-d6): d 9.79 (s, ÍH), 7.16 (m, 5H), 6.74 (d, J = 8.8 Hz, ÍH), 3.82 (s, 2H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = methylene chloride-hexanes (1: 1); Rf = 0.38.
Step b: To a stirred solution of 4-bromo-2- (4-fluorobenzyl) phenol (16 g, 59.9 mmol) in CH2C12 (200 mL) at room temperature was added ethyl-diisopropylamine (15.6 mL, 89.85 mmol) and chloro-methoxy-methyl ether (6.1 mL, 79.67 mmol). After stirring at reflux for 16 h, water was added and the mixture was partitioned with ethyl acetate. The organic layer was collected and 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 give 4-bromo-2- (4-fluorobenzyl) methoxymethoxybenzene as a light yellow oil (16.4 g, 88%): 1 H NMR (200 MHz, DMSO-de): 6.96-7.40 (m, 7H), 5.20 (s, 2H), 3.89 (s, 2H), 3.26 (s, 3H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 6% ethyl acetate in hexanes; Rf = 0.79.
Step c: To a stirred solution of 4-bromo-2- (4-fluorobenzyl) methoxymethoxybenzene (6.2 g, 19.93 mmol) in THF (80 mL) at -78 ° C was added n-BuLi (8.8 mL, 2.5 M in hexanes). The mixture was stirred at -78 ° C for 1 h and 2,6-dimethyl-4-triisopropylsilanyloxy-benzaldehyde (6.11 g, 19.93 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 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: 9) to provide (2,6-dimethyl-4-triisopropylsilanyloxyphenyl) - [3- (4-fluorobenzyl) -4 -methoxymethoxyphenyl] methanol as a light yellow oil (8.3 g, 75%): H NMR (200 MHz, DMSO-de): d 6.88-7.20 (m, 7H), 6.47 (s, 2H), 5.97 (d, J = 4.0 Hz, HH), 5.65 (d, J = 4.0 Hz, HH), 5.14 (s, 2H), 3.85 (s, 2H), 3.25 (s, 3H), 2.11 (s, 6H), 1.24 (m , 3H), 1.08 (d, J = 7.2 Hz, 18H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 10% ethyl acetate in hexanes; Rf = 0.47.
Step d: To a stirred solution of (2,6-dimethyl-4-) triisopropylsilanyloxyphenyl) - [3- (4-fluorobenzyl) -4-methoxymethoxyphenyl] methanol (8.3 g, 15.01 mmol) in CH2C12 (150 mL) at room temperature was added Et3SiH (9.6 mL, 60.04 mmol) and TFA (4.5 mL, 60.04 mmol). The reaction mixture was stirred at room temperature for 6 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 4, filtered and concentrated under reduced pressure. Then to this stirred solution of the crude product in CH 2 Cl 2 (150 mL) at room temperature was added ethyl-diisopropylamine (2.6 L, 15.01 mmol) and chloro-methoxy-methyl ether (1 mL, 13.51 mmol). The mixture was refluxed for 16 h, water was added. The organic layer was dried over NaSO 4, 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 give [3,5-dimethyl-4- (3 '- (4-fluorobenzyl) -4' - methoxymethoxybenzyl) phenoxy] triisopropylsilane as a light yellow oil (7 g, 87%): X H NMR (200 MHz, DMSO-de): d 6.66 - 7.19 (m, 7H), 6.54 (s, 2H), 5.12 (s, 2H), 3.82 (s, 4H), 3.25 (s, 3H), 2.11 (s, 6H), 1.23 (m, 3H), 1.06 (d, J = 7.2 Hz, 18H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 9); Rf = 0.68.
Step e: To a stirred solution of [3,5-dimethyl-4- (3 '- (4-fluorobenzyl) -4'-methoxymethoxybenzyl) phenoxy] triisopropylsilane (7 g, 13.04 mmol) in THF (100 mL) at room temperature. At room temperature, tetrabutylammonium fluoride (16.3 mL, 1.0 M in THF) was added. The reaction mixture was stirred at room temperature for 2 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, eluting with ethyl acetate-hexanes (3: 7) to provide 3,5-dimethyl-4- [3 '- (4-fluorobenzyl) -4'-methoxymethoxybenzyl. ] phenol as a colorless oil (4.6 g, 93%): XH NMR (200 MHz, DMSO-de): d 6.99 (s, ÍH), d 7.13 (m, 4H), 6.85 (m, 2H), 6.67 ( m, ÍH), 6.43 (s, 2H), 5.12 (s, 2H), 3.84 (s, 2H), 3.76 (s, 2H), 3.24 (s, 3H), 2.07 (s, 6H), CCD conditions : Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (15:85); Rf = 0.45.
Step f: To a solution of 3,5-dimethyl-4- [3 '- (4-fluorobenzyl) -4'-methoxymethoxybenzyl] phenol (4.6 g, 12.09 mmol) and DMAP (4.4 g, 36.27 mmol) in CH 2 Cl 2 ( 100 mL) at 0 ° C was slowly added trifluoromethanesulfonyl anhydride (3.1 mL, 18.14 mmol). The reaction mixture was stirred at 0 ° C for 2 h and quenched with water (60 mL). 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 (15:85) to provide 3,5-dimethyl-4- [3 '- (4-fluorobenzyl) -4' trifluoromethanesulfonate. -methoxymethoxybenzyl] phenyl as a colorless oil (5.8 g, 94%):? H NMR (200 MHz, DMSO-d6): d 6.91 - 7.28 (m, 7H), 6.80 (s, ÍH), 6.69 (d, J = 8.4 Hz, ÍH), 5.15 (s, 2H), 3.91 (s, 2H), 3.84 (s, 2H), 3.25 (s, 3H), 2.22 (s, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (15:85); Rf = 0. 65 Step g: To a solution of trifluoromethanesulfonate of 3,5-dimethyl-4- [3 '- (4-fluorobenzyl) -4'-methoxymethoxybenzyl] phenyl (5.8 g, 11.32 mmol) in DMF (80 mL) in a pump apparatus was added MeOH (9.2 mL, 226.4 mmol), Pd (0Ac) 2 (0.25 g, 1.13 mmol), DPPP (0.47 g, 1.13 mmol) and TEA (3.2 mL, 22.64 mmol). 60 psi (4.218 kg / cm2) of CO was then emptied and the reaction mixture was stirred at 90 ° C for 16 h. The pump was cooled to 0 ° C, vented, the contents were emptied into cold IN HCl and extracted with EtOAc twice. The combined EtOAc extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (15:85) to provide methyl 3,5-dimethyl-4- [3 '- (4-fluorobenzyl) -4'-methoxymethoxybenzyl] benzoate as a colorless oil (4.8 g, 100%): ti NMR (200 MHz, DMSO-de): d 7.64 (s, 2H), 6.68 - 7.25 (m, 7H), 5.13 (s, 2H), 3.97 (s, 2H), 3.83 (s, 5H), 3.24 (s, 3H), 2.23 (s, 6H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (15:75); Rf = 0.52.
Step h: To a stirred solution of dimethyl methylphosphonate (1.44 mL, 13.26 mmol) in THF (60 mL) at -78 ° C was added n-BuLi (2.5 M in hexanes, 5.3 mL), the reaction mixture was stirred at -78 ° C for 1 h, then 3, 5-dimethyl-4- [3 '- (4-fluorobenzyl) -4'-methoxymethoxybenzyl] benzoate (1.4 g, 3.31 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 Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate to provide [2- (3,5-dimethyl-4- (3 '- (4-fluorobenzyl) -4'-methoxymethoxybenzyl) phenyl) - Dimethyl 2-oxo-ethyl] phosphonate as a light yellow oil (1.53 g, 90%): H NMR (200 MHz, DMSO-de): d 7.70 (s, 2H), 6.66 - 7.22 (m, 7H), 5.14 (s, 2H), 3.97 (s, 2H), 3.84 (s, 2H), 3.82 (d, J = 22.4 Hz, 2H), 3.65 (d, J = 11.0 Hz, 6H), 3.24 (s, 3H), 2.25 ( s, 6H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (4: 1); Rf = 0.35.
Step i: To a stirred solution of dimethyl [2- (3, 5-dimethyl-4- (3 '- (4-fluorobenzyl) -4'-methoxymethoxybenzyl) phenyl) -2-oxo-ethyl] phosphonate (1.34 g) , 2.6 mmol) in MeOH (60 mL) at 0 ° C was added NaBH4 (0.49 g, 13.02 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 Na 2 SO 4, filtered and concentrated under reduced pressure to provide [2- (3,5-dimethyl-4- (3 '- (4-fluorobenzyl) -4'-methoxymethoxybenzyl) phenyl) -2-hydroxy. ethyl) dimethyl phosphonate as a light yellow oil (1.4 g, 100%): 1 H NMR (200 MHz, DMSO-de): d 7.11 (m, 6H), 6.89 (m, 2H), 6.67 (m, ÍH), 5.44 (d, J = 4.2 Hz, ÍH), 5.12 (s, 2H), 4.80 (m, ÍH), 3.87 (s, 2H), 3.84 (s, 2H), 3.55 (m, 8H), 3.22 (s, 3H), 2.17 (s, 6H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate; Rf = 0.41.
Step j: To a stirred solution of [2- (3,5-dimethyl-4- (3 '- (4- fluorobenzyl) -4'-methoxymethoxybenzyl) phenyl) -2-hydroxy-ethyl] phosphonate (1.4 g, 2.7 mmol) in CH2C12 (80 mL) at room temperature in EtOAc (20 mL) and AcOH (2 mL) was added Pd / C (0.2 g), and the reaction mixture was stirred under 50 psi (3.515 kg / cm2) H2 at room temperature for 16 h. The mixture was filtered through a plug of Celite. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluted with ethyl acetate to provide 2- [3,5-dimethyl-4- (3 '- (4-fluorobenzyl) -4'-methoxymethoxybenzyl) phenyl] ethylphosphonate of dimethyl as a colorless oil (0.37 g, 27%): H NMR (200 MHz, DMSO-de): d 6.81 - 7.22 (m, 8H), 6.69 (m, 1H), 5.12 (s, 2H), 3.84 (s, 4H), 3.62 (d, J = 10.6 Hz, 6H), 3.24 (s, 3H), 2.65 (m, 2H), 2.14 (s, 6H), 2.02 (m, 2H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate; Rf = 0.49.
Step k: To a stirred solution of dimethyl 2- [3,5-dimethyl-4- (3 '- (4-fluorobenzyl) -4'-methoxymethoxybenzyl) phenyl] ethylphosphonate (0.32 g, 0.64 mmol) in MeOH (4). mL) at room temperature was added HCl (2.1 mL, 3 N), and heated at 100 ° C for 5 min 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 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 2- [3,5-dimethyl-4- (3 '- (4-fluorobenzyl) -4'-hydroxybenzyl) phenyl] ethylphosphonate of dimethyl as a colorless oil (0.27 g, 92%): X H NMR (200 MHz, DMSO-de): d 9.19 (s, ÍH), 6.98 - 7.22 (m, 4H), 6.89 (s, 2H), 6.63 (m, 3H), 3.79 (s, 2H), 3.76 (s, 2H), 3.62 (d, J = 10.8 Hz, 6H), 2.65 (m, 2H), 2.13 (s, 6H), 2.02 (m, 2H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate; Rf = 0.44.
Step 1: To a stirred solution of dimethyl 2- [3,5-dimethyl-4- (3 '- (4-fluorobenzyl) -4'-hydroxybenzyl) phenyl] ethylphosphonate (0.27 g, 0.59 mmol) in THF (10 mL). mL) at room temperature was added NaOH (2.4 mL, 1 N), and the reaction mixture was passed through reflux, after 48 h, IN HCl was added until pH = 2, and the mixture was partitioned between EtOAc and Saturated NaHCO3. The organic layer was dried over Na 2 SO 4, filtered and concentrated under reduced pressure to provide the title compound as a light yellow solid (0.2 g, 77%): X H NMR (300 MHz, DMSO-de): 9.18 (s, 1 H) , 6.88 - 7.22 (m, 4H), 6.86 (s, 2H), 6.71 (d, J = 2.1 Hz, ÍH), 6.65 (d, J = 8.1 Hz, ÍH), 6.55 (dd, J = 2.1, 8.1 Hz, ÍH), 3.78 (s, 2H), 3.76 (s, 2H), 3.52 (d, J = 11.1 Hz, 3H), 2.65 (m, 2H), 2.11 (s, 6H), 1.84 (m, 2H); mp: 125-127 ° C; LC-MS m / z = 443 [C25H28F04P + H] +; Analysis Calculated for (C25H28F04P + 0.5H2O): C, 66.51; H, 6.47. Found: C, 66.23; H, 6.61.
Example 79 Compound 79: [(3, 5-Dimethyl-4- [3 '- (4-fluorobenzyl) -4' -hydroxybenzyl] -phenylamino) methyl] methylphosphinic acid Step a: To a stirred solution of methyl 3,5-dimethyl-4- [3 '- (4-fluorobenzyl) -4'-methoxymethoxybenzyl] benzoate provided (compound 78, step f, 2.8 g, 6.63 mmol) in MeOH (80 mL) at 0 ° C was added NaOH (27 mL, 1 N). After heating at 50 ° C for 16 h, the solvent was removed under reduced pressure and the residue was made acidic with IN HCl until pH = 1, and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 / filtered and concentrated under reduced pressure to give 3,5-dimethyl-4- [3 '- (4-fluorobenzyl) -4'-methoxymethoxybenzyl] benzoic acid as a white solid (2.7 g, 100 g. %): XH NMR (300 MHz, DMS0-d6): 12.71 (s, ÍH), 7.64 (s, 2H), 7. 01 - 7.22 (m, 4H), 6.95 (d, J = 8.4 Hz, ÍH), 6.85 (d, J = 2.1 Hz, ÍH), 6.73 (dd, J = 2.1, 8.4 Hz, ÍH), 5.15 (s) , 2H), 3.98 (s, 2H), 3.86 (s, 2H), 3.27 (s, 3H), 2.25 (s, 6H).
Step b To a solution of 3,5-dimethyl-4- [3 '- (4-fluorobenzyl) -4'-methoxymethoxybenzyl] benzoic acid (2.3 g, 5.63 mmol) in toluene (80 mL) was added diphenylphosphoryl azide. (1.22 mL, 5.63 mmol), triethylamine (1.57 mL, 11.26 mmol) and BnOH (2.9 mL, 28.15 mmol) at room temperature. The mixture was refluxed for 16 h. 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 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 N- [3,5-dimethyl-4- (3 '- (4-fluorobenzyl) -4 benzoyl-methylmethoxybenzyl) phenyl] carbamate as a yellow oil (2.9 g, 100%): XH RM? (300 MHz, DMSO-de): d 9.59 (s, ÍH), 7.01- 7.44 (m, 11H), 6.92 (d, J = 8.7 Hz, ÍH), 6.86 (d, J = 1.8 Hz, ÍH), 6.76 (dd, J = 1.8, 8.7 Hz, ÍH), 5.15 (s, 2H), 5.14 (s, 2H), 3.87 (s, 2H), 3.85 (s, 2H), 3.27 (s, 3H), 2.14 (s, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = 15% ethyl acetate in hexanes; Rf = 0.55.
Step c: To a solution of benzyl N- [3,5-dimethyl-4- (3 '- (4-fluorobenzyl) -4'-methoxymethoxybenzyl) phenyl] carbamate (0.62 g, 1.21 mmol) in CH 3 C? (10 mL) at room temperature was added Cs C03 (0.79 g, 2.42 mmol) and ethyl [(4-methylphenyl) sulfonyloxymethyl] methylphosphinate (compound 740.35 g, 1.21 mmol). The reaction mixture was refluxed for 16 h. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated aHC03. The organic layer was dried over? A2S0, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate to provide [(N-benzyloxycarbonyl-3,5-dimethyl-4- (3 '- (4-fluorobenzyl) -4'-methoxymethoxybenzyl) ethyl phenylamino) methyl] methylphosphinate as a colorless oil (0.065 g, 8.5%): XH RM? (300 MHz, DMSO-de): d 7.01- 7.44 (m, ÍlH), 6.92 (d, J = 8.4 Hz, ÍH), 6.89 (d, J = 2.1 Hz, ÍH), 6.73 (dd, J = 2.1 , 8.4 Hz, 1H), 5.15 (s, 2H), 5.14 (s, 2H), 4.08 (d, J = 6.9 Hz, 2H), 3.91 (s, 2H), 3.85 (m, 3H), 3.63 (m , ÍH), 3.27 (s, 3H), 2.18 (s, 6H), 1.32 (d, J = 14.4 Hz, 3H), 1.01 (t, J = 7.0 Hz, 3H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (4: 1); Rf = 0.39.
Step d: To a solution of ethyl [(N-benzyloxycarbonyl-3,5-dimethyl-4- (3 '- (4-fluorobenzyl) -4'-methoxymethoxybenzyl) phenylamino) methyl] methylphosphinate (0.065 g, 0.1 mmol) in EtOH (30 mL) at room temperature Pd / C (0.04 g) was added and the reaction mixture was stirred under 50 psi (3.515 kg / cm2) of H2 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 (0.045 g, 0.09 mmol) was dissolved in CH2C12 (8 mL). TMSBr (0.12 mL, 0.9 mmol) was then added at -20 ° C. The reaction mixture was stirred at room temperature for 16 h and concentrated under reduced pressure. The MeOH was added to the residue and the solution was stirred at room temperature. After lh, the solution was concentrated under reduced pressure and purified by preparative LC-MS to give the title compound as a white solid (0.014 g, 36%): XH RM? (300 MHz, DMSO-d6): d 9.15 (s, ÍH), 7.01 - 7.22 (m, 4H), 6.77 (d, J = 2.1 Hz, ÍH), 6.67 (d, J = 8.1 Hz, ÍH), 6.59 (dd, J = 2.1, 8.1 Hz, ÍH), 6.41 (s, 2H), 3.79 (s, 2H), 3.71 (s, 2H), 3.25 (d, J = 10.2 Hz, 2H), 2.16 (s) , 6H), 1.37 (d, J = 14.1 Hz, 3H); LC-MS m / z = 428 [C 24 H 27 F? 03 P + H] +; Analysis Calculated for (C 24 H 27 F? 03 P + I.6 H 2 O): C, 63.18; H, 6.67; ?, 3.07. Found: C, 62.87; H, 6.50; ?, 2.96.
Example 80 Compound 80: [(3,5-Dichloro-4- (3 '- (4-fluorobenzyl) -4' hydroxybenzyl) phenoxy) methyl] methylphosphonic acid Step a: 4- [(4-Benzyloxy-2,6-dichlorophenyl) [3- (4-fluorobenzyl) -4-methoxymethoxyphenyl] methanol was prepared from 2,6-dichloro-4-benzyloxybenzaldehyde (Organic Letters 4: 2833 (2002)) in accordance with the procedure described by the synthesis of compound 78, step c. (0.58 gm, 20%); 1H NMR (200 MHz, DMSO-de): d 7.38 (m, 5H), 7.13 (m, 7H), 6.95 (s, 2H), 6.32 (d, J = 4.8 Hz, ÍH), 5.97 (d, J = 4.4 Hz, ÍH), 5.15 (s, 4H), 3.88 (s, 2H), 3.26 (s, 3H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (3: 1); Rf = 0.45.
Step b: 5-Benzyloxy-1,3-dichloro-2- [3 '- (4-fluorobenzyl) -4'-methoxymethoxybenzyl] benzene was synthesized by combining (1.21 gm, 2.48 mmol) starting material with dichloromethane. mL, TFA (0.92 mL, 12.4 mmol), and triethylsilane (2 mL, 12.4 mmol). The reaction was stirred at t.a. for 1.5 h in a bath Ice / water was poured into dichloromethane 50 mL, washed 1 x with 50 mL NaHCO3, 1 x with 25 mL H20, 1 x with 25 mL HCl. The organics were dried over Na 2 SO 4, filtered and concentrated under reduced pressure. (1,172 gm, 100%); NMR (300 MHz, DMSO-de): d 7.37 (m, 5H), 7.15 (m, 4H), 7.08 (m, 4H), 6.94 (m, 2H), 5.14 (s, 4H), 4.06 (s, 2H), 3.85 (s, 2H), 3.25 (s, 3H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (3: 1); Rf = 0.40.
Step c: 3,5-Dichloro-4- [3 '- (4-fluorobenzyl) -4'-methoxymethoxybenzyl] phenol was prepared according to the procedure described by the synthesis of compound 35, step c. (0.183 gm, 40%); X H NMR (300 MHz, DMSO-de): d 10.27 (bs, ÍH), 7.23 (m, 4H), 7.10 (m, 4H), 6.86 (m, 2H), 6.84 (m, 3H), 5.14 (s, 2H), 4.02 (s, 2H), 3.85 (s, 2H), 3.25 (s, 3H); conditions of CCD: Uniplaca of silica gel, 250 microns; Mobile phase = hexanes-ethyl acetate (3: 1); Rf = 0.32.
Step d: To a solution of 3,5-dichloro-4- [3 '- (4-fluorobenzyl) -4'-methoxymethoxybenzyl] phenol (0.08 gm, 0.19 mmol), acetonitrile (3 mL), ethyl [(4-methylphenyl) sulfonyloxymethyl] methylphosphinate (compound 74, 0.105 gm, 0.38 mmol), added cesium carbonate (0.153 gm, 0.47 mmol). The reaction was refluxed for 2 hours, then stirred overnight at r.t. The reaction was filtered in 25 ml ethyl acetate, washed 1 x with brine, dried over Na 2 SO 4, filtered and concentrated. Ethyl [(3,5-dichloro-4- (3- (4-fluorobenzyl) -4-hydroxybenzyl) phenoxy) methyl] methylphosphinate was obtained by preparative plate CCD using a 2mm x 20 x 20 cm SiO 2 plate eluted with ethyl acetate. (0.06gm, 60%); X H NMR (300 MHz, DMSO-de): d 7.23 (s, 2 H), 7.17 (m, 2 H), 7.07 (t, J = 8.7 Hz, 2 H), 6.95 (m, 2 H), 6.86 (m, 1 H) ), 5.14 (s, 2H), 4.41 (m, 2H), 4.07 (s, 2H), 4.04 (m, 2H), 3.86 (s, 2H), 3.25 (s, 3H); 31P NMR (121.4 MHz, DMSO-d6): d 46.13; CCD conditions: Uniplaca of silica gel, 250 microns; ethyl acetate; Rf = 0.22.
Step e: The title compound was prepared according to the procedure described by the synthesis of compound 7, step b (0.032 gm, 62%); X H NMR (300 MHz, DMSO-d 6): d 9.27 (s, 1 H), 7.18 (m, 4 H), 7.06 (t, J = 8.7 Hz, 2 H), 6.84 (d, J = 1.8 Hz, 1 H), 6.71 (m, 2H), 4.20 (d, J = 8.1 Hz, 2H), 4.01 (s, 2H), 3.78 (s, 2H), 1.39 (d, J = 14.7 Hz, 3 H); CCD conditions: Uniplaca of silica gel, 250 microns; isopropanol / AcOH / H20 [7: 2: 1]; Rf = 0.65; LC-MS m / z = 467 [C22H20Cl2FO4P + H] "; Analysis Calculated for (C22H20Cl2FO4P + 0. 1H20): C, 56.09; H, 4.32. Found: C, 55.94; H, 4.15.
Example 81: Compound 81: [3,5-Dichloro-4- (3 '- (4-fluorobenzyl) -4'-hydroxybenzyl) phenoxymethylphosphonic acid monomethyl ester Step a: Dimethyl 3,5-dichloro-4- (3 '- (4-fluorobenzyl) -4'-methoxymethylbenzyl) phenoxy] methylphosphonate was prepared from 3,5-dichloro-4- [3' - (4-fluorobenzyl) -4'-hydroxybenzyl] phenol according to the procedure described by the synthesis of compound 75, step b (0.091 gm, 69%); H NMR (200 MHz, DMSO-de): d 7.26 (s, 2H), 7.10 (m, 2H), 6.92 (m, 5H), 5.10 (s, 2H), 4.25 (d, J = 10.6 Hz, 2H), 4.07 (s, 2H), 3.85 (s, 3H), 3.74 (d, J = 11 Hz, 2H), 3.25 (s, 3H); CCD conditions: Uniplaca of silica gel, 250 microns; ethyl acetate-hexane [3: 1]; Rf = 0.32.
Step b Dimethyl [3,5-dichloro-4- (3 '- (4-fluorobenzyl) -4'-hydroxybenzyl) phenoxy] methylphosphonate was prepared according to the procedure described by the synthesis of the compound 7-14, stage a (0.093 gm, 81%); 1 H NMR (300 MHz, DMSO-de): d 9.27 (s, ÍH), 7.18 (m, 4H), 7.06 (t, J = 9 Hz, 2H), 6.84 (s, ÍH), 6.69 (m, 2H ), 4.57 (d, J = 10 Hz, 2H), 4.02 (s, 2H), 3.78 (s, 2H), 3.73 (d, J = 11 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; ethyl acetate-hexane [3: 1]; Rf = 0.23.
Step c: A solution of dimethyl [3,5-dichloro-4- (3 '- (4-fluorobenzyl) -4'-hydroxybenzyl) phenoxymethylphosphonate (compound 80, step, 0.093 gm, 0.18 mmol), THF (3mL) , and NaOH IN (0.75 mL) was heated to reflux for 12 h. The reaction was allowed to cool, concentrated under reduced pressure and diluted to a volume of 20 mL with H20. The liquor was washed with 2 x with 10 mL of ethyl acetate, then acidified using concentrated HCl to pH 3. The acidic solution was extracted with 2 x 10 mL of diethyl ether. The ether was dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (0.063 gm, 72%); X H NMR (200 MHz, DMSO-de): d 9.28 (s, ÍH), 7.10 (m, 4H), 6.85 (s, ÍH), 6.70 (s, 2H), 4.36 (d, J = 10 Hz, 2H ), 4.01 (s, 2H), 3.77 (s, 2H), 3.64 (d, J = 10.5 Hz, 3H); CCD conditions: Uniplaca of silica gel, 250 microns; isopropanol / AcOH / H20 [7: 2: 1]; Rf = 0.72; LC-MS m / z 485 [C 22 H 20 Cl 2 FO 5 P + H] +; Analysis Calculated for (C 22 H 20 Cl 2 FO 5 P): C, 54.45; H, 4.15. Found: C, 54.45; H, 4.12. Example 82 Compound 82: [3,5-Dibromo-4- (3 '- (4-fluorobenzyl) -4'-hydroxyphenoxy] methylphosphonic acid monomethyl ester Step a: A mixture of 4-bromo-2- (4-fluorobenzyl) phenol (compound 78, step a, 6.0 gm, 21.4 mmol), 1.2 g of palladium on activated carbon (10%) and 100 mL of methanol in a Glass reaction vessel was stirred at 50 psi (3.515 kg / cm2) of H2 overnight, filtered and concentrated under reduced pressure. The resulting light orange oil was dissolved in 180 mL dichloromethane and washed 1 x with saturated NaHCO 3 solution.
The organic was dried over Na S04, filtered and concentrated under reduced pressure to provide 2- (4-fluorobenzyl) phenol. (4.52 gm, 100%):? NMR (200 MHz, DMSO-de): d 9.39 (s, ÍH), 7.22 (m, 2H), 7.02 (m, 3H), 6.74 (m, 2H), 3.84 (s, 2H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = methylene chloride-hexanes (1: 1); Rf = 0.32.
Step b: A mixture of 2- (4-fluorobenzyl) phenol (4.51 gm, 22.41 mmol), DMF (60 mL), potassium carbonate (7.78 gm, 56.02 mmol) and methyl iodide (1.67 mL, 26.81 mmol) was stirred at r.t. for 16 h. The reaction was emptied into 150 mL ethyl acetate, filtered, washed 3x with 50 mL H2O, lx with 100 mL brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide 2- (4-fluorobenzyl) anisole (4.27 gm). 88%); 1 H NMR (200 MHz, DMSO-de): d 7.11 (m, 7 H), 3.88 (s, 2 H), 3.76 (s, 3 H); CCD conditions: Uniplaca of silica gel, 250 microns; methylene chloride-hexanes (1: 1); Rf = 0.64.
Step c: Bis [3- (4-fluorobenzyl) -4-methoxy] iodonium tetrafluoroborate was prepared from 2- (4-fluorobenzyl) anisole using the procedure of (Yokoyama et al., J. Med. Chem. : 695 (1995)). (5.49gm, 40%); X H NMR (200 MHz, DMSO-de): d 7.94 (m, 4 H), 7.15 (m, 12 H), 3.86 (s, 4 H), 3.25 (s, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; dichloromethane-methanol [10: 1]; Rf = 0.53.
Step d: 3,5-Dibromo-4- [3 '- (4-fluorobenzyl) -4'-methoxyphenoxy] phenyl benzoate was prepared from bis [3- (4-fluorobenzyl) -4-methoxy tetrafluoroborate. ] iodonium and 3-benzoyloxy-2,6-dibromophenol according to the procedure described by the synthesis of compound 4, step a (2.15gm, 63%); 1 HOUR NMR (200 MHz, DMSO-de): d 8.13 (dd, J = 6.8, 1 Hz, 2 H z), 7.90 (s, 2H), 7.75 (d, J = 7.2 Hz, ÍH), 7.63 (t, JA Hz, 2H), 7.19 (m, 4H), 6.92 (d, J = 8.8 Hz, ÍH), 6.76 (d, J = 3 Hz, ÍH), 6.51 (dd, J = 6, 2.2 Hz, ÍH) 3.87 (s, 2H), 3.74 (s, 3H); CCD conditions: Uniplaca of silica gel, 250 microns; Hexane-acetone [20: 1]; Rf = 0.24.
Step e: To a mixture of 3,5-dibromo-4- [3 '- (4-fluorobenzyl) -4'-methoxyphenoxy] phenyl benzoate (2.14 gm, 3.75 mmol) in THF 60 mL was added NaOH IN 20 mL. The reaction was stirred at t.a. overnight, then it was emptied into 120 mL ethyl acetate. The aqueous layer was stirred and the organic was washed 2 x with aqueous NaHCO 3, 1 x with IN HCl 30 mL. The ethyl acetate was dried over Na 2 SO 4, filtered and concentrated under reduced pressure to give 3,5-dibromo-4- [3 '- (4-fluorobenzyl) -4'-methoxyphenoxy] phenol (1.68 gm, 93%); X H NMR (300 MHz, DMSO-d 6): d 10.27 (s, ÍH), 7.20 (m, 2H), 7.05 (m, 4H), 6.87 (d, J = 9 Hz, ÍH), 6.65 (d, J = 3.3 Hz, ÍH), 6.46 (dd, J = 9, 3 Hz, ÍH), 3.84 (s, 2H), 3.71 (s, 3H); CCD conditions: Uniplaca of silica gel, 250 microns; hexane-ethyl acetate [3: 1]; Rf = 0.65. Step f: To a stirred solution of 3,5-dibromo-4- [3 '- (4-fluorobenzyl) -4'-methoxyphenoxy] phenol (1.66 gm, 3.44 mmol), lll dichloromethane 100mL, boron tribromide (8.6 mL, 8.60 mmol) was added in an ice / water bath. The reaction was stirred overnight under a nitrogen atmosphere. The reaction was diluted with ethyl acetate 60 mL, filtered and washed with water 2 x with 10 mL and brine 3 x 10 mL. The ethyl acetate was dried over Na 2 SO 4, filtered and concentrated under reduced pressure. 3, 5-Dibromo-4- [3 '- (4-fluorobenzyl) -4'-hydroxyphenoxy] phenol (1.06 gm, 66%) was obtained by flash chromatography using Si02 eluted with a hexane-ethyl acetate step gradient. ethyl [3: 1] 2L and hexane-ethyl acetate [3: 2]; 1 H NMR (300 MHz, DMSO-d 6): d 10.24 (s, ÍH), 9.14 (s, ÍH), 7.22 (m, 2H), 7.08 (m, 4H), 6.69 (td, J = 8.7 Hz, ), 6.54 (d, J = 3.3 Hz, ÍH), 6.55 (dd, J = 8.4, 3.3 Hz, ÍH), 6.35 (dd, J = 9, 3 Hz, ÍH), 3.80 (s, 2H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = methylene chloride-hexanes (1: 1); Rf = 0.55.
Step g: To a stirred solution of 3,5-dibromo-4- [3 '- (4-fluorobenzyl) -4'-hydroxyphenoxy] phenol (0.237 gm, 0.51 mmol), 8mL DMF, cesium carbonate (0.824, 2.53) pmol) diethyl trifluoromethylsulfonyloxymethylphosphonate (0.122 gm, 0.41 mmol) was added in an ice / water bath. The reaction was stirred overnight under a nitrogen atmosphere. The reaction was diluted with ethyl acetate 60 mL, filtered and washed with water 2 x with 10 mL and brine 3 x 10 mL. The ethyl acetate was dried over Na 2 SO 4, filtered and concentrated under reduced pressure. [3, 5-Dibromo-4- (3 '- (4-fluorobenzyl) -4'-hydroxyphenoxy] methylphosphonate diethyl ester (0.124 g, 39%) was obtained by preparative plate CCD using a preparative plate 2mm x 20cm x 20 cm eluted with ethyl acetate; 1 H NMR (300 MHz, DMSO-d 6): d 9.18 (s, ÍH), 7.47 (s, 2H), 7.22 (t, J = 5.7 Hz, 2H), 7.07 (t , J = 9 Hz, 2H), 6.70 (d, J = 8.7 Hz, ÍH), 6.55 (d, J = 3.3 Hz, ÍH), 6.35 (dd, J = 9 Hz and J = 3 Hz, ÍH), 4.54 (d, J = 8.7 Hz, 2H), 4.11 (q, J = 7.2 Hz, 4H), 3.80 (s, 2H), 1.26 (t, J = 7.2 Hz, 6H); 31P NMR (121 MHz, DMSO -d6): d 18.87 (s, 1 P); CCD conditions: Silica gel uniplaca, 250 microns; Mobile phase = ethyl acetate; Rf = 0.42.
Step h: To a stirred solution of diethyl [3,5-dibromo-4- (3 '- (4-fluorobenzyl) -4'-hydroxyphenoxy) phenoxymethylphosphonate (0.134 g, 0.22 mmol) in CH 2 Cl 12 (5 mL) at 0 ° C TMSBr (0.24 g, 0.2 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 converted to a co-evaporator 3 x 5 mL dichloromethane and 1 x 5 mL methanol to give [3, 5-dibromo- 4- (3 '- (4-f luorobenzyl) -4' -hydroxyphenoxy) f enoxy] methylphosphonic as a white foam (0.124 g, 100%); X H NMR (300 MHz, DMSO-de): d 7.35 (s, 2 H), 7.23 (m, 2 H), 7.06 (t, J = 9 Hz, 2 H), 6.70 (d, J = 8.4 Hz, Í H), 6.58 (d, J = 3.3 Hz, HH), 6.32 (dd, J = 9 Hz and J = 3 Hz HH), 3.92 (d, J = 8.7 Hz), 3.79 (s, 2H); LC-MS m / z = 561 [C2oH? 6Br2F06P-H] ".
Step i: Dimethyl 3,5-dibromo-4- (3 '- (4-fluorobenzyl) -4'-hydroxyphenoxy) phenoxy] methylphosphonate was prepared from [3, 5-dibromo-4- (3 '- (4-Fluorobenzyl) -4' -hydroxyphenoxy) phenoxy] methylphosphonic acid according to the procedure described by the synthesis of compound 69, step a (0.089 gm, 66%): XH NMR (300 MHz, DMSO-de): d 9.19 (s, ÍH), 7.48 (s, 2H), 7.22 (m, 2H), 7.07 (t, J = 9 Hz, 2H), 6. 70 (d, J = 9 Hz, ÍH), 6.55 (dd, J = 3.3 Hz, ÍH), 6.34 (dd, J = 3 Hz and J = 9 Hz, ÍH), 4.59 (d, J = 9.9 Hz, 2H), 3.80 (s, 2H), 3.75 (d, J = 10.5 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate; Rf = 0.40. Step j: The title compound was prepared from dimethyl [3,5-dibromo-4- (3 '- (4-fluorobenzyl) -4'-hydroxyphenoxy) phenoxymethylphosphonate in accordance with the procedure described by the synthesis of the compound 81, step c (0.064 gm, 80%); X H NMR (200 MHz, DMSO-de): d 9.19 (s, ÍH), 7.44 (s, 2H), 7.22 (t, J = 8 Hz, 2H), 7.07 (t, J = 8 Hz, 2H), 6.70 (d, J = 8.8 Hz, ÍH), 6.57 (d, J = 3 Hz, ÍH), 6.34 (dd, J = 8.8, 3 Hz, ÍH), 4.33 (d, J = 10 Hz, 2H), 3.80 (s, 2H), 3.63 (d, J = 11 Hz, 3H); CCD conditions: Uniplaca of silica gel, 250 microns; isopropanol / AcOH / H20 [7: 2: 1]; Rf = 0.74; LC-MS m / z 575 [C2? H18Br2F06P-H] "; Calculated Analysis for (C2? H? 8Br2F06P): C, 43.78; H, 3.15. Found: C, 43.66; H, 3.09.
Example 83: Compound 83: [3,5-dimethyl-4- (5'-iodo-4 '-hydroxy-3'-iso-propylbenzyl) phenoxy] methylphosphonic acid Step a: Diethyl [3,5-dimethyl-4- (5'-iodo-4'-hydroxy-3'-iso-propylbenzyl) phenoxymethylphosphonate was prepared from [3,5-dimethyl-4- (4 Diethyl '-hydroxy-3'-iso-propylbenzyl) phenoxymethylphosphonate (compound 69-1, step a) was prepared according to the procedure described by the synthesis of the compound 13-15-cisAH NMR (300 MHz, CD3OD): d 7.06 (d, J = 2.4 Hz, HH), 6.89 (d, J = 2.4 Hz, HH), 6.77 (s, 2H), 4.42 (d, J = 11.2 Hz, 2H), 4.28 (m, 4H), 3.93 (s, 2H), 3.28 (m, ÍH), 2.24 (s, 6H), 1.40 (t, J = 7.2 Hz, 6H), 1.17 (d , J = 7.0 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (1: 1); Rf = 0.6.
Step b: The title compound was prepared according to the procedure described by the synthesis of compound 7, step b: mp: 195-198 ° C; 7.06 (d, J = 2.4 Hz, HH), 6.89 (d, J = 2.4 Hz, HH), 6.77 (s, 2H), 4.24 (d, J = 11.2 Hz, 2H), 3.92 (s, 2H), 3.25 (m, ÍH), 2.23 (s, 6H), 1.17 (d, J = 7.0 Hz, 6H); LC-MS m / z = 491 [C19H24IO5P + H] +; Analysis Calculated for (C1C3H24IO5P): C, 46.55; H, 4.93. Found: C, 46.66; H, 5.26.
Example 84 Compound 84: [(3,5-dibromo-4- (4'-hydroxy-3'-iso-propylphenoxy) phenylamino) methyl] methylphosphinic acid Step a: To a stirred solution of tetrafluoroborate of bis (4-methoxyphenyl) iodonium (3.14 g, 6.12 mmol, Yokoyama et al., J. Med. Chem. 38: 695 (1995)) and copper powder (0.52 g, 8.12 mmol) in CH2C12 (12.0 mL) at 0 ° C a solution of 2,6-dibromo-4-nitrophenol (1.20 g) was added, 4.04 mmol) and Et3N (0.62 mL, 4.48 mmol) in CH2C12 (8.0 mL). The reaction was wrapped in aluminum foil (dark), stirred at room temperature for 216 h and filtered through a plug of Celite. The filtrate was concentrated and purified by column chromatography on silica gel, eluting with acetone-hexanes (3: 97) to provide 3,5-dibromo-4- (3'-isopropyl-4'-methoxyphenoxy) nitrobenzene as a solid. orange (1.95 g, 100%): H NMR (300 MHz, DMSO-d6): d 8.60 (s, 2H), 6.82 (m, 2H), 6.44 (m, ÍH), 3.73 (s, 3H), 3.12 (m, ÍH), 1.13 (d, J = 6.0 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (3:47); Rf = 0.45.
Step b: To a stirred solution of 3,5-dibromo-4- (3'-isopropyl-4'-methoxyphenoxy) -nitrobenzene (1.37 g, 2.98 mmol) in CH2C12 (30.0 mL) at -78 ° C was added BBr3 (8.93 mL, 8.93 mmol, 1 M solution in CHC12). The reaction mixture was stirred at room temperature for 2.5 h, quenched with ice / water, and stirred cold for several minutes. The reaction mixture was diluted with CH2C12 and H20, divided, and the aqueous solution it was extracted with CH2C12. The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1:10) to provide 3,5-dibromo-4- (4'-hydroxy). -3'-isopropylphenoxy) nitrobenzene as a solid (1.20 g, 90%): X H NMR (300 MHz, DMSO-d 6): d 9.19 (s, ÍH), 8.64 (s, 2 H), 6.73 (m, 2 H) , 6.37 (m, ÍH), 3.12 (m, ÍH), 1.16 (d, J = 6.0 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 5); Rf = 0.46.
Step c: To a stirred solution of 3,5-dibromo-4- (4'-hydroxy-3'-isopropylphenoxy) nitrobenzene (0.43 g, 0.96 mmol) in CH2C12 (9.0 mL) at 0 ° C was added diisopropylethylamine (0.50 g). mL, 2.89 mmol) and the reaction mixture was stirred for several minutes. The chloromethylmethyl ether (0.15 mL, 1.92 mmol) was added and the solution was refluxed for 16 h, cooling to 0 ° C, quenched with H20 and partitioned between CH2Cl2 and H20. The organic layer was concentrated under reduced pressure and co-evaporated with methanol and toluene to provide 3,5-dibromo-2- (3'-isopropyl- '-methoxymethoxyphenoxy) nitrobenzene as a glass (0.430 g, 91%): XH NMR (300 MHz, DMSO-d6): d 8.65 (s, 2H), 7.00 (m, HH), 6.86 (m, HH), 6.48 (m, HH), 5.19 (s, 2H), 3.41 (s, 3H), 3. 14 (m, ÍH), 1.17 (d, J = 6.0 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 5); Rf = 0.50.
Step d: To a stirred suspension of 3,5-dibromo-2- (3'-isopropyl-4'-methoxymethoxyphenoxy) nitrobenzene (0.72 g, 1.47 mmol) in MeOH / H20 (15.0 mL / 3.0 mL) was added Na2S204 ( 2.56 g, 14.68 mmol). The reaction mixture was stirred at room temperature for 20 min and the methanol was evaporated under reduced pressure. The reaction mixture was diluted with diethyl ether and H20, partitioned, and the aqueous solution treated with 1: 1 saturated aqueous NaHCO3 / brine. The treated aqueous layer was then extracted with ethyl acetate. The organic layers were then combined, washed with H0 (2X), concentrated, then co-evaporated with MeOH (2X) to provide 3,5-dibromo-4- (3'-isopropyl-4'-methoxymethoxyphenoxy) aniline as a solid (0.60 g, 89%):? H NMR (300 MHz, DMSO-d6): d 6.93 (m, 3 H), 6.72 (m, H), 6.40 (m, H), 5.16 (s, 2 H) , 3.40 (s, 3H), 3.21 (m, ÍH), 1.15 (d, J = 6.0 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 5); Rf = 0.27.
Step e: To a stirred suspension of 3,5-dibromo-4- (3'-isopropyl) 4'-methoxymethoxyphenoxy) aniline (0.50 g, 1.12 mmol) in THF (12.0 mL) was added t-BOC anhydride (0.61 g, 2.80 mmol), dimethylaminopyridine (0.025 g, 5% w / w), and t-BuOH (0.25 g, 3.36 mmol). The reaction mixture was stirred at reflux for 1 h and the solvent was evaporated under reduced pressure. The reaction mixture was diluted with ethyl acetate and H0, partitioned, and the organic layer was concentrated. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1: 10) to give t-butyl Nt-butoxycarbonyl- [3,5-dibromo-4- (3'-isopropyl-4 '-methoxymethoxyphenoxy) phenyl] carbamate as a solid (0.62 g, 86%): XH RM? (300 MHz, DMSO-d6): d 7.84 (s, 2H), 7.04 (m, HH), 6.66 (m, HH), 6.51 (m, HH), 5.18 (s, 2H), 3.41 (s, 3H) ), 3.15 (m, ÍH), 1.22 (s, 18H), 1.13 (d, J = 6.0 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 5); Rf = 0.68.
Step f: To a stirred solution of t-butyl Nt-butoxycarbonyl- [3,5-dibromo-4- (3'-isopropyl-4'-methoxymethoxyphenoxy) phenyl] carbamate (0.62 g, 0.96 mmol) in methanol (20.0) mL) was added 2M aOH (2.88 mL, 5.77 mmol). The reaction mixture was stirred at t.a. for 4.5 h and the solvent was evaporated under reduced pressure. The reaction mixture was treated with saturated aqueous ammonium chloride, diluted with ethyl acetate and H2O, was partitioned, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4, and concentrated to give [3, 5-dibromo-4- (3'-isopropyl-4'-methoxymethoxyphenoxy) phenyl] carbamate t-butyl as an oil (0.62 g, 86% ):? H NMR (300 MHz, DMSO-d6): d 9. 79 (s, ÍH), 7.87 (s, 2H), 6.97 (m, ÍH), 6.77 (m, ÍH), 6.39 (m, ÍH), 5.17 (s, 2H), 3.41 (s, 3H), 3.14 (m, ÍH), 1.50 (s, 9H), 1.17 (d, J = 6.0 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 5); Rf = 0.68.
Step g: To a stirred mixture of t-butyl [3,5-dibromo-4- (3'-isopropyl-4'-methoxymethoxyphenoxy) phenyl] carbamate (0.11 g, 0.20 mmol) and acetonitrile (3.0 mL) was added CS2C03 (0.859 g, 2.64 mmol) followed by ethyl [(4-methylphenyl) sulfonyloxymethyl] methylphosphinate (compound 74, 0.059 g, 0.20 mmol). The reaction mixture was stirred at reflux for 16 h then it was partitioned with ethyl acetate and H2O. The organic layer was concentrated and the crude product was purified by preparative thin-layer chromatography on silica gel, eluting with ethyl acetate-hexanes (4: 1) to give N-t-butoxycarboni-l- [(3,5-dibromo). -4- (3 '-isopropyl-4' -methoxymethoxyphenoxy) phenylamino) methyl] methylphosphinate ethyl as an oil (0.053 g, 39%): X H NMR (300 MHz, DMSO-d 6): d 7.88 (s, 2 H), 6.99 (m, H H), 6.72 (m, H H), 6.47 (m, H H) , 5.18 (s, 2H), 4.13 (m, 2H), 3.93 (m, ÍH), 3.75 (m, ÍH), 3.41 (s, 3H), 3.14 (m, ÍH), 1.43 (s, 9H), 1.12 (d, J = 6.0 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (4: 1); Rf = 0.17.
Step h: To a mixture of ethyl N- t -butoxycarbonyl- [(3,5-dibromo-4- (3'-isopropyl-4'-methoxymethoxyphenoxy) phenylamino) methyl] methylphosphinate (0.27 g, 0.41 mmol) in methanol (6.0 mL) was added 3? HCl (0.68 mL, 2.03 mmol). The reaction mixture was heated with microwave radiation at 100 ° C in a sealed vial for 5 minutes. The solvent was removed and the residue was partitioned with ethyl acetate and brine, partitioned, and the aqueous solution was extracted with ethyl acetate. The combined organic layers were co-evaporated with methanol and concentrated under reduced pressure. The crude residue was purified by preparative thin layer chromatography on silica gel, eluting with methanol-ethyl acetate (5:95) to provide [(3,5-dibromo-4- (4'-hydroxy-3'-isopropylphenoxy) ethyl) phenylamino) methyl] methylphosphinate (0.16 g, 77%) as an oil: 1ti RM? (300 MHz, DMSO-d6): d 8.97 (s, ÍH), 7.11 (s, 2H), 6.65 (m, 2H), 6.26 (m, 2H), 4.06 (m, 2H), 3.55 (m, 2H), 3.14 (, ÍH), 1.48 (d, J = 6.0 Hz, 6H), 1.22 (m, 3H), 1.12 (d, J = 6.0 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = methanol-ethyl acetate (5:95); Rf = 0.35.
Step i: To a solution of ethyl [(3, 5-dibromo-4- (4'-hydroxy-3'-isopropylphenoxy) phenylamino) methyl] methylphosphinate (0.08 g, 0.16 mmol) in CH2C12 (2.0 mL) a - 30 ° C was added bromotrimethylsilane (0.21 mL, 1.55 mmol). The reaction mixture was stirred at -30 ° C for 4 h, then at t.a. for 12 h and the solvent was removed under reduced pressure. The residue was treated with acetonitrile-H20 (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 filtered and concentrated under reduced pressure to provide the title compound as an opaque white powder (0.076 g, 100%); 1H NMR (300 MHz, CD30D): d 6.92 (s, 2H), 6.51 (m, 2H), 6.20 (m, ÍH), 3.38 (m, 2H), 3.12 (m, ÍH), 1.43 (d, J = 15.0 Hz, 3H), 1.05 (d, J = 6.0 Hz, 6H); LC-MS m / z = 494 [C? 7H2oBr2N04P-H] +; CLAR conditions: Column = Shimadzu LC-A8, SPD-10A; filter YMC Pack RP-18, 150x4.6; Mobile phase = Solvent A Acetonitrile / 0.05% TFA; Solvent B = H2O / 0.05% TFA. Flow ratio = 2.0 mL / min; UV @ 254 nm. tr = 14.52 min.
Example 85 Compound 85: 2- [3, 5-Dimethyl-4- (3 '- (4-fluorobenzyl) -4' hydroxybenzyl) phenyl] ethylphosphonic acid The title compound was prepared from dimethyl 2- [3,5-dimethyl-4- (3 '- (-fluorobenzyl) -4'-hydroxybenzyl) phenyl] ethylphosphonate (compound 78, step k) in accordance with procedure described by the synthesis of compound 7, step b (40 mg, 100%): * H NMR (200 MHz, DMSO-de): d 9.17 (s, 1 H), 7.11 (m, 4 H), 6.85 ( s, 2 H), 6.53-6.73 (m, 3 H), 3.76 (s, 4 H), 2.64 (m, 2 H), 2.12 (s, 6 H), 1.78 (m, 2 H); LC-MS m / z = 429 [C 24 H 26 F 04 P + H] +; Analysis Calculated for (C24H26F04P + 2.3H20): C, 61.35; H, 6.56. Found: C, 61.04; H, 6.36.
Example 86 Compound 86: dimethyl [2- (3,5-dimethyl-4- (3 '- (4-fluorobenzyl) -4'-methoxymethoxybenzyl) phenyl) -2-oxo-ethyl] phosphonic acid The title compound was prepared from (60 mg, 94%) [dimethyl 2- (3,5-dimethyl-4- (3 '- (4-fluorobenzyl) -4'-methoxymethoxybenzyl) phenyl) -2-oxo-ethyl] -phosphonate (compound 78, step h) according to the procedure described by the synthesis of compound 7, step b (60 mg, 94%):? H NMR (300 MHz, DMSO-de): d 9.23 (s, 1 H) , 7.66 (s, 2 H), 7.15 (m, 2 H), 7.07 (m, 2 H), 6.76 (d, J = 2.1 Hz, 1 H), 6.66 (d, J = 8.1 Hz, 1 H) , 6.55 (dd, J = 2.1, 8.1 Hz, 1 H), 3.90 (s, 2 H), 3.77 (s, 2 H), 3.47 (d, J = 22.5 Hz, 2 H), 2.23 (s, 6 H); LC-MS m / z = 443 [C 24 H 24 FO 5 P + H] +; Analysis Calculated for (C24H2 F05P + 0. lHBr + 0.2EtOAc + 0.8H2O): C, 61.73; H, 5.70; Br, 1.66. Found: C, 61.59; H, 5.64; Br, 1.84. Example 87 Compound 87: [4- (4-Hydroxy-3-methanesulfonylbenzyl) -3,5-dimethylphenoxymethyl] -phosphonic acid The title compound was prepared from (compound 76, step a) according to the procedure described by the synthesis of compound 7, step b: XH NMR (200 MHz, DMSO-dg): d 10.82 (s, 1 H ), 7.33 (d, J = 2.0 Hz, 1 H), 7.11 (dd, J = 2.0, 8.4 Hz, 1 H), 6.95 (d, J = 8.4 Hz, 1 H), 6.72 (s, 2 H, ), 4.03 (d, J = 10.2 Hz, 2 H), 3.88 (s, 2 H), 3.20 (s, 3 H), 2.15 (s, 6 H); LC-MS m / z = 401 [C17H21O7PS + H] +; Analysis Calculated for (C? 7H2? 07PS + 0.8H2O): C, 49.23; H, 5.49. Found: C, 49.11; H, 5.61.
Example 88 Compound 88: [(3,5-dibromo-4- (4'-hydroxy-3'-iso-propylphenoxy) phenoxy) methyl] methylphosphinic acid Step a: To a stirred mixture of DMF (20.0 mL) and NaH (0.074 g, 1.86 mmol) at 0 ° C was added 3,5-dibromo-4- (3-isopropyl-4-hydroxyphenoxy) phenol (Intermediary for synthesis of compound 8-1, 0.75 g, 1.86 mmol) was dissolved in DMF (2.0 mL). The reaction mixture was allowed to stir at t.a. 1 hr and cooled to 0 ° C. To the stirred mixture was ethyl [(4-methylphenyl) sulfonyloxymethyl] methylphosphinate (compound 74, 0.52 g, 1.77 mmol) and the reaction was stirred at t.a. for 16 h. The reaction was quenched with ice / H20 and the solvent was evaporated. The pH was adjusted to 1 with 2 M HCl and the mixture was partitioned with ethyl acetate and H20. The aqueous solution was extracted with ethyl acetate and the combined organic layers were concentrated under reduced pressure, purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (9: 1) to provide the crude product mixture ( 555 mg) and the starting material (270 mg) was recovered. The residue of the crude product was treated with acetone to provide ethyl [(3,5-dibromo-4- ('-hydroxy-3' -iso-propylphenoxy) phenoxy) methyl] methylphosphinate as a white solid (0.23 g, 24% ): XH NMR (200 MHz, DMSO-d6): d 9.03 (s, 1 H), 7.50 (s, 2 H), 6.67 (m, 2 H), 6.27 (m, 1 H), 4.49 (m, 2 H), 4.02 (m, 2 H), 3.14 (m, 1 H), 1.58 (d, J = 16.0 Hz, 3 H); 1.23 (m, 3 H), 1.12 (d, J = 6.0 Hz, 6 H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate; Rf = 0.26. Step b: To a stirred suspension of ethyl [(3, 5-dibromo-4- (4'-hydroxy-3'-iso-propylphenoxy) phenoxy) methyl] methylphosphinate (0.24, 0.45 mmol) in CH2C12 (6.0 mL) at -30 ° C was added bromotrimethylsilane (0.59 mL, 4.50 mmol). The reaction mixture was stirred at t.a. for 16 h and the solvent was removed under reduced pressure. The residue was treated with acetonitrile-H20 (5: 1, 5.0 mL) and stirred at 38 ° C for 20 minutes. min. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with H0. The organic solution was concentrated, co-evaporated with MeOH, and filtered to provide the title compound as a white powder (0.215 g, 97%); X H NMR (200 MHz, DMSO-d 6): d 9.02 (s, 1 H), 7.47 (s, 2 H), 6.63 (m, 2 H), 6.26 (m, 1 H), 4.26 (d, J = 12.0 Hz, 2 H), 3.14 (m, 1 H), 1.45 (d, J = 14.0 Hz, 3 H), 1.12 (d, J = 6.0 Hz, 6 H); LCMS m / z = 495 [C17H2oBr2? 5P -H] +; Analysis Calculated for (C? 7H2oBr205P + 0.2 H20 + 0.1 CH3COCH3): C, 41.27; H, 4.00 Found: C, 41.22; H, 4.06 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. Flow ratio = 2.0 mL / min; UV @ 254 nm. Retention time, (tr = 8.93 min).
EXAMPLE 89 Compound 89: [4- (5'-bromo-6 '-hydroxynaphthyl) -3,5-dimethyl-yl-enoxy] -methylphosphonic acid Step a: To a stirred solution of 6-methoxy-1-naphthol (Kasturi, TR Arunachalum, T. Can. Journal, Chem. 3625 (1968), 3.0 g, 17.2 mmol) in anhydrous CH2C12 (50 mL) at -40 ° C Et3N (4.66 mL, 34.4 mmol) was added and the reaction mixture was stirred at -40 ° C for 15 min. The trifluoromethanesulfonyl anhydride (5.8 g, 20.6 mmol) CH2C1 in (5 mL) was added and the reaction mixture was stirred for 2 h at -10 ° C and for 30 min at room temperature. The reaction mixture was quenched with saturated NaHCO3 (50 mL) and extracted with CH2C12 (2x100 mL). 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 purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1: 9) to give 6-methoxy-1-naphthyl trifluoromethanesulfonate as a colorless oil (5.10 g, 92%): 1H NMR (300 MHz, CDC13): d 8.0 (d, J = 9.0 Hz, HH), 7.77 (d, J = 8.4 Hz, HH), 7.44 (t, J = 8.1 Hz, HH), 7.35-7.32 (m , 2H), 7.22 (s, ÍH), 3.98 (s, 3H); CCD conditions: Uniplaca of silica gel, 250 microns; mobile phase = ethyl acetate-hexanes (1: 4); Rf = 0.6.
Step b: A mixture of 6-methoxy-1-naphthyl trifluoromethanesulfonate (0.85 g, 2.6 mmol), bis-picolinate-diborane (1.07 g, 3. 95 mmol) and anhydrous potassium acetate (0.77 g, 7.8 mmol) in DMSO (30 mL) was degassed by nitrogen sparging for 30 min and PdCl2dppf. dichloromethane (0.43 g, 0.52 mmol) was added. The reaction mixture was heated at 85 ° C for 4 h. The reaction mixture was filtered through a plug of Celite and washed with ethyl acetate (2x50 mL) 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 1,1,2,2-tetramethyl-6-methoxynaphthyl-1-boronate as a pale yellow solid. (0.64 g, 86%): XH NMR (300 MHz, CDC13): d 8.69 (d, J = 9.3 Hz, ÍH), 7.98 (d, J = 7.8 Hz, ÍH), 7.85 (d, J = 7.8 Hz , ÍH), 7.46 (dd, J = 1.5, 6.6 Hz, ÍH), 7.22 (dd, J = 2.4, 9.0 Hz, HH), 7.16 (d, J = 2.4 Hz HH), 3.96 (s, 3H), 1.45 (s, 12H); CCD conditions: Uniplaca of silica gel, 250 microns; mobile phase = ethyl acetate-hexanes (1: 4); Rf = 0.65.
Step c: To a stirred suspension of NaH (0.5 g, 22.0 mmol) in anhydrous DMF (20 mL) at 0 ° C was added 3,5-dimethyl-4-bromophenol (2.2 g, 11.0 mmol) in DMF (5 mL ) followed by diethyl tosyloxymethylphosphonate (3.9 g, 24.2 mmol) in DMF (5.0 mL) 30 min later. The reaction mixture was stirred for 14 h at room temperature and was poured into water (30 g. mL). The aqueous solution was extracted with ethyl acetate (2x100 mL) and the combined organic layers were washed with brine, dried over NaSO4 / filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (2: 3) to provide diethyl (3,5-dimethyl-4-bromophenoxy) methylphosphonate as a syrup. (1.85 g, 48%): XH NMR (300 MHz, CDC13): d 6.88 (s, 2H), 4.15-4.25 (m, 6H), 2.41 (s, 2H), 1.40 (t, J = 6.0 Hz, 6H); LC-MS m / z = 351 [C? 3 H20BrO4P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; mobile phase = ethyl acetate-hexanes (2: 3); Rf = 0.3.
Step d: To a stirred solution of 1, 1, 2, 2-tetramethyl-6-methoxynaphthyl-1-boronate (0.5 g, 1.76 mmol) and diethyl (3, 5-dimethyl-4-bromophenoxy) methylphosphonate (0.675 g) , 1.93 mmol) in anhydrous DME (40 mL) was degassed by nitrogen for 10 min. Tetrakis (triphenylphosphine) palladium (0.4 g, 0.35 mmol) and an aqueous solution of sodium carbonate (0.55 g, 5.28 mmol) in water (10 mL) were added. The reaction mixture was heated at 85 ° C for 24 h. and the reaction mixture was poured into water (30 mL). The aqueous solution was extracted with ethyl acetate (2x100 mL) and the combined organic layers were 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 ethyl acetate-hexanes (1: 2) to give [3,5-dimethyl-4- (6'-methoxynaphthyl) phenoxymethylphosphonate diethyl as a syrup. (0.45 g, 45%): X NMR (300 MHz, CDC13): d 7.77 (d, J = 8.1 Hz, HH), 7.52 (t, J = 7.2 Hz, HH), 7.27 (d, J = 6.0 Hz , ÍH), 7.24-7.23 (m, 2H), 7.13 (d, J = 1.5 Hz, ÍH), 7.05 (dd, J = 2.7, 9.0 Hz, ÍH), 6.81 (s, 2H), 4.34-4.27 ( m, 6H), 3.96 (s, 3H), 1.91 (s, 6H), 1.42 (t, J = 5.1 Hz, 6H); LC-MS m / z = 429 [C 24 H 2 905 P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; mobile phase = ethyl acetate-hexanes (2: 3); Rf = 0.3. Step e: To a stirred solution of diethyl [3,5-dimethyl-4- (6'-methoxynaphthyl) phenoxymethylphosphonate (130 mg, 0.30 mmol) in anhydrous CH 2 C 12 (10 mL) was added bromine (50 mg, 0.32 mmol) , the solution was stirred for 30 min. and the reaction mixture was washed with aqueous sodium bisulfate. The resulting solution was extracted with CH2C12 (2x50 mL) and the combined organic layers were washed with saturated N3 (25 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 (2: 3) to provide [4- (5'-bromo-6 '- diethyl methoxynaphthyl) -3,5-dimethylphenoxy] methylphosphonate as a brown solid (140 mg, 93%):? ti NMR (300 MHz, CDC13): d 8. 30 (d, J = 8.0 Hz, ÍH), 7.65 (t, J = 7.2 Hz, ÍH), 7.34-7.32 (m, 2H), 7.20-7.15 (m, 2H), 6.82 (s, 2H), 4.39-4.29 (m, 6H), 4.04 (s, 3H), 1.90 (s, 6H), 1.44 (t, J) = 6.9 Hz, 6H); LCMS m / z = 507 [C24H28Br05P] +; CCD conditions: Uniplaca of silica gel, 250 microns; mobile phase = ethyl acetate-hexanes (2: 3); Rf = 0.28.
Step f: To a stirred solution of diethyl [4- (5'-bromo-6'-methoxynaphthyl) -3,5-dimethylphenoxy] methylphosphonate (130 mg, 0.25 mmol) in CH2C12 (5 mL) at 0 ° C was added. added TMSBr (0.38 g, 0.35 mL, 2.5 mmol). 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, the residue was dissolved in CH 3 OH (3 mL) and the solvent was removed under reduced pressure. The residue was triturated with acetonitrile and dried under reduced pressure to give [4- (5'-bromo-6'-methoxy-naphthyl) -3,5-dimethylphenoxy] methylphosphonic acid as a white solid (0.12 g 100%, crude): X H NMR (300 MHz, CD 3 OD): d 8.12 (d, J = 8.8 Hz, HH), 7.55 (t, J = 7.0 Hz, HH), 7.13-6.92 (m, 3H), 6.80 (s, 2H), 4.20 (d, J = 10.4 Hz, 2H), 3.96 (s, 3H), 1.91 (s, 6H); LC-MS m / z = 451 [C2oH20Br05P] +; Step g: To a stirred solution of [4- (5'-bromo-6'-methoxynaphthyl) -3,5-dimethylphenoxy] methylphosphonic acid (0.12 g, 0.26 mmol) in CH2C12 (5 mL) at -78 ° C was added. added BBr3 (0.1 g, 0.39 mmol) in CH2C12 (5 mL). The reaction mixture was stirred at t.a. for 3 h and water (25 mL) was emptied on ice and stirred for 1 h. The reaction mixture was extracted with ethyl acetate (2x50 mL). 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 under reduced pressure to provide the title compound as a yellow solid (70 mg, 92%, 94% pure): 1 H NMR (200 MHz, CD3OD): d 8.14 (d, J = 8.8 Hz, ÍH), 7.39 (t, J = 7.0 Hz, ÍH), 7.15-6.99 (m, 3H), 6.81 (s, 2H), 4.19 (d, J = 10.4 Hz, 2H ), 1.81 (s, 6H); LC-MS m / z = 437 [C19H? 8Br05P + H] +; CLAR conditions: column YMC pack ODS-AQ12S051546W; mobile phase = TFA / ACN (0.05%) and TFA / H20 (0.05%) flow ratio = 1.0 mL / min; detection = UV @ 254 nm retention time in min: 7.14; Calculated analysis: (MF: C? 9H? 8BrO5P + 0.8 CH2C12) Calculated: C: 47.36, H: 3.92, Found: C: 47.12, H: 3.58.
Example 90 Compound 90: [3,5-dichloro-4- (4'-0-hydroxynaphthyloxy) phenylamino] -methylphosphonic acid Step a: To a stirred solution of 4-methoxy-1-naphthol (0.5 g, 2.86 mmol) and 3,5-dichloro-4-iodoitrobenzene (1.0 g, 3.16 mmol) in DMSO (30 mL) at room temperature was added K2C03 (0.6 g, 4.30 mmol). The reaction mixture was heated at 125 ° C for 18 h, cooled to room temperature and poured into water. The aqueous layer was extracted with ethyl acetate (2x100 mL). The combined organic layers were washed with brine and water, 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: 9) to give 3,5-dichloro-4- (4'-O-methoxynaphthyloxy) -nitrobenzene as a yellow solid. (0.8 g, 78%): XH NMR (300 MHz, CDC13): d 8.15 (s, 2H), 8.0-8.16 (m, ÍH), 7.40-7.50 (m, 3H), 6.34 (d, J = 8.4 Hz, ÍH), 6.06 (d, J = 8.4 Hz, ÍH), 3.76 (s, 3H); CCD conditions: Uniplaca of silica gel, 250 microns; mobile phase = ethyl acetate-hexanes (1: 4); Rf = 0.7.
Step b: A suspension of 3,5-dichloro-4- (4 '-O-methoxynaphthyloxy) -nitrobenzene (0.47 g, 2.6 mmol) in acetic acid (20 mL) and water (2 mL) was heated to 50 ° C. until all the material dissolved it then cooled down to Iron powder (108 mg, 1.94 mmol) was added at room temperature and the reaction mixture was stirred overnight, filtered through a plug of Celite and washed with EtOAc (100 mL). The filtrate was extracted with ethyl acetate (2x100 mL). The combined organic layers were washed with water and brine, dried over Na 2 SO 4 / filtered and concentrated under reduced pressure to give 3,5-dichloro-4- (4'-O-methoxynaphthyloxy) aminobenzene as a brown solid (0.32 g , 75%): H NMR (200 MHz, CD3OD): d 8.15 (dd, J = 2.2, 5.8 Hz, ÍH), 8.0 (dd, J = 2.2, 5.8 Hz, ÍH), 7.37-7.31 (m, 2H ), 6.58 (s, 2H), 6.45 (d, J = 8.4 Hz, ÍH), 6.07 (d, J = 8.4 Hz, ÍH), 3.73 (s, 3H); CCD conditions: Uniplaca of silica gel, 250 microns; mobile phase = ethyl acetate-hexanes (2: 3); Rf = 0.3.
Step c: To a stirred solution of 3,5-dichloro-4- (4 '-O-methoxynaphthyloxy) aminobenzene (14.3 g, 0.90 mmol) in CH2C12 (10 mL) at 0 ° C were added Et3N (0.27 g, 2.25 mmol), (Boc) 20 (0.21 g, 1.0 mmol) and a catalytic amount of DMAP (25 mg). The reaction mixture was stirred at t.a. for 4 h and it went out with water (15 mL). The reaction mixture was extracted with CH2Cl2 (2x50 mL). 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 purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (2: 8) to give N- [3,5-dichloro-4- (4'-O-methoxynaphthyloxy) benzene] carbamate of t-butyl as a yellow solid (0.22 g, 58%): H RM? (300 MHz, CDC13): d 8.21 (dd, J = 2.2, 6.0 Hz, ÍH), 8.04 (d, J = 2.2, 6.0 Hz, ÍH) 7.43-7.36 (m, 2H), 7.07 (s, 2H), 6.33 (d , J = 8.4 Hz, ÍH), 6.07 (d, J = 8.4 Hz, ÍH), 3.74 (s, 3H), 1.32 (s, 9H).
Step d: To a stirred solution of N- [3,5-dichloro-4- (4 '-0-methoxynaphthyloxy) benzene] t-butyl carbamate (0.22 g, 0.5 mmol) in anhydrous acetonitrile (15 mL) at room temperature At room temperature, Cs2CO3 (0.33 g, 1.0 mmol) and diethyl tosyloxymethylphosphonate (0.16 g, 0.5 mmol) were added. The reaction mixture was heated at 80 ° C for 8 h and cooled to room temperature, then it was poured into water (20 mL). The aqueous solution was extracted with ethyl acetate (2x50 mL) and the combined organic layers were washed with brine, dried over? A2SO4 / filtered and concentrated under reduced pressure. The crude product was purified by chromatography of column on silica gel, eluting with ethyl acetate-hexanes (1: 1) to give N- t-butoxycarbonyl- [3,5-dichloro-4- (4'-O-methoxynaphthyloxy) phenylamino] methylphosphonate diethyl ester as a viscous oil. (145 mg, 50%): XH RM? (200 MHz, CDC13): d 8.21 (dd, J = 1.8, 7.4 Hz, ÍH), 8.04 (dd, J = 2.0, 6.2 Hz, ÍH), 7.43-7.36 (m, 2H), 7.24 (s, 2H) ), 6.33 (d, J = 8.4 Hz, HH), 6.07 (d, J = 8.4 Hz, HH), 4.0-3.86 (m, 6H), 3.75 (s, 3H), 1.29 (s, 12H), 1.11 (t, J = 6.9 Hz, 6H); LC-MS m / z = 584 [C28H34Cl2? 06P + 2] +; CCD conditions: Uniplaca of silica gel, 250 microns; mobile phase = ethyl acetate-hexanes (1: 1); Rf = 0.3.
Step e: [3,5-Dichloro-4- (4'-0-methoxynaphthyloxy) phenylamino] methyl-phosphonic acid was prepared from N-t-butoxycarbonyl- [3,5-dichloro-4- (4 ' -0-methoxynaphthyloxy) phenylamino] methyl diethylphosphonate in accordance with the procedure described by the synthesis of compound 89, step f; solid brown tone (92 mg, 100%): 1H RM? (200 MHz, CD3OD): d 8.13 (dd, J = 2.2, 6.6 Hz, ÍH), 7.99 (dd, J = 2.6, 6.0 Hz, ÍH), 7.40-7.31 (m, 2H), 6.67 (s, 2H ), 6.44 (d, J = 8.4 Hz, HH), 6.07 (d, J = 8.4 Hz, HH), 3.74 (s, 3H), 3.27 (d, J = 12.0 Hz, 2H); LC-MS m / z = 427 [C? 8H? 6Cl2? 05P + H] A- Step f: The title compound was prepared from acid [3,5-dichloro-4- (4'-O-methoxynaphthyloxy) phenylamino] methylphosphonic acid according to the procedure described by the synthesis of compound 89, step g; solid coffee (38 mg, 40%): XH NMR (200 MHz, CD3OD): d 8.09 (dd, J = 2.2, 6.6 Hz, ÍH), 7.95 (dd, J = 2.6, 6.0 Hz, ÍH), 7.33-7.28 (m, 2H), 6. 64 (s, 2H), 6.35 (d, J = 8.4 Hz, ÍH), 5.97 (d, J = 8.4 Hz, ÍH), 3.21 (d, J = 12.0 Hz, 2H); LC-MS m / z = 414 [Ci 7 H 14 Cl 2 N0 5 P + H] +; CLAR conditions: column YMC pack ODS- AQ12S051546; mobile phase = TFA / ACN (0.05%) and TFA / H20 (0.05%) flow ratio = 1.0 mL / min; detection = UV0254 nm retention time in min: 9.58; Calculated analysis: (MF: Ci7Hi4Cl2NO5P + 1.0 H20) Calculated: C: 47.24, H: 3.73, N: 3.24 Found: C: 47.35, H: 3.51, N: 3.00.
Example 91: Compound 91: [(3,5-dichloro-4- (4'-0-hydroxynaphthyloxy) phenylamino) -methyl] methylphosphinic acid Step a: N- t -butoxycarbonyl- [(3,5-dichloro-4- (4-O- methoxynaphthyloxy) -phenylamino) methyl] methylphosphinate was prepared from N- [3,5-dichloro-4- (4 '-0-methoxynaphthyloxy) benzene] t-butyl carbamate (compound 90, step c) and [ Ethyl (4-methylphenyl) sulfonyloxymethyl] methylphosphinate (compound 74) according to the procedure described by the synthesis of compound 90, step d; syrup (80 mg, 29%): XH RM? (200 MHz, CDC13): d 8.21 (dd, J = 1.8, 7.4 Hz, ÍH), 8.04 (dd, J = 2.0, 6.2 Hz, ÍH), 7.45-7.36 (m, 2H), 7.26 (s, 2H) ), 6.33 (d, J = 8.4 Hz, ÍH), 6.06 (d, J = 8.4 Hz, ÍH), 4.0-3.86 (m, 4H), 3.75 (s, 3H), 1.35 (d, J = 13.8 Hz, 3H), 1.29 (s, 12H), 1.07 (t, J = 6.9 Hz, 3H); LC-MS m / z = 555 [C26H32C12? 06P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; mobile phase = ethyl acetate-hexanes (1: 1); Rf = 0.3.
Step b: [(3,5-Dichloro-4- (4'-0-ethoxynaphthyloxy) phenylamino) methyl] -methylphosphinic acid was prepared from [(3,5-dichloro-4- (4'-0- ethyl methoxynaphthyloxy) phenylamino) methyl] methylphosphinate according to the procedure described by the synthesis of compound 89, step f; solid coffee (50 mg, 88%):? H RM? (200 MHz, CD3OD): d 8.12 (dd, J = 2.2, 6.6 Hz, ÍH), 7.98 (dd, J = 2.6, 6.0 Hz, ÍH), 7.41-7.31 (m, 2H), 6.69 (s, 2H ), 6.45 (d, J = 8.4 Hz, ÍH), 6.07 (d, J = 8.4 Hz, ÍH), 3.74 (s, 3H), 3.29 (d, J = 12.0 Hz, 2H), 1.38 (d, J = 14.0 Hz, 3H); LC-MS m / z 427 [C? 8H16Cl2N05P + H] + Step c: The title compound was prepared from [(3,5-dichloro-4- (-0-methoxynaphthyloxy) phenylamino) methyl] methylphosphinic acid in accordance with the procedure described by the synthesis of compound 89, step g; solid brown (24 mg, 50%): 1 H NMR (200 MHz, DMSO-d 6): d 9.58 (s, ÍH), 8.01 (d, J = 7.8 Hz, ÍH), 7.89 (d, J = 7.8 Hz, ÍH), 7.48-7.34 (m, 2H), 6.73 (s, 2H), 6.43 (d, J = 8.0 Hz, ÍH), 5.99 (d, J = 8.0 Hz, ÍH), 3.13 (d, J = 10.4 Hz, 2H) 1.14 (d, J = 13.8 Hz, 3H); LC-MS m / z = 412 [C? 8H? 6Cl2N05P + H] A Example 92 Compound 92: [(3,5-Dibromo-4- (3 '- (4-fluorobenzyl) -4' -hydroxyphenoxy) -methyl] methylphosphinic acid Step a [(3,5-Dibromo-4- (4'-hydroxy-3 '- (4-fluorobenzyl) phenoxy) methyl] methyl phosphinate was prepared from 3, 5-dibromo-4- [3 '- (4-fluorobenzyl) -4' -hydroxyphenoxy] phenol (compound 82, step g) and ethyl [(4-methylphenyl) sulfonyloxymethyl] methylphosphinate (compound 74) according to the procedure described by the synthesis of compound 77, step a; (0.014.8 gm, 14%); 1 H NMR (200 MHz, CD 3 OD): d 7.18 (s, 2 H), 6,944 (m, 2 H), 6.74 (t, J = 8.6 Hz, 2H), 6.48 (d, J = 8.8 Hz, ÍH), 6.70 (m, 2H), 4. 23 (dd, J = 5, 8.6 Hz, 2H), 3.96 (m, 2H), 3.65 (s, 2H), 1. 46 (d, 3 H, J = 14.6 Hz), 1.16 (t, J = 1 Hz, 3H); CCD conditions: Uniplaca of silica gel, 250 microns; ethyl acetate; Rf = 0.18; LC-MS m / z 589 [C23H22Br2F05P + H] A Step b: The title compound was prepared according to the procedure described by the synthesis of compound 7, step b; (0.010 gm, 81%); X H NMR (200 MHz, CD 3 OD): d 7.36 (s, 2 H), 7.14 (m, 2 H), 6.94 (t, J = 8.8 Hz, 2 H), 6.65 (d, J = 8.4 Hz, ÍH), 6.70 ( m, 2H), 4.28 (d, J = 8.6 Hz, 2H), 3.96 (m, 2H), 3.85 (s, 2H), 1.65 (d, 3 H, J = 15.2 Hz); CCD conditions: Uniplaca of silica gel, 250 microns; IPA / AcOH / H20 [7: 2: 1]; Rf = 0.73; LC-MS m / z 559 [C2? H? 8Br2F05P-H] A Example 93 Compound 93: [3,5-Dimethyl-4- (3'-Isopropyl-1'H-indol-5'-methylmethyl) -phenoxy] methylphosphonic acid Stage a: To the suspension of 4-bromophenylhydrazine hydrochloride (6.0 g mg, 26.85 mmol) in water was added 3.5 M NaOH (11.5 ml, 40. 82 mmol), followed by isovaleraldehyde (2 μl, 32.21 pmol). The reaction was stirred for 10 min, then the reaction was made acidic with AcOH (25 ml). The reaction was further stirred for 30 min, and toluene was then added to the extract of the product twice. The combined toluene layer was washed with saturated NaHCO 3, dried over MgSO 4, filtered and concentrated to give N- (4-bromo-phenyl) -N '- (3-methyl-butyl) -hydrazide (7.6 g, 100 %): XH RM? (200 MHz, CDC13): d 9.63 (s, ÍH), 7.07 (d, J = 8.6 Hz, ÍH), 6.97 (m, ÍH), 6.62 (d, J = 8.6 Hz, 2H), 1.88 (m, 2H), 1.60 (m, ÍH), 0.71 (d, J = 6.6 Hz, 6H).
Step b: To the solution of N- (4-bromo-phenyl) -N '- (3-methyl-butyl) -hydrazide (7.6 g, 31.54 mmol) in xylene (150 ml) was added ZnCl 2 (5.16 g, 37.84 mmol). The reaction was refluxed for 1.5 hrs, then concentrated, and the residue was partitioned between toluene and? AHC03 sat. The organic layer was collected and the layer of water was further extracted with toluene once. The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1: 9) to give 5-bromo-3-isopropyl-1H-indole (4.55 g, 60.9%):? H NMR ( 300 MHz, CDC13): d 8.72 (s, ÍH), 8.57 (s, ÍH), 8.05 (m, 2H), 7.77 (s, ÍH), 3.95 (m. ÍH), 2.15 (d, J = 6.6 Hz , 6H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 9); Rf = 0.51.
Step c: To a suspension of NaH (509 mg, 20.16 mmol) in THF (50 ml) was added 5-bromo-3-isopropyl-1H-indole (4.55 g, 19.20 mmol). The reaction mixture was stirred at t.a. for 30 min, and TIPSC1 was then added to t.a. The reaction was further stirred for 1 hr, diluted with EtOAc, and water added to quench the reaction. The organic layer was collected and the water layer was further extracted with EtOAC once. The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with hexane to give 5-bromo-3-isopropyl-1-triisopropylsilyl-1H-indole (5.1 g, 67.6%): 1 H NMR (200 MHz, CDC13): d 7.53 (d, J = 1.8 Hz, 1H), 7.13 (d, J = 8.8 Hz, ÍH), 6.99 (m, ÍH), 6.76 (s, ÍH), 2.92 (m, ÍH), 1.44 (m, 3H), 1.14 (d, J = 6.6 Hz, 6H), 0.93 (d, J = 7.4 Hz, 18H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = Hexane (1: 9); Rf = 0.65.
Step d: (2,6-Dimethyl-4-triisopropylsilanyloxyphenyl) - (3-isopropyl-l-triisopropylsilyl-lH-indol-5-yl) -methanol was prepared from 5-bromo-3-isopropyl-l- triisopropylsilyl-lH-indole and 2,6-dimethyl-4-triisopropyl-silanyloxybenzaldehyde according to the procedure described by the synthesis of compound 27, step c; Brown oil (2.44g, 77.2%):? H NMR (200 MHz, CDC13): d 7.47 (s, ÍH), 7.36 (d, J = 8.8 Hz, ÍH), 6. 98 (d, J = 8.8 Hz, ÍH), 6.93 (s, ÍH), 6.58 (s, 2H), 6.40 (d, J = 3.6 Hz, HH), 3.10 (m, HH), 2.24 (s, 6H), 1.69 (m, 6H), 1.28 (d, J = 6.6 Hz, 6H), 1.12 (d, J = 6.2 Hz, 36H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1:19); Rf = 0.62.
Step e: To a solution of (2,6-dimethyl-4-triisopropylsilanyloxyphenyl) - (3-isopropyl-1-triisopropylsilyl-1H-indol-5-yl) -methanol (1.86 g, 3.0 mmol) in CH 2 Cl 12 (20 ml ), tiethylsilane (1.74 g, 15.0 mmol) was added, followed by AcOH (1.11 mL), then TFA (1.11 mL, 15.0 mmol). The reaction was stirred at t.a. for 1 hr, the mixture of The reaction was diluted with EtOAc and water and the layers separated. The EtOAc layer was collected and the water layer was further extracted with EtOAc once. The combined organic layers were washed with NaHCO 3 Sat., water and brine, dried over MgSO 4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1:49) to provide 5- (2,6-dimethyl-4-triisopropylsilyloxybenzyl) -3-isopropyl-1H-indole (1.0 g, 74.6%): XH NMR (200 MHz, CDC13): d 7.59 (s, ÍH), 7.02 (d, J = 8.2 Hz, ÍH), 6.97 (s, ÍH), 6.70 (s, ÍH), 6.63 (d, J = 8.2 Hz, HH), 3.89 (s, 2H), 2.88 (m, HH), 2.01 (s, 6H), 1.2 (m, 3H), 1.05 (d, J = 6.6 Hz, 6H) , 0.99 (d, J = 6.2 Hz, 18H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1:49); Rf = 0.70.
Step f: 3,5-Dimethyl-4- (3-isopropyl-1H-indol-5-ylmethyl) phenol was prepared according to the procedure described by the synthesis of compound 35, step e; yellow oil (420mg, 64%): XH NMR (200 MHz, CDC13): d 7.61 (s, ÍH), 7.06 (s, ÍH), 7.02 (d, J = 8.0 Hz, ÍH), 6.72 (s, ÍH) ), 6.63 (d, J = 8.2 Hz, 2H), 6.38 (s, 2H), 3.89 (s, 2H), 2.93 (s, ÍH), 2.04 (s, 6H), 1.05 (d, J = 7.2 Hz , 6H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 3); Rf = 0.65.
Step g: Diethyl [3, 5-dimethyl-4- (3'-isopropyl-1H-indol-5'-ylmethyl) -phenoxylmethylphosphonate was prepared by the procedure used for the synthesis of compound 35, step f as a colorless oil (130 mg, 43%): XH NMR (200 MHz, CDC13): d 7.82 (s, ÍH), 7.23 (s, ÍH), 7.20 (d, J = 8.8 Hz, ÍH), 6.90 (s, ÍH), 6.79 (d, J = 8.8 Hz, ÍH), 6.68 (s, 2H), 4. 11 (m, 6H), 4.09 (s, 2H), 3.07 (m, ÍH), 2.24 (s, 6H), 1.28 (m, 12H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 1); Rf = 0. 65 Step h: The title compound was prepared according to the procedure described by the synthesis of compound 35, step h; yellow foam (50 mg, 63.6%): X H NMR (200 MHz, DMSO-de): d 10.60 (s, ÍH), 7.18 (D, J = 8.0 Hz, ÍH), 7.13 (s, ÍH), 6.98 ( s, ÍH), 6.71 (s, 2H), 6.63 (d, J = 8.0 Hz, ÍH), 4.02 (m, 4H), 3.02 (m, ÍH), 2.20 (s, 6H), 1.22 (d, J = 7.0 Hz, 6H). LC-MS m / z = 388 [C2? H26N04P + H] +; Analysis Calculated for (C2? H26N04P + 0.5 HBr): C, 58.95; H, 6.24; N, 3.27. Found: C, 58.99; H, 6.42; N, 3.20.
Example 94: Compound 94: mono- [3,5-dimethyl-4- (4'-hydroxy-3 '- ester isopropylbenzyl) benzyl] of methylphosphonic acid Step a: To a solution of 3,5-dimethyl-4- (3'-iso-propyl-4'-methoxymethoxybenzyl) phenol (example 38, step c, 1.11 g, 3.52 mmol) and DMAP (1.72 g, 14.1 mmol ) in CH2C12 (27 mL) at 0 ° C was slowly added trifluoromethanesulfonyl anhydride (0.89 mL, 5.27 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 4 / filtered and concentrated under reduced pressure to give 3,5,5-dimethyl-4- (3'-iso-propyl-4'-methoxymethoxybenzyl) -phenyl trifluoromethanesulfonate as an oil (1.39 g, 89% ): X H NMR (300 MHz, DMSO-d 5): d 7.14 - 7.28 (m, 7H), 6.94 (d, J = 8.4 Hz, HH), 6.85 (d, J = 2.4 Hz, HH), 6.70 (m , ÍH), 5.15 (s, 2H), 3.94 (s, 2H), 3.88 (s, 2H), 3.27 (s, 3H), 2.24 (s, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (15:85); Rf = 0.55.
Step b: To a solution of trifluoromethanesulfonate of 3,5-dimethyl-4- (3 '-iso-propyl-4' -methoxymethoxy-benzyl) phenyl (1.36) g, 3.05 mmol) in DMF (15.3 mL) in a pump apparatus was added MeOH (2.5 mL, 61.6 mmol), Pd (OAc) 2 (68 mg, 0.3 mmol), bis- (diphenphosphino) propane (138 mg, 0.3 mmol) and Et3N (0.85 mL, 6.1 mmol). 60 psi (4.218 kg / cm2) of CO was then emptied and the reaction mixture was stirred at 90 ° C for 16 h. The cold bomb was vented and the reaction mixture was emptied into cold IN HCl, extracted with EtOAc twice, the combined EtOAc was washed with brine, dried over Na 2 SO 4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1: 9) to provide 3,5-dimethyl-4- (3'-iso-propyl-4'-methoxymethoxybenzyl) benzoate. methyl as a yellow oil (1.00 g, 92.3%): XH NMR (300 MHz, DMSO-de): d 7.66 (s, 2H), 7.16 (m, 5H), 6.90 (m, 2H), 6.71 (m, ÍH), 5.15 (s, 2H), 3.98 (s, 2H), 3.87 (s, 2H), 3.85 (s, 3H), 3.26 (s, 3H), 2.25 (s, 6H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (15:85); Rf = 0.50.
Step c: To a mixture of methyl 3,5-dimethyl-4- (3'-iso-propyl-4'-methoxymethoxybenzyl) benzoate (1.00 g, 2.81 mmol) in THF (11.3 mL) at 0 ° C was added a solution of DIBAL-H (8.44 mL, 8.44 mmol, 1.0 M solution in hexanes). The reaction mixture was stirred at room temperature for 16 h, quench with cold IN HCl and dilute with ethyl acetate. The organic layer was washed with IN HCl and brine, dried over Na 2 SO 4, filtered and concentrated under reduced pressure to provide 3,5-dimethyl-4- (3'-iso-propyl-4'-methoxymethoxy-benzyl) benzyl alcohol. as an opaque white solid (0.75 g, 81.3%): X H NMR (300 MHz, DMSO-d 6): d 7.54 (s, 2 H), 6.81 (m, 2 H), 6.40 (m, H H), 5.51 (m, ÍH), 4.54 (d, J = 6.0 Hz, 2H), 3.75 (s, 3H), 3.21 (m, ÍH), 1.13 (d, J = 6.0 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (15:85); Rf = 0.27.
Step d: To a mixture of 3,5-dimethyl-4- (3'-iso-propyl-4'-methoxymethoxy-benzyl) benzyl alcohol (0.26 g, 0.79 mmol) in dichloromethane (1.5 mL) was added TEA (0.11). mL, 0.79 mmol) and a solution of methylphosphonic dichloride (0.11 g, 0.79 mmol) in dichloromethane (0.5 mL). The reaction mixture was stirred at room temperature for 2.75 h, filtered to remove the salts and the filtrate was then concentrated to remove the dichloromethane. The reaction mixture was taken up in ethyl acetate, and extracted into INN NaOH (2 x 10 mL). The basic layer was then acidified to pH = 2 with IN HCl and extracted into ethyl acetate (2 x 10 mL). The organic layer was dried over a2SO4, filtered and concentrated under reduced pressure.
The residue was then purified by 500 μm preparative CCD on a silica gel plate eluted with methanol / ethyl acetate [3: 7] to give mono- [3,5-dimethyl-4- (3'-isopropyl-4 'ester. -methoxymethoxy-benzyl) benzyl] of methylphosphonic acid (55 mg, 17.1%): XH NMR (300 MHz, CDC13): d 7.07 (s, 2H), 6.94 (s, ÍH), 6.88 (d, J = 8.4 Hz , HH), 6.62 (d, J = 6.0 Hz, HH), 5.14 (s, 2H), 5.00 (d, J = 7.5 Hz, 2H), 3.96 (s, 2H), 3.46 (s, 3H), 3.30 -3.26 (m, J = 13.8 Hz, ÍH), 2.24 (s, 6H), 1.56 (d, J = 18.3 Hz, 3H), 1.19 (d, J = 7.2 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate; Rf = 0.05.
Step e: To a mixture of mono- [3,5-dimethyl-4- (3'-isopropyl-4'-methoxymethoxy-benzyl) benzyl] methylphosphonic acid ester (40 mg, 0.10 mmol) in methanol (0.98 mL) ) IN HCl (0.49 mL, 0.49 mmol) was added. The reaction mixture was stirred at room temperature for 7 days and concentrated to remove the methanol. The reaction mixture was taken in ethyl acetate (5 mL) and IN HCl (5 mL). The organic layer was rinsed with H 2 O, brine, dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was then purified by preparative CCD 250 μm silica gel plate eluted with methanol-ethyl acetate [5: 95] to give the title compound (7.0 mg, 19.6%):? H NMR (200 MHz, DMSO- d6): d 9.02 (s, ÍH), 7.04 (s, 2H), 6.85 (s, ÍH), 6.63 (d, J = 8.2 Hz, ÍH), 6.46 (d, J = 7.0 Hz, ÍH), 4.85 (d, J = 7.8 Hz, 2H), 3.87 (s, 2H), 3.16 (m, J = 14.4 Hz, ÍH), 2.20 (s, 6H), 1.38 (d, J = 17.2 Hz, 3H), 1.11 (d, J = 7.0 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = methanol-ethyl acetate [3: 7]; Rf = 0.70.
Compound 94-1: methyl ester of [3,5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) benzyl] ester of phosphoric acid Step a: To a mixture of 3,5-dimethyl-4- (3'-iso-propyl-4'-methoxymethoxybenzyl) benzyl alcohol (0.10 g, 0.30 mmol) in methanol (1.5 mL) IN HCl (1.5 mL, 1.5 mmol) was added. The reaction mixture was stirred at 45 ° C for 16 h, then cooled to room temperature and concentrated to remove methanol. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The organic layer was dried over NaSO4, filtered and concentrated under reduced pressure. 3, 5-Dimethyl-4- (3'-iso-propyl-4'-hydroxybenzyl) benzyl alcohol (73 mg, 84.5%) was used without further purification: 1 H NMR (300 MHz, CDC13): d 7. 06 (s, 2H), 6.95 (s, ÍH), 6.57 (m, J = 5.1 Hz, 2H), 4.64 (s, 2H), 3.96 (s, 2H), 3.17 (m, J = 14.1 Hz, ÍH), 2.25 (s, 6H), 1.22 (d, J = 2.7 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes [1: 1]; Rf = 0.54.
Step b: To a mixture of 3,5-dimethyl-4- (3'-iso-propyl-4'-hydroxybenzyl) -benzyl alcohol (73 mg, 0.26 mmol) in tetrahydrofuran (2.0 mL) was added t-BuMgCl ( 0.26 mL, 1.0 M in THF, 0.26 mmol) and dimethyl chlorophosphate (0.03 mL, 0.26 mmol). The reaction mixture was stirred at 45 ° C for 16 h, then cooled to room temperature and concentrated to remove dichloromethane. The reaction mixture was taken up in ethyl acetate, and extracted into INN NaOH (2 x 10 mL). The basic layer was then acidified to pH = 2 with IN HCl and extracted into ethyl acetate (2 x 10 mL). The organic layer was dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was then purified by preparative CCD 500 μm silica gel plate eluted with ethyl acetate-hexanes [7: 3] to give dimethyl ester of the acid ester [3, 5-dimethyl-4- (3'-iso -propyl-4 '-hydroxybenzyl) benzyl] phosphoric acid (31 mg, 30.7%): XH NMR (300 MHz, CDC13): d 7.11 (d, J = 9.3 Hz, 2H), 7.05 (s, 2H), 7.00 ( s, ÍH), 6.67 (d, J = 10.5 Hz, ÍH), 4.62 (s, 2H), 3.98 (s, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.30 (m, J = 13.8 Hz, ÍH), 2.22 (s, 6H), 1.20 (d, J = 6.9 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes [1: 1]; Rf = 0.24. Step c: To a solution of dimethyl ester of the [3,5-dimethyl-4- (3'-iso-propyl-4'-hydroxybenzyl) benzyl] ester of phosphoric acid (31 mg, 0.08 mmol) in THF (0.4 mL) was added NaOH IN (0.4 mL, 0.40 mmol). The reaction mixture was stirred at 60 ° C for 16 h, then cooled to room temperature and concentrated to remove the solvent. The reaction mixture was taken in ethyl acetate and extracted into IN NaOH (2 x 10 mL). The basic layer was then acidified to pH = 2 with IN HCl and extracted into ethyl acetate (2 x 10 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (3.1 mg, 10.4%): X H NMR (300 MHz, CDC13): d 7.07 (m, 3H), 6.99 (s, ), 6.64 (d, J = 8.4 Hz, 2H), 4.63 (s, 2H), 3.99 (s, 2H), 3.79 (d, J = 11.4 Hz, 3H), 3.29 (m, ÍH), 2.22 (s) , 6H), 1.17 (d, J = 6.6 Hz, 6H); LC-MS m / z = 377.4 [C20H27O5P-H] "; CCD conditions: Silica gel uniplaca, 250 microns; Mobile phase = methanol-ethyl acetate [3: 7]; Rf = 0.45.
Example 95: Compound 95: [4- (4-Hydroxy-3-isopropyl-benzyl) -3,5-dimethyl-phenoxymethyl] -amino-phosphinic acid monobenzyl ester Step a: To a solution of [3,5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) -phenoxy] methylphosphonic acid (compound 7), 0.49 g, 1.36 mmol) in acetonitrile (13.6 mL), diisopropylethylamine (0.90 mL, 5.43 mmol) and benzyl bromide (0.65 mL, 5.43 mmol) were added. The reaction mixture was stirred at 80 ° C for 16 h, then cooled to room temperature and concentrated to remove dichloromethane. The reaction mixture was taken up in ethyl acetate, rinsed with water, a saturated solution of sodium bicarbonate, and brine. The organic layer was dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was then purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes [1: 9] to give [3,5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) phenoxymethylphosphonate dibenzyl (0.50 g, 0.92 mmol): * H NMR (200 MHz, DMSO-de): d 9.00 (s, ÍH), 7.37 (m, J = 6.6 Hz, 5H), 6.83 (s, ÍH), 6.70 (s) , 2H), 6.61 (d, J = 8.6 Hz, 2H), 6.44 (d, J = 8.2 Hz, ÍH), 5.14 (d, J = 8.2 Hz, 2H), 4.50 (d, J = 9.8 Hz, 2H ), 3.79 (s, 2H), 3.14 (m, J = 13.2 Hz, ÍH), 2.15 (s, 6H), 1.10 (d, J = 7.0 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes [1: 1]; Rf = 0.77.
Step b: To a solution of dibenzyl [3, 5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) phenoxymethylphosphonate (0.50 g, 0.92 mmol) in tetrahydrofuran (4.6 mL), IN NaOH (4.6 mL, 4.6 mmol). The reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was diluted in ethyl acetate and IN NaOH. The organic layer was extracted with water, and then the pH was adjusted to pH = 12 with INOH NaOH. The aqueous layer was then extracted with ethyl acetate. The organic layer was dried over Na 2 SO 4, filtered and concentrated under reduced pressure to give [3, 5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) phenoxy] methyl-phosphonic acid monobenzyl ester (0.45 g, 100%) as a yellow foam: XH NMR (200 MHz, DMSO-d6): d 9.12 (s, ÍH), 7.35 (m, J = 31.4 Hz, 5H), 6.84 (s, ÍH), 6.64 (d, J = 10.2 Hz, HH), 6.59 (s, 2H), 6.44 (d, J = 8.0 Hz, HH), 4.83 (d, J = 7.0 Hz, 2H), 3.77 (m, J = 9.2 Hz, 4H) , 3.15 (m, J = 14.0 Hz, ÍH), 2.13 (s, 6H), 1.11 (d, J = 7.0 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes [1: 1]; Rf = 0.04.
Step c: To a mixture of [3,5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) -phenoxylmethylphosphonic acid monobenzyl ester (108 mg, 0.238 mmol) and DMF (0.1 mL, 1. 29 mmol) in dichloromethane (1.0 mL) at 0 ° C, oxalyl chloride (0.04 mL, 0.476 mmol) was added. After 3 h, the reaction mixture was concentrated under reduced pressure, re-dissolved in dichloromethane (1.5 mL), and cooled to -78 ° C. To the reaction mixture triethylamine (0.07 mL, 0.476 mmol) was added, followed by liquid ammonia at -78 ° C (0.25 mL). The reaction mixture was stirred in a sealed vial heated at room temperature for 16 h. The vial was cooled to 0 ° C, vented and concentrated under reduced pressure. The reaction mixture was taken in ethyl acetate and IN NaOH. The organic layer was dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was then purified by preparative CCD 1000 μm silica gel pite eluting with ethyl acetate to give benzyl ester [3,5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) phenoxy] -methylphosphamic ester (18 mg, 16.7%): XH NMR (300 MHz, CDC13): d 7.40 (m, 5H), 6.93 (s, ÍH), 6.65 (d, J = 8.1 Hz, ÍH), 6.61 (s, 2H), 6.51 (d, J = 8.4 Hz, ÍH), 5.17 (d, J = 8.1 Hz, 2H), 4.28 (dd, J = 10.5, 5.4 Hz, 2H), 3.89 (s, 2H), 3.22 (, ÍH), 2.19 (s, 6H), 1.22 (d, J = 6.6 Hz, 6H); LC-MS m / z = 454.4 [C26H32N04P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate; Rf = 0.56.
Stage d: The title compound obtained from the benzyl ester [3,5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) phenoxymethylphosphamic according to the procedure described by Valentijn et al., SYNLETT, 9: 633 (1991).
Compound 95-2: benzyl ester N-methyl- [3,5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) phenoxy] methylphosphamic ester To a mixture of [3,5-dimethyl] monobenzyl ester -4- (4'-Hydroxy-3'-isopropylbenzyl) -phenoxy] methylphosphonic acid (108 mg, 0.238 mmol) and DMF (0.1 mL, 1.29 mmol) in dichloromethane (1.0 mL) at 0 ° C, oxalyl chloride was added (0.04 mL, 0.476 mmol). After 3 h, the reaction mixture was concentrated under reduced pressure, redissolved in dichloromethane (1.5 mL), and cooled to -78 ° C. To the reaction mixture triethylamine (0.07 mL, 0.476 mmol) was added, followed by methylamine (0.24 mL, 2.0 M solution in THF, 0.476 mmol) at -78 ° C (0.25 mL). The reaction mixture was stirred, heated to room temperature for 16 h, then concentrated under reduced pressure. The reaction mixture was taken in ethyl acetate and IN NaOH. The organic layer was dried over Na 2 SO, filtered and concentrated under reduced pressure. The residue was then purified by preparative CCD 1000 μm silica gel plate eluted with ethyl acetate to give benzyl ester N-methyl- [3,5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) phenoxy) ] methylphosphamic (23 mg, 20.7%): 1 H NMR (300 MHz, CDC13): d 7.39 (m, 5H), 6.92 (s, ÍH), 6.63 (s, 2H), 6. 62 (d, J = 8.1 Hz, ÍH), 6.51 (d, J = 2.1 Hz, ÍH), 5.14 (m, 2H), 5.05 (s, ÍH), 4.30 (dd, J = 10.2, 3.6 Hz, 2H), 3.89 (s, 3H), 3.19 (m, ÍH), 2.71 (d, J = 10.8 Hz, 3H), 2.19 (s, 6H), 1.22 (d, J = 6.9 Hz, 6H); LC-MS m / z = 468.4 [C27H34N04P + H] +; CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate; Rf = 0.44.
Step b: The title compound is obtained from the benzyl ester N-methyl [3, 5-dimethyl-4- (4 '-hydroxy-3'-isopropylbenzyl) phenoxy] methylphosphamic according to the procedure described by Valentijn et al., SYNLETT, 9: 663 (1991).
Example 96 Compound 96: [(3,5-Dimethyl-4- (3'-Isopropyl-1'H-indol-5'-methylmethyl) -phenoxy) methyl] methylphosphinic acid Step a: To the solution of 3,5-dimethyl-4- (3-isopropyl-lH-indol-5-ylmethyl) phenol (compound 93, step f, 200 mg, 0.683 mmol) in acetonitrile (10 ml) was added Cs2CO3 (450 mg, 1.365 mmol), followed by ethyl [(4-methylphenyl) sulfonyloxymethyl] methylphosphinate (compound 74, 200 mg, 0.683 mmol) at rt, the reaction mixture was then heated to reflux during the night. On the second day, it was concentrated, the residue was partitioned between EtOAc and water, the organic layer was collected, the water layer was further extracted with EtOAc once, the combined organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with ethyl MeOH-EtOAc (1:49) to provide [(3,5-dimethyl-4- (3'-Isopropy1-1 'H-indole-5' ethyl-methylmethyl) phenoxy) methyl] -methylphosphinate (131 mg, 46.4%): TH NMR (300 MHz, CDC13): d 7.85 (s, ÍH), 7.26 (s, ÍH), 7.24 (d, J = 8.4 Hz, ÍH), 6.95 (s, ÍH), 6.84 (d, J = 8.4 Hz, ÍH), 6.72 (s, 2H), 4.20 (m, 4H), 4.14 (s, 2H), 3.15 (m, ÍH) ), 2.30 (s, ÍH), 1.67 (d, J = 14.7 Hz, 3H), 1.40 (m, 3H), 1.34 (d, J = 6.6 Hz, 6H). CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate; Rf = 0.33.
Step b: The title compound was prepared from ethyl [(3,5-dimethyl-4- (3'-Isopropyl-1'H-indol-5'-ylmethyl) phenoxy) methyl] methylphosphinate in accordance with procedure described by the synthesis of compound 93, step h; (100 mg, 81.3%): X H NMR (300 MHz, DMSO-d 6): d 10. 58 (s, ÍH), 7.17 (d, J = 8.4 Hz, ÍH), 7.13 (s, ÍH), 6.98 (d, J = 1.8 Hz, ÍH), 6.72 (s, 2H), 6.67 (dd, J = 8.4, 1.8 Hz, ÍH), 4.08 (d, J = 8.4 Hz, 2H), 3.99 (s, 2H), 2.98 (m, ÍH), 2.19 (s, 6H), 1.40 (d, J = 14.4 Hz , 3H), 1.22 (d, J = 6.9 Hz, 6H). LC-MS m / z = 386 [C 22 H 28 N 0 3 P + H] +; Analysis Calculated for (C21H26N04P + 0.2 HBr): C, 65.79; H, 7.08; N, 3.49. Found: C, 65.97; H, 7.28; N, 3.30.
EXAMPLE 105 Compound 105-1: 3, 5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) benzyl ester of Methylfosfonic acid Step a: A mixture of methyl-3,5-dimethyl-4- (3'-isopropyl-4'-methoxymethoxybenzyl) benzoate (Example 24-1, 1.52 g, 4.26 mmol) in methanol (8.0 mL) and 4 N HCl- dioxane (3.2 mL, 12.8 mmol) was heated at 100 ° C for 5 min in a microwave oven. The solvent was removed under reduced pressure and the residue was dissolved in THF (25.0 mL). The solution was cooled to 0 ° C and DIBAL (14.7 mL, 14.7 mmol) was slowly added thereto. The reaction mixture was stirred at 0 ° C for 2 h, quenched with saturated sodium potassium tartrate and diluted with hexanes (20 mL). The reaction mixture was stirred at room temperature for 2 h and the organic layer was separated. The organic solution was dried over MgSO4, filtered and concentrated under reduced pressure to give 3,5-dimethyl-4- (4'-hydroxy-3'-isopropyl-benzyl) benzyl alcohol (1.01 g, 83%) as a white solid: X H NMR (300 MHz, CD 3 OD): d 7.05 (s, 2 H), 6.84 (d, J = 2.1 Hz, H H), 6.58 (m, 2 H), 4.55 (s, 2 H), 3.96 (s, 2 H), 3.22 (m, ÍH), 2.25 (s, 6H), 1.14 (d, J = 7.0 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (1: 3); Rf = 0.4.
Step b To a solution of 3,5-dimethyl-4- (4'-hydroxy-3'-isopropyl-benzyl) benzyl alcohol (0.13 g, 0.46 mmol), methylphosphonic acid (0.04 g, 0.38 mmol) and pyridine (0.11) mL) in DMF (3.5 mL) at room temperature was slowly added EDC (0.18 g, 0.91 mmol). The reaction mixture was stirred at 70 ° C for 24 h and allowed to cool to room temperature. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluted with 20% methanol in dichloromethane to give the title compound (0.04 g, 24%) as a white solid: PF: 125- 127 ° C; X H NMR (300 MHz, CD 3 OD): d 7.09 (s, 2 H), 6.83 (d, J = 2.1 Hz, H H), 6.56 (m, 2 H), 4.87 (d, J = 6.9 Hz, H H), 3.96 (s, 2H), 3.21 (m, ÍH), 2.24 (s, 6H), 1.30 (d, J = 17.7 Hz, 3H), 1.15 (d, J = 7.0 Hz, 6H); LC-MS m / z = 361 [C20H27O4P-H] A Compound 105-2: 3,5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) phenyl ester of methyl phosphonic acid Step a To a solution of 3,5-dimethyl-4- (3-isopropyl-4-methoxymethoxybenzyl) phenol (Chiellini et al., Bioorg. Med.
Chem. Let t. 10: 2601 (2000), 0.30 g, 0.95 mmol) in methanol (6.0 mL) was added 2 N HCl (1.4 mL, 2.8 mmol). The reaction mixture was stirred at room temperature for 72 h, diluted with water (15 mL) and extracted with ethyl acetate (10 mL). The organic solution was dried over MgSO4, filtered and concentrated under reduced pressure to provide 3,5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) phenol (0.23 g, 89%) as a colorless oil: XH NMR ( 300 MHz, CD3OD): d 6.84 (d, J = 2.1 Hz, ÍH), 6.58 (m, 2H), 6.53 (s, 2H), 3.87 (s, 2H), 3.23 (m, ÍH), 2.17 (s) , 6H), 1.15 (d, J = 7.0 Hz, 6H); CCD conditions: Uniplaca of silica gel, 250 microns; Mobile phase = acetone-hexanes (1: 3); Rf = 0.5 Step b The title compound was prepared from 3,5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) phenol according to the procedure described by the synthesis of compound 105-1. PF: 53-56 ° C; X H NMR (300 MHz, CD 3 OD): d 6.91 (s, 2 H), 6.84 (d, J = 2.1 Hz, H H), 6.54 (m, 2 H), 3.96 (s, 2 H), 3.21 (m, H H), 2.24 (s, 6H), 1.59 (d, J = 17.7 Hz, 3H), 1.14 (d, J = 7.0 Hz, 6H); LC-MS m / z = 349 [Ci9H2504P + H] +; Analysis Calculated for (C? 9H25? 4P): C, 65.51; H, 7.23. Found: C, 65.23; H, 7.47.
Example 113 Compound 113: monomethyl ester of 3,5-dichloro-4- (4'-hydroxynaphthyloxy) phenylaminomethyl-phosphonic acid To a stirred solution of dimethyl-N- t -butoxycarbonyl- [3,5-dichloro-4- (4'-O-methoxynaphthyloxy) phenylamino] methylphosphonate prepared in accordance with the procedure described by the synthesis of compound 90, step d , (220 mg, 0.48 mmol) in CH2C12 (10 mL) at -78 ° C was added BBr3 (0.3 g, 1.4 mmol). The reaction mixture was allowed to warm to t.a. and stirred for 14 h and emptied on ice water (100 mL) and stirred for 1 h. The reaction mixture was extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude dimethyl 3,5-dichloro-4- (4 '-hydroxynaphthyloxy) phenylaminomethyl phosphonate (140 mg, 0.3 mmol) was dissolved in tert-butylamine (11. 4 mL, 11.4 mmol) and the reaction mixture was heated to pH. 70 ° C for 12 h. The solvent was removed under reduced pressure and the crude residue was purified by preparative HPLC to provide the title compound (20 mg, 34%, PF: 85-87 ° C). X H NMR (300 MHz, CD3OD): d 8.33 (dd, J = 0.9, 7.5 Hz, HH), 8.22 (dd, J = 0.9, 7.5 Hz, HH), 7.56-7.51 (m, 2H), 6.86 (s) , 2H), 6.59 (d, J = 7.8 Hz, ÍH), 6.21 (d, J = 8.1 Hz, ÍH), 3.72 (d, J = 10.5 Hz, 3H), 3.44 (d, J = 12.3 Hz, 2H ); LC-MS m / z = 428 [C18H? 6Cl2N05P + H] +; CLAR conditions: Aglient Zorbax SB-Aq-3.0 xl50 mm column; mobile phase = 'CH3OH: TFA (7: 3) flow ratio = 1.0 mL / min; detection = UV 220, 254, 280 nm retention time in min: 9.01; Calculated analysis: (MF: C? 8H? 6Cl2N05P +0.35 t-BuNH2 + 0.64 TFA) Calculated: C: 47.15, H: 3.92, N: 3.59 Found: C: 46.86, H: 4.23, N: 4.04. For all the chemical structures illustrated herein, when an oxygen is described with only a single bond to another atom, the presence of a hydrogen bonded to oxygen can be assumed. When a nitrogen is described only with two bonds to one or more other atoms, the presence of a hydrogen bound to nitrogen can be assumed. CH2C12: dichloromethane DMF: dimethylformamide TEA: triethylamine THF: tetrahydrofuran TFA: trichloroacetic acid MgSO4; magnesium sulfate TBSC1: t-butyldimethylsilyl chloride H2O: water DMSO: dimethyl sulfoxide CH3CN: acetonitrile 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 solely to these examples. For purposes of clarity and brevity, chemical compounds are referred to by their synthetic example numbers in the biological examples below.
Example A: Receptor Link The purpose of these studies was to determine the affinity of T3 and several thyromimetics for 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 are first grown to a density of l-5xl05 cells / mL. TRal or TRßl and RXRa baculovirus stock solutions 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 assay buffer (50 mM NaCl, 10% Glycerol, 20 mM tris, pH 7.6 2 mM EDTA, 5 mM β-mercaptoethanol and 1.25% CHAPS) and the lysates were evaluated for T3 binding as follows: 125 I -T3 was incubated with the lysates of and co-infected cells of TR baculovirus and recombinant RXR (50 μl) in assay buffer for one hour and then the 125I-T3-TR / RXR complex was separated from free 125I-T3 by a column of filtration in minigel (Sephadex G50). The 125I-T3 linkage was counted with a scintillation counter. The binding of the compounds to either the TRal or TRßl was also performed by means of scintillation proximity assays (SPA). The SPA assay, a common method used for the quantification of receptor-ligand balance, makes use of special beads coated with a scintillant and a capture molecule, copper, which binds to the α or β receptor labeled with histidine. When the labeled T3 is mixed with the SPA receptor and beads, radioactive beads are observed only when the protein and radiolabeled ligand complex is captured on the surface of the bead. Displacement curves were also generated with labeled T3 and increased unlabeled thyromimetic 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 l (c). Table 3 below shows the SPA data generated with several thyromimetics of interest. The binding results for T3 demonstrate a Kd = 0.29nM for TRa and a Kd = 0.67nM for TRβ. ? 3 Compound Ki TRa (nM) Ki TRfS (nM) 17 1.21 0.29 I 285 36.1 12-1 1666 662 3 46 5.42 6 16 26 9 350 204 II 121 30.3 13-1-cis 2583 1979 13-1-trans 1744 1322 Compound Ki TRa (nM) Ki Iß (nM) 13-6 - cis 4710 3589 13-2 - cis 488 419 13-2 - trans 1354 469 13-3 - cis 2837 3431 13-3 - trans 2006 2456 13-6 - trans 1526 1574 13- 5 - trans 354 281 13-5 - cis 4432 1008 1 133--77 --- ttrraannss 1 1555544 3798 13-4 - trans 2129 1815 13-4 - cis 5531 1521 13-7 - cis 49632 45135 7 58 3.3 2 1 1441166 271 4 14.1 0.99 5 1.84 0.84 8 3.74 0.97 10 > 2000 > 2000 8 8--11 18.6 2.51 15-3 > 2000 > 2000 19 304 52 8-2 114 20 24-1 378 31 7 7--55 6 677 9.5 Compound Ki TRa (nM) Ki Rß (nM) 25 > 2000 363 22 186 31 21 > 1400 > 180 7-6 98 7.6 24-2 > 2000 24 26 594 87 19-2 343 20 7-4 > 2000 > 2000 30 > 2000 > 2000 23 > 2000 > 2000 19-3 1760 128 28 375 14.0 20 > 2000 > 2000 7-3 31 6.6 7-2 > 2000 146 29 661 47 7-1 1166 106 32 284 96 24 > 2000 > 2000 27 > 2000 > 2000 31 540 73 24-3 113 2.87 33 267 16.7 34 118 6.5 Compound Ki TRa (nM) Ki TRß (nM) 41-2 > 2000 > 2000 38 254 5.4 42-2 > 2000 > 2000 39 > 2000 58 7-7 898 90 41-3 > 2000 280 24-4 > 2000 92 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 > 2000 181 7-10 112 48 47 24.3 2.5 48 128.6 9 45 216 14 46 20 2 52 > 2000 48 Compue st o Ki TRa (nM) Ki TRß (nM) 44 832 44 54 143 42 43 363 108 7 1 4 0.4 69- -2 2.8 0.8 61 42.7 1.4 69 13.5 3 22 - • 1 10.3 1.5 7700 183 5.4 67 37 1.8 66 863.2 121 Conclusion: The proven thyminimetic precursors have a good to excellent affinity for the TRal and / or TRßl receptors. The prodrugs have a poor affinity for the receptors and therefore it is impossible for them to exert a thyromimetic effect until they are activated in the liver. Example B: Subacute Studies in Mice / Normal Rats Demonstrating Liver Selectivity Against Phosphonic Acid Heart and Carboxylic Acid T3 Mimetics The purpose of these studies was to compare the difference in efficacy, cardiac effects and endocrine effects between T3 and T3 mimetics that are T3 carboxylic acids and mimetics that are phosphonic acids. In a 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, were compared. Efficacy endpoints include serum cholesterol, mitochondrial glycerol phosphate dehydrogenase activity of the liver (mGPDH) and the expression of relevant liver genes (eg, LDL receptor, apoB, cpt-1, spotl4 and apoAI). Safety parameters include heart weight, heart rate, mGPDH activity of the heart, expression and key genes involved in cardiac structure and function (eg, Serca2, HCN2, Kvl.5, MHCa, MHCß, Alphalc), and analysis of standard plasma chemistry (liver enzymes, electrolytes, creatinine). The endocrine effects are monitored by serum thyroid stimulating hormone (TSH) analysis. [Taylor et al, Mol Pharmacol 52 (3): 542-7 (1997); Weitzel et al, Eur J Biochem 268 (14): 4095-4103 (2001)]. Methods: mGPDH activity was analyzed in isolated mitochondria using 2- (4-iodophenyl) -3- (4-nitrophenyl) -5-phenyl tetrazolium chloride as the electron terminal acceptor (Gardner RS, Analytical Biochemistry 59: 272 (1974 )). The commercially available GPDH was used in each assay as a standard (Sigma, St. Louis, MO). Changes in mRNA levels for liver and heart genes were analyzed using reverse transcriptase followed by time PCR analysis real. The analysis was performed using an iCycler instrument (Biorad) and appropriate primers by means of standard methodology [for example, Schwab DA et al. (2000) Life Sciences 66: 1683-94]. The amounts of mRNA are normalized to an internal control, typically cyclophilin. Serum TSH is measured using an immunoassay kit (EIA) designed for rat TSH (Amersham Pharmacia Biotech, Arlington Heights, IL). The cholesterol in the serum is analyzed using a commercially available enzyme kit (Sigma Diagnostics, St. Louis, MO). Normal rats (Sprague-Dawley) are 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 0. NaOH solution and the pH is adjusted to 7.4-8.0. The compounds were brought to an appropriate 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, T3 mimic of phosphonic acid, produces a significant thyromimetic effect in the liver equivalent to that of T3 or Compound 17, a T3 mimetic of carboxylic acid, without producing any significant effect on the heart. Compound 17 produces 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 GPDH of liver GPDH of heart Weight of the heart control 100 100 100 T3 406 284 146 Compound 17 426 277 134 Compound 7 399 112 108 Conclusion: Based on the activity of the mGPDH enzyme, Compound 7 has significant thyromimetic activity in the liver and not in the heart. In addition, Compound 7 does not cause cardiac hypertrophy. T3 and Compound 17, in contrast, do not show selective thyromimetic effects of the liver. In this way, the results demonstrate that T3 mimetics have a higher selectivity for the heart in terms of drug activity and distribution than the T3 carboxylic acid mimetics.
Example C: Subacute Studies in ZDF Rats Show an Improved Therapeutic Index for T3 Mimetics Containing Phosphoric Acid ZDF rats were treated with either Compound 18 (a T3 carboxylic acid mimetic) or Compound cis-13-1 (a HepDirect prodrug) of a T3 mimic of phosphonic acid) for 28 days dosed orally once a day. Compound 18 was administered at doses of up to 5mg / kg / d. He cis-13-1 compound was administered at doses up to 50 mg / kg / d. It has been argued that the ZDF rat, as a metabolically induced animal model, should be more sensitive to the potential adverse cardiac effects of thyromimetics than a normal, cholesterol-fed rat. At sacrifice, the heart rate, 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 the increased heart rate (Grover et al., PNAS 2003). The TI measurement was such a dose as ED15 for the heart rate, that is, a dose such that it increases the heart rate greater than or equal to 15% compared to ED50 to reduce cholesterol. The therapeutic index for Compound 18 in ZDF rats with respect to heart rate was 0.4, indicating that the model is much more sensitive to cardiac effects than an animal not metabolically triggered. Additionally, the TI for LV dP / dt was 0.15. An increase in LV dP / dt of 25% was the value used in the TI calculation. The most sensitive measurement of cardiac effects in this animal was LV dP / dt. The ZDF rats treated with Compound cis-13-1 show no changes in any of the measured parameters. Since only 50 mg / kg / day was digested, the exact therapeutic index for some of these parameters is not known. However the improvement of IT over Compound 18 is listed in the table below: Parametero IT Enhancement ED15 HR > 39 ED25 LV dP / dt > 102 The reason TI is listed as greater than, that is, ">" is because the doses of Compound cis-13-1 were not high enough to reach the threshold of 15% or 25% even at 50 mg / kg / d. By extrapolation with the cholesterol-fed rat for the data of Compound 18, the rats were 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 has been calculated that the IT in a metabolically induced animal will be > 3900 with respect to heart rate and > 10,000 with respect to LV dP / dt. It has not been chosen to dose at such high levels at this time since the results of the ZDF animals demonstrate a significantly improved safety window. In this way 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: Subacute Studies in Rats Fed with Cholesterol The rat fed with cholesterol is an animal model of hypercholesterolemia generated by feeding the animals a diet high in cholesterol. The purpose of these studies was to evaluate the effects of Compounds 7 and 17 on serum cholesterol (an efficacy parameter) and on cardiac weight and cardiac mGPDH activity (parameters of potential toxicity). Methods: Rats were maintained on a diet containing 1.5% cholesterol and 0.5% colic acid for 2 weeks before the start of treatment. Serum cholesterol values were evaluated and animals were raffled in groups for treatment. The cholesterol in the serum was analyzed using a commercially available enzyme kit (Sigma Diagnostics, St. Louis, MO). Compound 17 and Compound 7 at various concentrations were administered IP once a day for seven days. RESULTS: The dose of 0.1-1 mg / kg / day of Compound 17 significantly reduces serum cholesterol. The dose of Compound 7 from 1-100 mg / kg / day significantly reduces serum cholesterol. Cholesterol reductions in serum at 1 mg / kg / day were identical for Compound 17 and Compound 7 (see Figures 2a and 2b). Undesirable cardiac hypertrophy was observed with the Compound 17 at all doses that significantly reduce serum cholesterol, 0.1-1 mg / kg / day. Cardiac hypertrophy was not observed with Compound 7 (see Figs 3a and 3b). Cardiac GPDH activity was also increased by Compound 17 at 1 mg / kg / day while a trend towards increased cardiac GPDH activity was observed with Compound 7 only at 100 mg / kg (see Fig. 4a). No effects were observed cardiac adverse events with Compound 7 at any dose. These studies also indicate that cardiac weight is more sensitive to thyromimetic effects than GPDH activity. CONCLUSION: There is no separation between efficacy (cholesterol reduction) and toxicity (cardiac hypertrophy, induction of cardiac GPDH) for compound 17. Compound 7, in contrast, shows a therapeutic window of 10 to 100 times. In this way, the results show that the T3 mimetics of phosphonic acid have a greater therapeutic window than the T3 mimetics of carboxylic acid.
Example E: Microsorne Hepatocyte Stability Studies / Primary i. Activation of prodrug in rat liver microsomes The purpose of these studies was to determine the kinetics of activation of thyromimetic prodrugs in microsomal preparations. Microsomes contain the P450 enzyme that is required for the activation of many of the prepared prodrugs. The determined Km, Vmax, and intrinsic release values are measured from the affinity of the prodrugs for the microsomal enzymes, the ratio 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. The microsomes were isolated by standard differential centrifugation methods of rats treated with dexamethasone. The treatment is to increase the activity P450-3A (CYP3A4) cytochrome. The induction of CYP3A4 was confirmed by an increase in the hydroxylation of testosterone. Several concentrations of Compound 7 HepDirect ™ were incubated with microsomes of rat hepatocytes. The formation of Compound 7 was analyzed by CLAR using UV-Vis detection. The kinetic parameters (Vmax and Km) were calculated from the transformed data and the intrinsic release is 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 good affinity for the microsomal enzymes that catalyze their activation: TABIA 5 Vmax Km CLint Compound (pmol / min / mg) (μM) (μL /? Min / mg) 13-1-cis 1746 31 56 13-6-cis 598 10 62 13-2-cis 694 8 86 13- 3-cis 2118 46 46 13-5-cis 3266 113 29 Compound 12-3 775 14 54 13-4-cis 2983 100 30 ii. Activation of Pro-drug by S9 of Human Liver The prodrugs were tested for conversion to their respective precursor compounds by S9 of human liver. Fraction S9 is a fraction that contains both cytosolic and microsomal proteins. Method: Reaction mixtures (0.5 mL at 37 ° C) consisting of 0.2 M potassium phosphate pH 7.14, 13 mM glucose-6-phosphate, 2.2 mM NADP +, 1 glucose-6-phosphate dehydrogenase unit, 0-2.5 mg / mL of human liver S9 fraction (In Vitro Technologies, Inc.), and up to 250 μM of drug. The activation of the prodrugs to the respective precursor compounds is monitored by reverse phase HPLC or LC-MS / MS (Example F). Results: The compound formation ratio precursor is measured. The enzyme kinetics parameters of Vmax, Km, and CLint of intrinsic release are calculated. Conclusion: The prodrugs of T3 mimetics are easily activated in their respective precursor compounds by S9 of human liver. iii. Activation of Prodrug in Rat Hepatocytes Isolated The purpose of these studies was to monitor the uptake and activation of the T3 mimetic prodrugs to their respective species in fresh, isolated rat hepatocytes. Methods: The hepatocytes are prepared from fed Sprague-Dawley rats (250-300 g) in accordance with the Berry and Friend procedure (Berry, M. N., Friend, D.S. J. Cell Biol. 43, 506-520 (1969)) as modified by Groen (Groen, A. K. et al, Eur J. Biochem 122, 87-93 (1982)). The hepatocytes (60 mg wet weight / mL) are incubated in 1 mL Krebs bicarbonate buffer solution containing 10 mM glucose, and 1 mg / mL BSA. The incubations are carried out in an atmosphere of 95% oxygen, 5% carbon dioxide in 50 mL Falcon tubes, closed, immersed in a rapidly agitated water bath (37 ° C). The prodrugs are dissolved in DMSO to provide 10 mM stock solutions, and then diluted in the cell suspension to provide a final concentration of 100 μM. At appropriate time points during the course of 1 h, aliquots of cell suspension are removed and rotated through a silicon / mineral oil layer 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-time profile of the precursor compound. Results: The results are shown in Table 6 below: TABLE 6 AUC (0-2h) Compound (nmol * h / g) Compound 13-1-cis 967 Compound 13-6-cis 433 Compound 13-2-cis 533 Compound 3-3-cis 459 Compound 13-5-cis 1988 Compound-13-7-cis 806 Compound 13-4-cis 784 Conclusion: The prodrugs of T3 mimetics are readily taken and activated for their active species in fresh rat hepatocytes.
Example F: Studies of Oral Bioavailability / Efficacy in Normal Rats i. Oral Bioavailability The oral bioavailability (OBAV) of Compound 12-1, a bisPOM prodrug of Compound 7, was estimated in comparison to the normalized area per dose under the curve (AUC) of the plasma concentration-time profile of Compound 7 after IV and PO administration of Compound 7 and Compound 12-1, respectively, to normal rats. Methods: Groups of male SD rats without fasting were administered either 5 mg / kg of Compound 7 per IV bolus or 20 mg / kg of Compound 12-1 by oral feeding. Before administration of the drug, the rats are catheterized in the tail artery to facilitate blood collection. Plasma samples are obtained at previously specified time points, and then evaluated by a CL-UV method using a Cld column eluting with a gradient of 20% to 45% v / v of acetonitrile in a potassium phosphate buffer. pH 6.2 for 15 minutes with UV absorbance monitored at 280 nm. The AUC values were determined not in compartment of the plasma concentration-time diagrams by trapezoidal sum to the less measurable time point. In another experiment, the OBAV of Compound 19-2, a T3 mimetic of phosphonic acid, was evaluated using catered rats. The plasma levels of the compound are analyzed by CLAR and the AUC for the i.v. of 5 mg / kg and the p.o. of 20 mg / kg were compared. The maximum OBAV for Compound 19-2 was 0.003%. Typically, compounds that are taken 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 homogenous model system ensures that exposure can be monitored exactly when humans are treated with the compound. Additionally, in a genetically variable backup such as humans, the variable capacity for the compound with lower OBAV in genetically homogeneous model systems can be widely variable, leading to some subjects having much greater than the anticipated exposure, while other subjects They do not have exposure. The OBAV of Compound cis-13-1 is calculated to be 25% when the AUC of Compound cis-13-1 is used and to be 40-50% when comparing the AUC of Compound 7 using plasma samples in series of a compound administered iv against a compound administered p.o. Liver levels at 1.5 h after the dose of Compound 7 and prodrugs thereof are listed in Table 7, example F (ii). Resulted: Compound 12-1 is suitably adsorbed in the rat with an estimated OBAV of 25%. After oral administration of the prodrug, the concentrations of Plasma of Compound 7 generated (Cmax = 1.2 ± 0.2 μg / mL at a Tmax = 3 ± 1 hr) was sustained for a period of 8 hours (t / 2 6 ± 6 hr). Compound 19-2 was not absorbed properly. CONCLUSION: The adequate systemic exposure of Compound 7 was maintained for 8 hours after oral administration of Compound 12-1 to rats. ii. Hepatic Distribution After Oral Administration The hepatic levels of Compound 7 were evaluated in normal rats after oral administration of HepDirect ™ or other prodrugs. The levels were used to estimate the potential efficacy. The hepatic levels were evaluated by LC-MS using a peak area 363.3 / 63.0 to estimate the levels of Compound 7 generated by prodrugs administered orally. RESULTS: The results are shown in Table 7.
TABLE 7 Hepatic Levels (ug / g) Compound (10 mg / kg @ l .5h) Compound 7 Not Detected Compound 12-1 1.39 Compound 13-1-cis 0.98 Compound 13-6-cis 0.39 Compound 13-2-cis 0.25 Compound 13-3-cis 0.77 Compound 12-2 0.67 Compound 13-5-cis 0.56 Compound 13-1-cis 0.23 Compound 13-4-cis 0.32 Conclusion: All tested compounds produce adequate liver levels of compound 7. All are predicted to induce thyromimetic effects 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 heat expenditure and therefore cause loss of body weight and its benefits associated with metabolic status (eg, insulin sensitivity). Thermogenesis was evaluated in subcellular fractions of various tissues, or in whole animals using changes in oxygen consumption as the end point. Oxygen was used when caes were burned by various metabolic processes. Methods: The animals were dosed once or several times a day by means of a parenteral or oral route by a treatment period in the range from 1 day to several weeks. Oxygen consumption is measured following a single or multiple day of treatment. Mitochondrial thermogenesis is measured polaographically with a Clark-type oxygen electrode using mitochondria isolated from various tissues, including liver. The mitochondria were isolated by differential centrifugation. As those skilled in the art are familiar, state 3 respiration or cytochrome c oxidase activity is measured in isolated mitochondria. The mitochondria were incubated at 30 ° C in a buffer medium containing 80 mM KCl, 50 mM HEPES, 5 M KH2P04, 1 mm EGTA, 0.1% (w / w) fatty acid free bovine serum albumin (BSA), pH 7.0 in the presence of 10 mM succinate, 3/75 μM rotenone and 0.3 mM ADP (Tossa, S, FEBS Letters, 544: 133-7 (2003)). Oxygen consumption ratios were measured in isolated hepatocytes using portable Clark-type oxygen electrodes placed in the hepatocyte medium. Hepatocytes were isolated from the liver using a two-step collagenase perfusion (Berry, MN, Friend, DSJ Cell Biol. 43: 506-520 (1969)) as modified by Groen (Groen, AK et al, Eur J. Biochem 122: 87-93 (1982)). The non-parenchymal cells were removed using a Percoll gradient and the cells resuspended in tissue culture medium in a rotating flask. The oxygen consumption of the cells it was measured for a time once the system was sealed. Oxygen consumption was measured in isolated perfused liver (Fernandez, V., Toxicol Lett, 69: 205-10 (1993)). The liver was 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, the consumption of complete animal oxygen is measured using indirect cametry (Oxymax, Columbus Instruments, Columbus, OH). The animals were removed from their cages and placed in the chambers. The remaining oxygen consumption is measured in animals during periods of inactivity as measured by activity on the monitors. Oxygen consumption is calculated based on the flow through the chamber and the difference in partial oxygen pressures 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 Compound cis-13-1 orally for 14 days. The rats were placed in the FoxBox apparatus (Sable Systems, Las Vegas, NV), allowing to acclimate and the remaining oxygen consumption was measured. Oxygen consumption ratios were compared to measurements prior to the doses taken in each individual animal. Oxygen consumption after treatment was 116, 125, 132% of the ratio prior to doses, for 3, 10, and 30, respectively. In this manner, the compounds of the present invention are useful for increasing oxygen consumption.
Example H: Tissue Distribution Studies The tissue distribution and the pharmacokinetics of Compound 7 and Compound 17 were evaluated after IP administration to normal rats. Method: In separate studies, Compound 7 of T3 phosphonate mimetic and its carboxylate analogue Compound 17 were administered at 10 mg / kg to groups of male SD rats by means of the peritoneal cavity. At pre-selected time points after the dose, the rats were anesthetized using iso-fluoran and the peritoneal cavity was then opened and a blood sample was obtained from the abdominal vena cava. 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 volumes of methanol, processed, and analyzed by CL-UV as described in Example G. Frozen liver, kidney, and heart tissues are homogenized in 60% v / v acetonitrile, they are centrifuged, and then analyzed by LC-UV. The pharmacokinetic parameters and AUC of the plasma and tissue concentration-time profiles were determined without compartment by inNonLin. RESULTS: The following plasma pharmacokinetics were calculated for Compound 17 and Compound 7 as shown in Table 8.
TABLE 8 The AUC values of the plasma-tissue concentration-time profiles were calculated for Compound 17 and Compound 7 and are shown in Table 9.
TABLE 9 Concluding: In comparison to the T3 mimetic of phosphonic acid (Compound 7), the T3 mimic of carboxylic acid (Compound 17) has significantly higher plasma release and volume of distribution in the rat. The substantially higher levels of Compound 7 measured in the liver indicate a good penetration of the T3 mimetic phosphonate into the target organ. Compound 7 shows greater liver exposure relative to Compound 17. Thus, the T3 mimetics of phosphonic acid have a greater liver specificity, as compared to cardiac tissue, than the T3 carboxylic acid mimetics.
Example I: Subacute Studies in Cholesterol Reduction in Rats Fed with Cholesterol The purpose of these studies was to evaluate the effects of a carboxylic acid mimetic (Compound 18) a phosphonic acid T3 mimetic prodrug (Compound 13-1- cis) in serum TSH and cholesterol levels, hepatic and cardiac gene expression and enzyme activities, cardiac weight, and clinical chemical parameters. Methods: Rats are maintained on a diet containing 1.5% cholesterol and 0.5% cholic acid for 2 weeks before the start of treatment. The cholesterol values in the serum were evaluated and the animals are drawn in groups for treatment. Cholesterol in the serum was analyzed using a commercially available enzyme kit (Sigma Diagnostics, St. Louis, MO). Compound 13-1-cis and Compound 18 were administered PO once a day for seven days. TSH in the serum was measured using an enzyme immunoassay kit (EIA) designed for rat TSH (Amersham Pharmacia Biotech, Arlington Heights, IL). The expression levels of liver genes (e.g., LDL receptor, apoB, cpt-1, spotl4 and apoAI) and heart genes (e.g., Serca2, HCN2, Kvl.5, MHCa, MHCβ, Alphalc) were quantified by Northern blot analysis or by RT-PCR. For Northern analysis, RNA is isolated from liver tissue by a guanidinium thiocyanate method, and total RNA is obtained using an RNeasy column (Quiagen). The mRNA is separated on a 1% agarose gel and transferred to a nylon membrane. Oligonucleotides specific for the sequences of complementary genes are used to make probes labeled with 32P (multiple 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. RT-PCR is performed using an iCycler instrument (Biorad) using 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 were measured as described in Example B. The activities of PEPCK and 6-phosphatase glucose 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 Northern blot analysis or RT-PCR as described above. RESULTS: Dose of 0.6-50 mg / kg / day of Compound 13-1-cis significantly reduces serum cholesterol (see Figure 5). Compound 18 at 1 mg / kg / day significantly reduces serum cholesterol. No significant undesirable cardiac hypertrophy was observed with Compound 13-1-cis at any dose tested. Conclusion: Compound 13-1 shows a significant cholesterol reduction even at the lowest dose evaluated (0.6 mg / kg). Additionally, there is no evidence of undesirable effects on cardiac weight across the dose range complete test (up to 50 mg / kg).
Example J: Reduction in Hepatic Fat Content After Treatment with a Phyllosilicate of Phosphonic Acid: Chronically infused into normal rats with Compound 7 for 7 days. The triglycerides of the liver were analyzed after lipid extraction by the Blight Dyer method (Bligh EG and Dyer WJ, A rapid method of total lipid extraction and purification, Can J Med Sci. 1959 (August); 37 (8): 911 -7, incorporated herein by reference). The total triglycerides were analyzed in the liver extracts by an enzymatic assay (Thermo Electron Corporation). The total lipid was normalized to the initial liver weight and the triglyceride content was normalized to the liver weight. The administration of T3 would not be expected to reduce the content of hepatic triglycerides. The analysis of hepatic triglyceride content in rats with T3 infusion shows no significant reduction in triglyceride content. There was a 4% reduction in hepatic triglycerides for this group and the results are not statistically significant. The animals infused with Compound 7 demonstrate a reduction in the hepatic triglyceride content of 64%, an unexpected and significantly different result. In other experiments, Compound 7 was administered orally to ZDF rats for 28 days. The hepatic triglycerides were analyzed as described above. Total hepatic triglycerides were reduced in the treated animals by 42% in the 2.5 mg / kg / d group. Histological analysis of liver sections after staining H & E demonstrates a pronounced and diffuse microvesicular statosis through the hepatic lobe in the vehicle-treated group. Hepatic stetosis is a well-known and described phenomenon for the ZDF rat, and is therefore not attributable to vehicle treatment. There was a dose-dependent reduction in microvesicular statosis and a reportable appearance of intact cytoplasm within the hepatocytes consistent with a non-statotic liver.
Example K: Effects of T3 Mimetic Prodrugs of In vivo Phosphonic Acid in Cholesterol Another experimental trial evaluated the effects of phosphonic acid T3 mimetic prodrugs of the present invention on serum cholesterol. The rats became hypercholesterolemic by keeping them on a diet containing 1.5% cholesterol and 0.5% colic acid for at least 2 weeks before the start of treatment. The plasma cholesterol values were evaluated before and after the treatment and the effects of the compound were expressed as a percentage of change in cholesterol levels before the dose. Total cholesterol was analyzed using a commercially available enzyme kit (Sigma Diagnostics, St. Louis, MO). The compounds were routinely tested for 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 the Compound 19-2), Compound 12-5 (a bisPom 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. The vehicle, Compound 13-9 and Compound 19-1 fail to demonstrate cholesterol reduction in this assay, while Compound 13-1-cis, Compound 12-5 and Compound 15-5 demonstrate a significant reduction in cholesterol. HepDirect versions of T3 phosphonic acid mimetics usually show good results, however, the diethyl ester versions of T3 mimetics of phosphonic acid of the present invention are found to be unsuitable as prodrugs. In another experiment, the efficacy of Compound 7 was compared to Compounds 12-9, cis-13-2 and 15-6, which are prodrugs of the compounds that bind poorly to both TRa and TRβ (Ki of about 300nM). Compound 7 was effective while Compounds 12-9, cis-13-2 and 15-6 were not effective in reducing cholesterol. Table 10 (below) shows the results for additional compounds of the present invention evaluated in the current method.
TABLE 10 Compound administered i.p% reduction of (0.2 mg / kg / d) untreated cholesterol -3.6 Vehicle -5.3 40 -64.2 7-5 -63.3 7-9 -63.2 24-3 -48.6 8-2 -48.0 45 -46.3 7-3 -45.4 22 -44.0 66 -42.9 7 -41.5 11 -36.4 24-1 -35.4 7-14 -32.9 33 -32.5 46 -. 46 -. 46 -29..6 47 -29. .3 42 -28. .8 7-8 -28. .6 7-10 -25. .8 -24. .3 48 -23. .4 29 -21. .9 38 -21. .7 31 -21. .1 27 -20, .8 24-2 -20, .5 28 -20. .5 6 -20 .5 19 -19 52 -18 .8 7-6 -13 .5 37 -o.-4 Compound administered po,% reduction of (0.5 mg / kg / d) untreated cholesterol -4.1 0 Vehicle -5: 1 15-4 -39 .6 12-8 -33 .7 12-5 -32 .5 cis-13-1 -31.8 12-4 -30.5 15-5 -29.9 15-7 -29.1 13-8 -26.5 13-11 -24.8 13-9 -10.9 19-1 -6.6 12-7 -39.1 13-10 -25.8 15-8 -31.1 Compound administered po % reduction (0.2 mg / kg / d) cholesterol Vehicle -5.1 71 -54.4 69-2 -49.9 69 -41.9 45 -40.4 7-9 -38.4 7-5 -38.0 7-3 -36.5 61 -33.7 70 -32.8 8-1 -32.2 40 -27.3 46 -23.8 8 -20.6 22-1 -19.9 67 -17.0 22 -16.5 66 -12.5 7-1 -12.2 11 -5.1 Example L: Effects of T3 Mimetic Prodrugs of In vivo Phosphonic Acid in TSH Circulating Another point concerning synthetic thyromimetics is the suppression of the endogenous thyroid axis. Thyroid homeostasis is maintained by the action of the hormone that releases the thyroid (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 pituitary releasing TSH that then acts on the thyroid organ on its own. and TSH are concentrated by a feedback-sensitive mechanism so that low levels of thyroid hormone (TH) (T3 or T4) cause an increase in HRT and TSH and high levels of TH cause a suppression of HRT and TSH. that TSH can be measured more rapidly than TRH, TSH levels are tested as a measure of systemic effects of TH or synthetic thyromimetics. Reduced TSH levels are a point of concern because suppression of the thyroid axis would lead to systemic hypothyroidism. Although this particular side effect has been noted, it has typically been treated with fewer points of concern than cardiac safety issues. However, new evidence indicates that, in addition to possible systemic hypothyroidism, which is a point that concerns any potential long-term therapy, suppression of TSH would increase osteoclast function leading to a 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 TSH 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 T3 carboxylic acid mimetics) for 7 days, are 0.8 and 0.4, respectively. Therefore, both compounds suppress TSH at lower doses than those required to reduce circulating cholesterol. In ZDF rats treated with 50mg / kg / d of Compound 7 for 28 days, TSH levels are reduced by more than 90%. In mice treated with 10 mg / kg / d of Compound 7 for 77 days, no reduction in TSH was observed, indicating that Compound 7 It 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 in 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 the Compound cis-13-1. The reduction was dose dependent. Blood glucose levels at those doses that correspond to 442 mg / dL and 243 mg / dL, respectively. Changes similar to the two weeks after treatment were also evident. There was a dose-dependent reduction in water consumption of the treated animals, which is consistent with an improvement in glycemic control.
Example N: T3 and T3 mimetic mediate the transcription of the myosin heavy chain gene in the heart An RT-PCR assay as described in: Sara Danzi, Kaie Ojamaa, and Irwin Klein Am J Physiol Heart 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 heavy chain genes a- and β-myosin (MHC) in I live based on the amount of nuclear RNA heterogeneous specific (hnRNA). We show the temporal relationship of changes in transcriptional activity for the amount of a-MHC mRNA and the coordinated transcription regulation of more than one gene in response to T3 and T3 mimetics. Analysis of the time course of T3 and T3 mimetics that are not specific to the liver shows a mediated induction of an a-MHC hnRNA and the repression of the hnRNA ß-MHC, while it is not observed to significantly affect 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 T3 mimetics containing phosphonic acid against T3 mimetics containing carboxylic acid, on cardiovascular function (cardiac rhythm, inotropic state, and aortic pressure) in the Sprague Dawley rat model (SD). Method: Compound cis-13-1 (a HepDirect prodrug of Compound 7) was dissolved in PEG400 and administered daily to male SD 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) was only given a vehicle. Compound 18 (a T3 carboxylic acid mimetic) was administered at 1 mg / kg p.o. as a positive control (n = 6). The day 7 after the start of dosing, the 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 lead ECG, and heart rate (HR) triggers the ECG waveform, were recorded digitally. The LV dP / dt is a well-accepted measurement of the ionotropic state. Systolic and diastolic aortic pressures were measured by retracting the catheter in the proximal aorta. RESULTS: Compared to animals treated with 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 pressures in all groups treated with Compound cis-13-1 were not significantly different compared to animals treated with the vehicle. The weight of the heart and the normalized heart weight up to body weight in animals treated with Compound 18 is significantly increased compared to the control animals. There are no significant changes in cardiac weight or cardiac weight ratios / body weight 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, it is free of important chronotropic and ionotropic effects in the normal SD rat. This is established in contrast to Compound 18 which is associated with marked effects when given at 1 mg / kg / day.
Example P: Continuous Infusion Study Exclusion separation for thyromimetic activity was performed in normal rats maintained on a diet containing cholesterol. The compounds were administered by continuous infusion using an osmotic pump at 1 mg / kg / day. The compounds were dissolved in 0. NaOH solution and the pH was adjusted to 7.4-8.0. The compounds were chemically stable as an aqueous solution at 37 ° C for 14 days. Compounds 7, 69, 70, and 69-1 were compared to the changes tested in the 17th and vehicle in heart rate, LV dP / dt, systolic and diastolic blood pressure, and reductions in total cholesterol. Compound 17 increases the heart rate by 40% when analyzed on day 7 and the elevation was up to dl4. At the end of life it was shown that Compound 17 also increases LV dP / dt by 71% and left ventricular weight. The systolic and diastolic pressure was also increased by 30%. Compound 17 produces a significant reduction in cholesterol when measured on day 7, but no significant reduction in cholesterol was observed on day 14. For some reason, Compound 17 stops the production of an effect that reduces cholesterol for a longer time, while still maintaining the adverse cardiovascular effects. Compounds 1, 69, 70, and 69-1 do not show changes in any of the cardiovascular parameters either on day 7 or day 14. Compounds 7, 69, 70, and 69-1 demonstrate effects that lower cholesterol on the day 7 and day 14. The reductions in cholesterol on day 7 were equivalent for all the compounds tested. Having now fully described the invention, it will be understood by those skilled in the art that the same can be done within a broad and equivalent range of conditions, formulations, and other parameters without affecting the scope of the invention or any modality thereof. All patents, patent applications and publications cited herein are incorporated herein by reference in their entirety. It is noted that in relation to this date, the best known method for carrying out the aforementioned invention is that which is clear from the present description of the invention.

Claims (1)

  1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A compound of Formula VIII: characterized in that: G is selected from the group consisting of -Se- and CH2 linked to any of -O-, -S-, -Se-, -S (= 0) -, -S (= 0) 2-, - CH2-, -CF2-, -CHF-, -C (O) -, -CH (OH) -, -NH-, and -N (C1-C4 alkyl) -; or G is R50-R51 wherein; R50_R5i together are -c (R52) = C (R52) - or alternatively R50 and R51 are independently selected from O, S and -CH (R53) -, with the proviso that at least one R50 and R51 is -CH (R53) ) -, and when one of R50 and R51 is O or S, then R53 is R54; R54 is hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl; R53 is selected from hydrogen, halogen, hydroxyl, mercapto, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; R 52 is selected from hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; T is selected from the group consisting of - (CRa2) ~, CRb = CRb- (CRa2) n-, - (CRa2) n-CRb = CRb-, - (CRa2) -CRb = CRb- (CRa2) -, -0 (CR ° 2) (CRa2) n- (-S (CRD2) (CRa2) n- -N (RC: cRb2: (CRa2) n-, -N (R) C (0) (CRa2) n-, - (CRa2) mC (RD) (NRbDnRCC), -, -C (O) (CRa2) m-, - (CRa2) mC (0) -, - (CRß2) -0- (CRß2) - (CRa2) p-, - (CRb2) -S- (CRb2) - (CRa2) p-, - (CRb2) "N (Rc) - (CRb2) - (CRa2) p-, - (CRa2) p- (CRD2) -O- (CRD2) -, - (CRa2) p- (CRb2) -S- (CRb2) -, - ( CRa2) p- (CRb2) -N (Rc) - (CRb2) -y- (CH2) PC (0) N (Rb) C (Ra2) -; 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 C1-C4 alkyl, -OCF3, -OCHF2, -OCH2F, -S- optionally substituted C1-C4 alkyl, -NRbRc, C2-C4 alkenyl optionally substituted, and optionally substituted C2-C4 alkynyl; with the proviso that when one Ra is linked to C through an atom of 0, S, or N, then the other Ra linked to the same C is a hydrogen, or 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 (O) -alkyl optionally substituted C 1 -C 4 alkyl, and -C (0) H; R 1, R 2, R 6, and R 7 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 4 alkyl, -S- optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C2-C4 alkynyl, -CF3, -CHF2, -CH2F, -0CF3, -0CHF2, -0CH2F, -0-C1-C3 alkyl optionally substituted, and cyano; with the proviso that at least one of R1 and R2 is not hydrogen; R 8 and R 9 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 4 alkyl, -S- optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 4 alkenyl, C 2 -C 8 alkynyl optionally substituted, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, -O- optionally substituted C? -C3 alkyl, hydroxy, - (CRa2) aryl, - (CRa2) cycloalkyl, (CRa2) heterocycloalkyl, -C (0) aryl, -C (0 ) cycloalkyl, C (0) heterocycloalkyl, -C (0) alkyl and cyano; or R6 and T are taken in conjunction with the carbons to which they are bound to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation in the ring to which R3 and R5 are linked, including 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 from nitrogen then both heteroatoms have to be separated by at least one carbon atom; and X is bonded to this ring by a direct bond to a ring carbon, or by - (CRa2) - or -C (0) - linked to a ring carbon or a ring nitrogen; 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; or R1 and R7 are taken in conjunction with the carbons to which they are bonded to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation in the ring to which R1 and R7 are linked, including 0 to 2 heteroatoms independently selected from -NRh-, -0-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms they are different from nitrogen then both heteroatoms have to be separated by at least one carbon atom; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, cyano, optionally substituted -C1 -C2 alkyl, alkenyl- C2-Ci2 optionally substituted, C2-C12 alkynyl optionally substituted, - (CRa2) optionally substituted maryl, - (CRa2) optionally substituted cycloalkyl, - (CRa2) mheterocycloalkyl optionally substituted, -C (Rb) = C (Rb) -aryl , -C (Rb) = C (Rb) -cycloalkyl, -C (R) = C (Rb) -heterocycloalkyl, -C = C (aryl), -C = C (cycloalkyl), -C = C (heterocycloalkyl), - (CRa2) n (CRb2) NRfRg, -ORd, -SRd, -S (= 0) Re, -S (= 0) 2R% -S (= 0) 2NRfRg, -C (0) NRfRg, -C ( 0) ORh, -C (0) Re, -N (Rb) C (O) 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 -Ci 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 1 -C 2 -Ci 2, optionally substituted C 2 -C 20 alkenyl, C 2 -C 2 alkynyl optionally substituted, - (CR2) optionally substituted, optionally substituted - (CRa2) nCycloalkyl, and optionally substituted - (CRa2) nheterocycloalkyl; R f and R g are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 2 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl, optionally substituted C 1 -C 2 -C 2 optionally substituted, - (CRb2) optionally substituted cycloalkyl, and - (CRb2) nheterocycloalkyl optionally substituted, or Rf and Rg may together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, the heterocyclic ring may contain a second heterogroup 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 1 -C 4 -alkyl, -ORb, oxo, cyano, -CF3, -CHF2, -CH2F, optionally substituted phenyl, and -C (0) 0Rh; Each Rh is selected from the group consisting of optionally substituted C 1 -Ci 2 -alkyl, optionally substituted C 2 -C 2 -alkenyl, optionally substituted C 2 -C 2 alkynyl, optionally substituted - (CRb 2) naryl, - (CR 2) nCycloalkyl optionally substituted, and - (CRb2) optionally substituted n-heterocycloalkyl; or R3 and R8 are taken together with the carbon atoms to which they are bonded to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the insatuation in the ring to which R3 and R8 are linked, including 0 to 2 heteroatoms independently selected from -NRh-, -O-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms have to be separated by at least a carbon atom; or R8 and G are taken together with the carbon atoms to which they are bonded to form an optionally substituted ring comprising -CH = CH-CH =, -N = CH-CH =, -CH = N-CH = or -CH = CH-N =; R5 is selected from the group consisting of -OH, -O optionally substituted C6-C6 alkyl, -OC (0) Re, -OC (0) ORh, -NHC (0) ORh, -OC (0) NH (Rh ), -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2 Re, -NHC (= S) NH (Rh), and -NHC (O) NH (Rh); or R3 and R5 are taken together with the carbons to which they are bound to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation in the ring to which R3 and R5 are linked, including 0 to 2 heteroatoms independently selected from -NRh-, -O-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms are they have to separate by at least one carbon atom; X is P (0) (YR11) (Y'R11); Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are both -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 'both are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] qC (0) 0Ry, -C (Rx) 2C ( 0) 0Ry, - [C (Rz) 2] qC (0) SRy, and -cycloalkylene-C (0) 0Ry; 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, -alkylaryl optionally substituted, -C (Rz) 20C (0) NRZ2, -NRz-C (0) -Ry, -C (Rz) 2-OC (0) Ry, -C (Rz) 2-0-C (O) 0Ry, -C (Rz) 20C (O) SRy, -alkyl-S-C (0) Ry, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] qC (0) 0Ry, -C (Rx) 2C (0) 0Ry, - [C (Rz)] qC (0) SRy, and -cycloalkylene-C (0) ORy; or when Y and Y 'are independently selected from -0- and -NRV-, then R11 and R11 together form a cyclic group comprising -alkyl-S-S-alkyl-, 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, where 0-1 atoms are hetero atoms and the atoms the remainder are carbon, substituted with hydrogen, hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy linked to a carbon atom which is of 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 or carbon replaced by hydrogen, and the cyclic group is fused to a group aryl in the beta position and gamma to the Y linked to phosphorus; or together V and W are connected by means of 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms or carbon replaced by hydrogen and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, bonded to one of the carbon atoms that is three atoms of a Y bonded 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 or carbon substituted by hydrogen, and V can 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, where 0-2 atoms they are heteroatoms and the remaining atoms are carbon or carbon substituted by hydrogen, and V can 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, -NHC0Rz, -NHC02Ry, -CH2NHaril, - (CH2) q-0Rz, and - (CH2) q-SRz; q is an integer 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 cycloalkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the conditions that: a) when G is -CH2-0-, where the oxygen atom is linked to the ring being the group T, T is - (CH2)? -2CH (Rcc), Rcc is -OH, -SH, -NH2, or -NH (C? _4), R1 and R2 are each independently selected from chlorine, bromine, C? _4 alkyl, C2_4 alkenyl, and C2_4 alkynyl, then X is not acid phosphonic or phosphamic acid or a lower alkyl ester thereof; b) V, Z, W, 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. 2. A compound of Formula VIII: characterized in that: G is selected from the group consisting of -O-, -S-, -Se-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF -, -C (O) -, -CH (OH) -, -NH-, and -N (C 1 -C 4 alkyl) -, or CH 2 linked to any of the above groups; or G is R50-R51 wherein; R50-R51 together are -C (R52) = C (R52) - or alternatively R50 and R51 are independently selected from O, S and -CH (R53) -, with the proviso that at least one R50 and R51 is -CH (R53) -, and when one of R50 and R51 is O or S, then R53 is R54; R54 is hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl; R53 is selected from hydrogen, halogen, hydroxyl, mercapto, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; R52 is selected from hydrogen, halogen, C?-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C?-C4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, 'difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; T is selected from the group consisting of - (CRa2)? -2-0- (CRa2)? - 2- and - (CH2) pC (0) N (Rb) C (Ra2) -, 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, -OCHF 2, -0CH 2 F, -S- C1 alkyl C4 optionally substituted, -NRbRc, optionally substituted C2-C4 alkenyl, and optionally substituted C2-C4 alkynyl; with the proviso that when one Ra is linked to C through an atom of O, S, or N, then the other Ra linked to the same C is a hydrogen, or 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) - optionally substituted C 1 -C 4 alkyl, and -C (0) H; R 1, R 2, R 6, and R 7 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 4 alkyl, -S- optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C2-C4 alkynyl, -CF3, -CHF2, -CH2F, -0CF3, -0CHF2, -0CH2F, -0-C1-C3 alkyl optionally substituted, and cyano; with the proviso that at least one of R1 and R2 is not hydrogen; R8 and R9 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted -C4-C4 alkyl, -S- optionally substituted C?-C3 alkyl, optionally substituted C2-C4 alkenyl, C2-C4 alkynyl optionally substituted, -CF3, -CHF2, -CH2F, -0CF3, -OCHF2, -0CH2F, -0- optionally substituted C? -C3 alkyl, hydroxy, - (CRa2) aryl, - (CRa2) cycloalkyl, (CRa2) heterocycloalkyl , -C (O) aryl, -C (0) cycloalkyl, C (0) heterocycloalkyl, -C (0) alkyl and cyano; or R6 and T are taken in conjunction with the carbons to which they are bound to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation in the ring to which R3 and R5 are linked, including 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 from nitrogen then both heteroatoms have to be separated by at least one carbon atom; and X is bonded to this ring by a direct bond to a ring carbon, or by - (CRa2) - or -C (0) - linked to a ring carbon or a ring nitrogen; R1 is selected from the group consisting of hydrogen, -C (0) C? -C4 alkyl, C? -C4 alkyl, and C? -C4 aryl; or R1 and R7 are taken together with the carbons to which they are bonded to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation in the ring to which R1 and R7 are linked, including 0 to 2 heteroatoms independently selected from -NRh-, -0-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms have to be separated by at least one carbon atom; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, cyano, optionally substituted -C1-C2-alkyl, optionally substituted C2-C2-alkenyl, optionally substituted C2-C2-C2-alkynyl, optionally substituted - (CRa2) maryl, - (CRa2) optionally substituted cycloalkyl, - (CRa2) mheterocycloalkyl optionally substituted, -C (Rb) = C (Rb) -aryl, -C (Rb) = C (Rb) -cycloalkyl, -C (Rb) = C ( Rb) -heterocycloalkyl, -C = C (aryl), -C = C (cycloalkyl), -C = C (heterocycloalkyl), - (CRa2) n (CRb2) NRfRg, -0Rd, -SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRfRg, -C (0) NRfRg, -C ( 0) ORh, -C (0) Re, -N (Rb) C (O) 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 -Ci 2 -alkyl, optionally substituted C 2 -C 2 -alkenyl, optionally substituted C 2 -C 2 alkynyl, optionally substituted - (CR 2 2) naryl, - (CR b 2) 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 1 -C 2 -alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl, optionally substituted - (CRa 2) naryl, - (CRa 2) n Optionally substituted cycloalkyl, and - (CRa 2) n -heterocycloalkyl optionally substituted; Rf and Rg are each independently selected from a group consisting of hydrogen, 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) n-cycloalkyl optionally substituted, and optionally substituted - (CRb2) nheterocycloalkyl, or Rf and Rg can together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, the heterocyclic ring can contain a second hetero group within the ring selected from the group which consists 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, -CHF2, -CH2F, optionally substituted phenyl, and -C (0) ORh; Each Rh is selected from the group consisting of optionally substituted C 1 -Ci -C 2 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl, optionally substituted (CRb) naryl, - (CR 2) nCycloalkyl optionally substituted, and - (CRb2) optionally substituted n-heterocycloalkyl; or R3 and R8 are taken together with the carbon atoms to which they are bonded to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation in the ring to which R3 and R8 are link, including 0 to 2 heteroatoms independently selected from -NRh-, -0-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms have to be separated by at least one carbon atom; or R8 and G are taken together with the carbon atoms to which they are bonded to form an optionally substituted ring comprising -CH = CH-CH =, -N = CH-CH =, -CH = N-CH = or -CH = CH-N =; R5 is selected from the group consisting of -OH, -0 optionally substituted C6-C6 alkyl, -0C (0) Re, -0C (0) 0Rh, -NHC (0) 0Rh, -0C (0) NH (Rh ), -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); or R3 and R5 are taken together with the carbons to which they are bound to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation in the ring to which R3 and R5 are linked, including 0 to 2 heteroatoms independently selected from -NRh-, -0-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms have to be separated by at least one carbon atom; X is P (0) (YR11) (Y'R11); Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are both -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 'both are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] qC (0) 0Ry, -C (Rx) 2C ( 0) 0Ry, - [C (Rz) 2] qC (0) SRy, and -cycloalkylene-C (0) 0Ry; 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 (Rz) 2-0-C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-S-C (0) Ry, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; and R11 linked to -NRV- is independently selected from group consisting of -H, - [C (Rz) 2] qC (0) 0Ry, -C (Rx) 2C (0) 0Ry, - [C (Rz) 2] qC (0) SRy, and -cycloalkylene- C (0) ORy; or when Y and Y 'are independently selected from -0- and -NRV-, then R11 and R11 together form a cyclic group comprising -alkyl-S-S-alkyl-, 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, optionally 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 hydrogen, hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom that is 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 or carbon replaced by hydrogen, and the cyclic group is fused to an aryl group in the beta position and gamma to the 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 or carbon substituted by hydrogen and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, bonded to one of the carbon atoms which is of three atoms of a Y bonded 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 or carbon substituted by hydrogen, and V can 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 or carbon substituted by hydrogen, and V can 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, -NHCOR2, -NHC02Ry, -CH2NHaril, - (CH2) q-ORz, and - (CH2) q-SRz; q is an integer 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 cycloalkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the conditions 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. 3. A compound of Formula VIII: characterized in that: G is selected from the group consisting of -0-, -S-, -Se-, -S (= 0) -, -S (= 0) 2-, "CH2-, -CF2-, -CHF -, -C (0) -, -CH (OH) -, -NH-, and -N (C? -C4 alkyl) -, or CH2 linked to any of the above groups, or G is R50-R51 where; R50-R51 together are -C (R52) = C (R52) - or alternatively R50 and R51 are independently selected from 0, S and -CH (R53) -, with the proviso that at least one R50 and R51 is - CH (R53) -, and when one of R50 and R51 is 0 or S, then R53 is R54; R54 is hydrogen, halogen, C? -C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl; R53 is selected from hydrogen, halogen, hydroxyl, mercapto, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; R52 is selected from hydrogen, halogen, C?-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, alkyl C1-C4 oxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; T is selected from the group consisting of - (CRa2) k_, ~ CRb = CRb- (CRa2) n-, - (CRa2) n-CRb = CR-, - (CRa2) -CRb = CRb- (CRa2) -, -0 (CRb2) (CRa2) n-, -S (CRb2) (CRa2) n-, -N (Rc) (CRb2) (CRa2) n ", -N (Rb) C (0) (CRa2) n- , - (CRa2) mC (Rb) (NRbRc) -, -C (O) (CRa2) m-, - (CRa2) mC (0) -, - (CRb2) -0- (CRb2) - (CRa2) p -, - (CRb2) -S- (CRb2) - (CRa2) p-, - (CRb2) -N (Rc) - (CRb2) - (CRa2) p-, - (CRa2) p- (CRb2) -O - (CRb2) -, - (CRa2) p- (CRb2) -S- (CRb2) -, - (CRa2) p- (CRb2) -N (Rc) - (CRb2) - and - (CH2) pC (0 ) N (Rb) C (Ra2) -; 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 selects 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, -OCHF 2, -OCH 2 F, -S- C 1 alkyl- Optionally substituted C4, -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 O, S, or N atom, then the other Ra linked to the same C is a hydrogen, or 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, C-C-alkyl optionally substituted, -C (0) -alkyl optionally substituted Cx-C4, and -C (0) H; R 1, R 2, R 6, and R 7 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 4 alkyl, -S- optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C2-C4 alkynyl, -CF3, -CHF2, -CH2F, -0CF3, -0CHF2, -0CH2F, -0-C-C3 alkyl optionally substituted, and cyano; with the proviso that at least one of R1 and R2 is not hydrogen; R8 and R9 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted C -C alkyl, optionally substituted -S-C ?C3 alkyl, optionally substituted C2-C4 alkenyl, C2-C4 alkynyl optionally substituted, -CF3, -CHF2, -CH2F, -0CF3, -0CHF2, -0CH2F, -O-C-C3 alkyl optionally substituted, hydroxy, - (CRa2) aryl, - (CRa2) cycloalkyl, (CRa2) ethercycloalkyl , -C (0) aryl, -C (0) cycloalkyl, C (0) heterocycloalkyl, -C (0) alkyl and cyano; or R6 and T are taken in conjunction with the carbons to which they are bound to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation in the ring to which R3 and R5 are linked, including 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 from nitrogen then both heteroatoms have to be separated by at least one carbon atom; and X is bonded to this ring by a direct bond to a ring carbon, or by - (CRa2) - or -C (0) - linked to a ring carbon or a ring nitrogen; 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; or R1 and R7 are taken together with the carbons to which they are bonded to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation in the ring to which R1 and R7 are linked, including 0 to 2 heteroatoms independently selected from -NRh-, -O-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms have to be separated by at least one carbon atom; R 4 is selected from the group consisting of hydrogen, halogen, -CF 3, -CHF 2, -CH 2 F, -0CF 3, -OCHF 2, -OCH 2 F, cyano, optionally substituted C 1 -Ci 2 alkyl, optionally substituted C 2 -C 20 alkenyl , optionally substituted C2-C2-alkynyl-2, optionally substituted - (CRa2) maryl, optionally substituted - (CRa2) m-cycloalkyl, - (CRa2) mheterocycloalkyl optionally substituted, C (Rb) = C (Rb) -aryl, -C ( Rb) = C (Rb) -cycloalkyl, -C (Rb) = C (Rb) - heterocycloalkyl, -C = C (aryl), -C = C (cycloalkyl), -C = C (heterocycloalkyl), - (CRa2) n (CRb2) NRfRg, -OR, -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 12 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl 2, optionally substituted - (CR b), - (CR 2) n Optionally substituted cycloalkyl, - (CRb2) n-heterocycloalkyl optionally substituted, and -C (0) NRfRg; Each Re is selected from the group consisting of optionally substituted C 1 -Ci 2 -alkyl, optionally substituted C 2 -C 2 -alkenyl, optionally substituted C 2 -C 2 alkynyl, optionally substituted - (CRa 2), optionally substituted - (CRa 2) nCycloalkyl, and - (CRa2) optionally substituted n-heterocycloalkyl; Rf and R are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 2 alkynyl, optionally substituted C 1 -C 2 -alkyl, - (CRb2) optionally substituted cycloalkyl, and - (CRb) nheterocycloalkyl optionally substituted, or Rf and R9 can together form a ring optionally substituted heterocyclic of 3-8 atoms containing 0-4 unsaturations, the heterocyclic ring may contain a second heterogroup within the ring selected from the group consisting 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, -CHF 2, -CH 2 F, optionally substituted phenyl, and -C (0) ORh; Each Rh is selected from the group consisting of optionally substituted C 1 -C 2 -C 2 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl 2, optionally substituted - (CR 2) naryl, - (CR 2) n Optionally substituted cycloalkyl, and - (CRb 2) n -heterocycloalkyl optionally substituted; or R8 and G are taken together with the carbon atoms to which they are bonded to form an optionally substituted ring comprising -CH = CH-CH =, -N = CH-CH =, -CH = N-CH = or -CH = CH-N =; R3 and R5 are taken in conjunction with the carbons to which they are bonded to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation in the ring to which R3 and R5 are linked, including 0 to 2 heteroatoms independently selected from -NRh-, -O-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms have to be separated by at least one carbon atom; X is P (0) (YR11) (Y'R11); Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are both -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 'both are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] qC (0) 0Ry, -C (Rx) 2C ( 0) 0Ry, - [C (Rz) 2] qC (0) SRy, and -cycloalkylene-C (0) 0Ry; 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) 2OC (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-S-C (0) Ry, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] qC (0) 0Ry, -C (Rx) 2C (0) 0Ry, - [C (Rz) 2 ] qC (0) SRy, and -cycloalkylene-C (0) ORy; or when Y and Y 'are independently selected from -0- and -NRV-, then R11 and R11 together form a cyclic group comprising -alkyl-S-S-alkyl-, 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 atoms additional to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydrogen, hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom which is of 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 or carbon replaced by hydrogen, and the cyclic group is fused to a group aryl in the beta position and gamma to the 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 or carbon substituted by hydrogen and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, bonded to one of the carbon atoms which is of three atoms of a Y bonded 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 or carbon substituted by hydrogen, and V can 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, characterized in that 0-2 atoms are heteroatoms and the remaining atoms are carbon or carbon substituted by hydrogen, and V can 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, -SCORy, -SC02Ry, -NHCOR2, -NHC02Ry, -CH2NHaril, - (CH2) q-ORz, and - (CH2) q-SRz; q is an integer 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 cycloalkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the conditions that: a) when G is O, T is - (CH2)? _ 3- or - (CH2)? _2-CH (Raa), Raa is -OH, -NH2, -NH (alkylC? ), -NH (C2.4 alkenyl), or -NH (C2_ alkynyl), R4 is hydrogen, R1 and R2 are independently selected from halogen, Ci alkyl substituted with 1, 2, or 3 hydrogen, fluorine, or a bioisostomeric equivalent, C? -4 alkyl and CF3, and R3 and R5 are taken together with the carbon atoms to which they are bonded to form a five-membered heterocyclic ring of the formula -AC (Rbb) = B- where A, where the group R5 is linked, is selected from -0-, -S-, and -NRh-, B is selected from -CH-, and -N-, Rbb is selected from C6-? Aryl, C5-9 heteroaryl, or C1-alkyl, then X is not phosphonic acid, phosphamic acid, or a lower alkyl ester or acyloxyalkyl ester thereof; b) when G is -CH2-0-, where the oxygen atom binds to the ring being the group T, T is - (CH2)? -2CH (Rcc), Rcc is -OH, -SH, -NH2, or -NH (d-), R1 and R2 are each independently selected from chlorine, bromine, Ci-4 alkyl, C2- alkenyl, and C2_4 alkynyl, then X is not phosphonic acid or phosphamic acid or a lower alkyl ester of the same; 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. 4. A compound of Formula VIII: characterized in that: G is selected from the group consisting of -0-, -S-, -Se- (= 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 (C 1 -C 4 alkyl) -, or CH2 linked to any of the above groups; or G is R50-R51 wherein; R50-R51 together are -C (R52) = C (R52) - or alternatively R50 and R51 are independently selected from 0, S and -CH (R53) -, with the proviso that at least one R50 and R51 is -CH (R53) -, and when one of R50 and R51 is 0 or S, then R53 is R54; R54 is hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl; R53 is selected from hydrogen, halogen, hydroxyl, mercapto, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; R52 is selected from hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C4-4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; T is selected from the group consisting of - (CRa2) k_, -CRb = CRb- (CRa2) n-, - (CRa2) n-CRb = CRb-, - (CRa2) -CRb = CRb- (CRa2) -, -0 (CR2) (CRa2] -S (CR2) (CR = -N (RC (CRb2) (CRa2) n-, -N (Rb) C (0) (CRa2) n-, - (CRa2) mC (Rt (NRbRc) -, -C (O) (CRa2) - (CRa2) mC (0) -,; CRb2) -0- (CRD2) - (CRa2) p- (- (CRD2) -S- (CRD2) - (CRa2) p-, - (CRb2) -N ( Rc) - (CRb2) - (CRa2) p-, - (CRa2) p- (CRb2) -O- (CRb2) -, - (CRa2) p- (CRB2) -S- (CRB2) -, - (CRa2) p- (CRb2) -N (Rc) - (CRb2) - and - (CH2) pC (0) N (Rb) C (Ra2) -; 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, Ci-alkyl Optionally substituted C, halogen, -OH, -O- optionally substituted C? -C4 alkyl, -OCF3, -OCHF2, -OCH2F, -S- optionally substituted C? -C4 alkyl, -NRbRc, C2-C4 alkenyl optionally substituted, and optionally substituted C2-C4 alkynyl; with the proviso that when one Ra is linked to C through an atom of O, S, or N, then the other Ra linked to the same C is a hydrogen, or linked by means of a carbon atom; Each Rb is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 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; R 2 and R 6 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 4 alkyl, -S-C optionally substituted C 3 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, C 2 -C 4 alkynyl optionally substituted, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, -O- optionally substituted C? -C3 alkyl, and cyano; with the proviso that at least one of R1 and R2 is not hydrogen; R8 and R9 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted -C4-C4 alkyl, -S-C optionally substituted alkyl, optionally substituted C2-C4 alkenyl, C4-alkynyl optionally substituted, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, -O- optionally substituted C? -C3 alkyl, hydroxy, - (CRa2) aryl, - (CRa2) cycloalkyl, (CRa2) heterocycloalkyl , -C (O) aryl, -C (O) cycloalkyl, C (O) heterocycloalkyl, -C (O) alkyl and cyano; or R6 and T are taken together with the carbons to which they are bonded to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations including 0 to 2 heteroatoms independently selected from -NR1-, -O-, and -S - with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms must be separated by at least one carbon atom; and X is linked to this ring by a direct bond to a ring carbon, or by - (CRa2) - or -C (O) - linked to a ring carbon or a ring nitrogen; R 1 is selected from the group consisting of hydrogen, -C (O) C 1 -C 4 alkyl, and C 1 -C 4 alkyl; R1 and R7 are taken together with the carbons to which they are bonded to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation in the ring to which R1 and R7 are linked, including 0 to 2 heteroatoms independently selected from -NRh-, -O-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms must be separated by at least one atom of carbon; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, cyano, optionally substituted-C2-C2-alkyl, alkenyl- C2-C? 2 optionally substituted, optionally substituted C2-Ci2 alkynyl, - (CRa2) optionally substituted maryl, - (CRa2) optionally substituted cycloalkyl, - (CRa2) mheterocycloalkyl optionally substituted, -C (Rb) = C (Rb) -aryl, -C (Rb) = C (Rb) -cycloalkyl, -C (Rb) = C (Rb) -heterocycloalkyl, -C = C (aryl), -C = C (cycloalkyl), -C = C (heterocycloalkyl), - (CRa2) n (CRb2) NRfRg, -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 20 alkynyl, optionally substituted - (CRb 2) naryl, - (CRb 2) n Optionally substituted cycloalkyl, - (CRb2) n-heterocycloalkyl optionally substituted, and -C (0) NRfRg; Each Re is selected from the group consisting of optionally substituted C 1 -C 2 -C 2 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 20 alkynyl, optionally substituted - (CR a 2) naryl, - (CR a 2) 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 1 -C 12 alkyl, C 2 -C alkenyl? optionally replaced, optionally substituted C2-Ci2 alkynyl, - (CRb2) optionally substituted Naryl, - (CRb) optionally substituted N-cycloalkyl, and - (CRb) optionally substituted N-heterocycloalkyl, or Rf and Rg can together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, the heterocyclic ring can contain a second heterogroup within the ring selected from the group consisting of O, NRC, and S, characterized in that the optionally substituted heterocyclic ring can be substituted with 0-4 substituents selected from the group it consists of optionally substituted -C1-C4 alkyl, -ORb, oxo, cyano, -CF3, -CHF2, -CH2F, optionally substituted phenyl, and -C (0) ORh; Each Rh 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) n Optionally substituted cycloalkyl, and - (CRb 2) n -heterocycloalkyl optionally substituted; or R3 and R8 are taken together with the carbon atoms to which they are bonded to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation in the ring to which R3 and R8 are linked , including 0 to 2 heteroatoms independently selected from -NRh-, -0-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms have to be separated by at least one carbon atom; or R8 and G are taken together with the carbon atoms to which they are bonded to form an optionally substituted ring comprising -CH = CH-CH =, -N = CH-CH =, -CH = N-CH = or -CH = CH-N =; R5 is selected from the group consisting of -OH, -0 optionally substituted C6-C6 alkyl, -0C (0) Re, -0C (0) 0Rh, -NHC (0) 0Rh, -0C (0) NH (Rh ), -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2 Re, -NHC (= S) NH (Rh), and -NHC (O) NH (Rh); or R3 and R5 are taken together with the carbons to which they are bound to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation in the ring to which R3 and R5 are linked, including 0 to 2 heteroatoms independently selected from -NRh-, -0-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms have to be separated by at least one carbon atom; X is P (0) YRnY'Rn; Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'both are -0-, R11 linked to -O- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl where 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) 20C (0) SRy, -alkyl-SC (0) Ry, - alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; when Y and Y 'both are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] qC (0) 0Ry, -C (Rx) 2C ( 0) 0Ry, - [C (Rz) 2] qC (0) SRy, and -cycloalkylene-C (0) 0Ry; 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 (Rz) 2-0-C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-SC (0) Ry, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-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 selected independently of -0- and -NRV-, then R and R together form a cyclic group comprising -alkyl-S-S-alkyl-, 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, characterized in that 0 - 1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydrogen, hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom that is 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 or carbon substituted by hydrogen, and the cyclic group is fused to an aryl group in the beta position and gamma to the Y linked 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 or carbon substituted by hydrogen and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, bonded to one of the carbon atoms that is three atoms of a Y bonded 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 or carbon substituted by hydrogen, and V can 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 or carbon substituted by hydrogen, and V can 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 = CR2) OH, -Rz, -NRZ2, -OCORy, -OC02Ry, -SCORy, -SC02Ry, -NHCOR2, -NHC02Ry, -CH2NHaril, - (CH2) q-ORz, and - (CH2) q-SRz; q is an integer 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 cycloalkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the conditions 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. 5. A compound of Formula II: Characterized because: A is selected from the group consisting of -NR1-, -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 (C 1 -C 4 -alkyl, and C 1 -C 4 -alkyl; R b is selected from the group consisting of hydrogen and optionally substituted C 1 -C alkyl; which consists of -Se- and CH linked to either -0-, -S-, -Se-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, - CHF-, -C (0) -, -CH (OH) -, -NH-, and -N (C1-C4 alkyl) -; or G is R50-R51 where: R50_R5i together are -c (R52) = C (R52) - or alternatively R50 and R51 are independently selected from 0, S and -CH (R53) -, with the proviso that at least one R50 and R51 is -CH (R53) -, and when one of R50 and R51 is 0 or S, then R53 is R54, R54 is hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl; R53 is selected from hydrogen, halogen, hydroxyl, mercapto , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fl uoromethylthio, difluoromethylthio and trifluoromethylthio; R is selected from hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; 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, -0-C 1 -C 4 alkyl optionally substituted, -0CF 3, -0CHF 2, -0CH 2 F, -S-C alkyl Optionally substituted -C4, -NRRc, optionally substituted C2-C4 alkenyl, and optionally substituted C2-C4 alkynyl; with the proviso that when one Ra is linked to C through an atom of 0, S, or N, then the other Ra linked to the same C is a hydrogen, or linked by means of a carbon atom; R 1 and R 2 are each independently selected from the group consisting of halogen, optionally substituted C 1 -C 4 alkyl, -S- optionally substituted C 1 -C 3 alkyl, optionally substituted C 4 -C alkenyl, optionally substituted C 2 -C 4 alkynyl , -CF3, -CHF, -CH2F, -0CF3, -0CHF2, -OCH2F, -0- optionally substituted C? -C3 alkyl, and cyano; R8 is selected from the group consisting of hydrogen, halogen, optionally substituted-C-C4-alkyl, optionally substituted -S-C-C3 alkyl, C2-C4-alkenyl optionally substituted, optionally substituted C2-C-alkynyl, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, -O- optionally substituted C1-C3 alkyl, hydroxy, - (CRa2) aryl, (CRa2) cycloalkyl , - (CRa) heterocycloalkyl, -C (O) aryl, C (O) cycloalkyl, -C (O) heterocycloalkyl, -C (O) alkyl and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, cyano, optionally substituted-C? -C? 2 alkyl, alkenyl- C2-C? optionally substituted, optionally substituted C 2 -C 2 alkynyl, optionally substituted - (CR a 2) maryl, - (CR a 2) optionally substituted cycloalkyl, - (CR a) optionally substituted -heterocycloalkyl, -C (R b) = C (R b) -aryl, -C (Rb) = C (Rb) -cycloalkyl, -C (Rb) = C (Rb) -heterocycloalkyl, -C = C (aryl), -C = C (cycloalkyl), -C = C (heterocycloalkyl), - (CRa2) n (CRb2) NRfRg, -ORd, -SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRfRg, -C (0) NRfRg, -C ( 0) 0Rh, -C (0) Re, -N (Rb) C (O) 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 -C 2 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl 2, optionally substituted - (CR 2) naryl, - (CR 2) n Optionally substituted cycloalkyl, optionally substituted - (CRb2) nheterocycloalkyl, 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 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted (CRa 2) naryl, - (CR a 2) n Cycloalkyl optionally substituted, and - (CRa2) optionally substituted n-heterocycloalkyl; R f and R g are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 2 alkyl, optionally substituted C 2 -C 20 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 1 -C 2 -alkyl, - (CRb2) optionally substituted cycloalkyl, and - (CRb2) nheterocycloalkyl optionally substituted, or Rf and Rg can together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, which may contain a second heterogroup selected from the a 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 , -CHF2, CH2F, 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 12 alkenyl, C 2 -C 12 alkynyl optionally substituted, - (CRb2) optionally substituted naril, - (CRb2) n Optionally substituted cycloalkyl, and - (CRb2) nheterocycloalkyl optionally substituted; or R3 and R8 are taken together with the carbon atoms to which they are bonded to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation in the ring to which R3 and R8 are linked , including 0 to 2 heteroatoms independently selected from -NRh-, -O-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms have to be separated by minus one carbon atom; or R8 and G are taken together with the carbon atoms to which they are bonded to form an optionally substituted ring comprising -CH = CH-CH =, -N = CH-CH =, -CH = N-CH = or -CH = CH-N =; R5 is selected from the group consisting of -OH, -O optionally substituted C6-C6 alkyl, -OC (0) Re, -0C (0) 0Rh, -NHC (0) ORh, -OC (0) NH (Rh ), -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2 Re, -NHC (= S) NH (Rh), and -NHC (O) NH (Rh); or R3 and R5 are taken together with the carbons to which they are bonded to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation in the ring to which R3 and R5 are link, including 0 to 2 heteroatoms independently selected from -NRh-, -0-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms have to be separated by at least one carbon atom; 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 both -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 'both are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (R2) 2] qC (0) 0Ry, -C (Rx) 2C ( 0) 0Ry, - [C (Rz) 2] qC (0) SRy, and -cycloalkylene-C (0) 0Ry; 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-S-C (0) Ry, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] qC (0) 0Ry, -C (Rx) 2C (0) 0Ry, - [C (Rz) 2 ] qC (0) SRy, and -cycloalkylene-C (0) 0Ry; or when Y and Y 'are independently selected from -0- and -NRV-, then R11 and R11 together form a cyclic group comprising -alkyl-SS-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 hydrogen, hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom that is 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 or carbon replaced by hydrogen, and the cyclic group is fused to a group aryl in the beta position and gamma to the 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 or carbon substituted by hydrogen and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, bonded to one of the carbon atoms which is of three atoms of a Y bonded 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 or carbon substituted by hydrogen, and V can 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, where 0-2 atoms are heteroatoms and the remaining atoms are carbon or carbon substituted by hydrogen, and V can 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) 0H, -Rz, -NRz2, -OCORy, -OC02Ry, -SCORy, -SC02Ry, -NHC0Rz, -NHC02Ry, -CH2NHaril, - (CH2) q-0Rz, and - (CH2) q-SRz; q is an integer 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 cycloalkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the conditions that: a) V, Z, W, W are not all -H; Y b) when Z is -R2, 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. 6. 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 -CR-, and -N-; R 1 is selected from the group consisting of hydrogen, -C (O) C 1 -C 4 alkyl, and C 4 -C 4 alkyl; 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-, -Se-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF-, - C (O) -, -CH (OH) -, -NH-, and -N (C-C4 alkyl) -, or CH2 linked to any of the above groups; or G is R50-R51 wherein; R50-R51 together are -C (R52) = C (R52) - or alternatively R50 and R, 51 are independently selected from O, S and -CH (R 53,) -, with the condition that at least one R50 and R51 is -CH (R53) -, and when one of R50 and R51 is 0 or S, then R53 is R54; R54 is hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl; R53 is selected from hydrogen, halogen, hydroxyl, mercapto, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio , difluoromethylthio and trifluoromethylthio; R 52 is selected from hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; 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, -O- optionally substituted C 1 -C 4 alkyl, -OCF 3, -OCHF 2, -OCH 2 F, -S- alkyl Optionally substituted C 1 -C 4, -NRbRc, optionally substituted C 2 -C alkenyl, and optionally substituted C 2 -C 4 alkynyl; with the proviso that when one Ra is linked to C through an atom of O, S, or N, then the other Ra linked to the same C is a hydrogen, or linked by means of a carbon atom; R 1 and R 2 are each independently selected from the group consisting of halogen, optionally substituted C 1 -C 4 alkyl, -S- optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl , -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, -0- optionally substituted C? -C3 alkyl, and cyano; R 8 is selected from the group consisting of halogen, optionally substituted C 1 -C 4 alkyl, -S- optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, -CF 3, - CHF2, -CH2F, -0CF3, -0CHF2, -0CH2F, -0- optionally substituted C? -C3 alkyl, hydroxy, - (CRa2) aryl, (CRa2) cycloalkyl, - (CRa2) heterocycloalkyl, -C (0) aryl , C (0) cycloalkyl, -C (0) heterocycloalkyl, -C (0) alkyl and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -CHF2, -CH2F, -0CF3, -OCHF2, -0CH2F, cyano, optionally substituted-C12-C12 alkyl, C2-alkenyl Ci2 optionally substituted, optionally substituted C2-Ci2 alkynyl, optionally substituted - (CRa2) maryl, - (CRa2) optionally substituted cycloalkyl, - (CRa2) optionally substituted -heterocycloalkyl, -C (Rb) = C (Rb) -aryl, - C (Rb) = C (Rb) -cycloalkyl, - C (Rb) = C (Rb) -heterocycloalkyl, -C = C (aryl), -C = C (cycloalkyl), -C = C (heterocycloalkyl), - (CRa2) n (CRb2) NRfRg, -ORd, -SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRfRg, -C (0) NRfRg, -C ( 0) ORh, -C (0) Re, -N (Rb) C (O) 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 Ci-Ci alkyl? optionally, optionally substituted C2-Ci2 alkenyl, optionally substituted C2-Ci2 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 -Ci-C 2 alkyl, optionally substituted C 2 -C 2 -alkenyl, optionally substituted C 2 -C 2 alkynyl, optionally substituted - (CRa 2), optionally substituted - (CRa 2) n -Cycloalkyl substituted, and - (CRa2) optionally substituted n-heterocycloalkyl; 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) naryl, - (CRb2) optionally substituted cycloalkyl, and - (CRb2) nheterocycloalkyl optionally substituted, or Rf and Rg can together form an optionally substituted heterocyclic ring of 3-8 atoms which contains 0-4 unsaturations, which may contain a second heterogroup selected from the group consisting of O, NRC, and S, wherein the optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting of C-alkyl ? -C4 optionally substituted, -ORb, oxo, cyano, -CF3, -CHF2, CH2F, optionally substituted phenyl, and -C (0) ORh; Each Rh 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 2, optionally substituted (CR 2) naryl, - ( CRb2) optionally substituted cycloalkyl, and - (CRb2) n -heterocycloalkyl optionally substituted; or R3 and R8 are taken together with the carbon atoms to which they are bonded to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation in the ring to which R3 and R8 are linked , including 0 to 2 heteroatoms independently selected from -NRh-, -O-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms have to be separated by minus one carbon atom; or R8 and G are taken together with the carbon atoms to which they are bonded to form an optionally substituted ring comprising -CH = CH-CH =, -N = CH-CH =, -CH = N-CH = or -CH = CH-N =; R5 is selected from the group consisting of -OH, -0 optionally substituted C6-C6 alkyl, -0C (0) Re, -0C (0) 0Rh, -NHC (0) 0Rh, -0C (0) NH (Rh ), -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2Re, -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); or R3 and R5 are taken together with the carbons to which they are bound to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation in the ring to which R3 and R5 are linked, including 0 to 2 heteroatoms independently selected from -NRh-, -0-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms have to be separated by at least one carbon atom; X is P (0) YRuY'Rn; Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'are both -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-S-C (0) Ry, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; when Y and Y 'both are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] qC (0) 0Ry, -C (Rx) 2C ( 0) 0Ry, - [C (Rz) 2] qC (0) SRy, and -cycloalkylene-C (0) 0Ry; 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) 2OC (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-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] qC (0) 0Ry, -C (Rx) 2C (0) 0Ry, - [C (Rz) 2 ] qC (0) SRy, and -cycloalkylene-C (0) 0Ry; or when Y and Y 'are independently selected from -0- and -NRV-, then R11 and R11 together form a cyclic group comprising -alkyl-SS-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 hydrogen, hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom that is 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 or carbon replaced by hydrogen, and the cyclic group is fused to a group aryl in the beta position and gamma to the Y 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 or carbon substituted by hydrogen and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, bonded to one of the carbon atoms that is three atoms of a Y bonded 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 or carbon substituted by hydrogen, and V can 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 or carbon substituted by hydrogen, and V can be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHR20H, -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) OH, -Rz, -NRZ2, -OCORy, -OC02Ry, -SCORy, -SC02Ry, -NHCOR2, -NHC02Ry, -CH2NHaril, - (CH2) q-ORz, and - (CH2) q-SRz; q is an integer 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 cycloalkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the conditions 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; and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs. 7. 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-; R1 is selected from the group consisting of hydrogen, - C (0) C 1 -C 4 alkyl, and C 1 -C 4 alkyl; 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-, -Se-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF-, - C (0) -, -CH (OH) -, -NH-, and -N (C? -C4 alkyl) -, or CH2 linked to any of the above groups; or G is R50-R51 wherein; R50_R5i together are -c (R52) = C (R52) - or alternatively R50 and R51 are independently selected from O, S and -CH (R53) -, with the proviso that at least one R50 and R51 is -CH (R53) ) -, and when one of R50 and R51 is 0 or S, then R53 is R54; R54 is hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl; R53 is selected from hydrogen, halogen, hydroxyl, mercapto, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; R 52 is selected from hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; D is selected from the group consisting of a bond, - (CRa2) -, and -C (0) -; Each R is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 -alkyl, halogen, -OH, -0- optionally substituted C 1 -C 4 alkyl, -0CF 3, -0CHF 2, -0CH 2 F, -S- alkyl Optionally substituted C? -C4, -NRbRc, optionally substituted C2-C4 alkenyl, and optionally substituted C2-C alkynyl; with the proviso that when one Ra is linked to C through an atom of 0, S, or N, then the other Ra linked to the same C is a hydrogen, or linked by means of a carbon atom; R 1 and R 2 are each independently selected from the group consisting of halogen, optionally substituted C 1 -C 4 alkyl, -S- optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 20 alkenyl, optionally substituted C 2 -C 4 alkynyl , -CF3, -CHF2, -CH2F, -0CF3, -0CHF2, -0CH2F, -0- optionally substituted C? -C3 alkyl, and cyano; R 8 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, -CF 3 , -CHF2, -CH2F, -0CF3, -0CHF2, -0CH2F, -0- optionally substituted C? -C3 alkyl, hydroxy, - (CRa2) aryl, (CRa) cycloalkyl, - (CRa2) heterocycloalkyl, -C (0 aril, C (O) cycloalkyl, -C (0) heterocycloalkyl, -C (0) alkyl and cyano; R4 is selected from the group consisting of hydrogen, halogen, -CF3, -CHF2, -CH2F, -0CF3, -0CHF2, -0CH2F, cyano, optionally substituted -C1 -C2 alkyl, optionally substituted C2-C12 alkenyl , optionally substituted C2-C2-alkynyl-2, optionally substituted - (CRa2) maryl, optionally substituted - (CRa2) m-cycloalkyl, - (CRa2) mheterocycloalkyl optionally substituted, C (Rb) = C (Rb) -aryl, -C ( Rb) = C (Rb) -cycloalkyl, -C (Rb) = C (Rb) -heterocycloalkyl, -C = C (aryl), -C = C (cycloalkyl), -C = C (heterocycloalkyl), - (CRa2 ) n (CRb2) NRfRg, -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 12 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl 2, optionally substituted (CR 2) naryl, - ( CRb2) n Optionally substituted cycloalkyl, - (CRb) nheterocycloalkyl optionally substituted, and -C (0) NRfRg; Each Re is selected from the group consisting of optionally substituted C 1 -C 2 alkyl, optionally substituted C 2 -Ci 2 alkenyl, optionally substituted C 2 -C 2 alkynyl, optionally substituted C 2 -C 2 alkynyl, - (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 C 1 -C 2 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl, optionally substituted (CR 2) naryl, - (CRb2) n Optionally substituted cycloalkyl, and - (CRb2) nheterocycloalkyl optionally substituted, or Rf and Rg can together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, which may contain a second heterogroup selected from the a 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 , -CHF2, CH2F, optionally substituted phenyl, and -C (0) ORh; Each R 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 2, optionally substituted (CR 2) naryl, - ( CRb2) optionally substituted cycloalkyl, and - (CRb2) n -heterocycloalkyl optionally substituted; or R8 and G are taken together with the carbon atoms to which they are bonded to form a ring optionally substituted which comprises -CH = CH-CH =, -N = CH-CH =, -CH = N-CH = or -CH = CH-N =; R3 and R5 are taken in conjunction with the carbons to which they are bonded to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation in the ring to which R3 and R5 are linked, including 0 to 2 heteroatoms independently selected from -NRh-, -O-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms must be separated by at least one atom of carbon; X is P (0) YRnY'Rn; Y and Y 'are each independently selected from the group consisting of -O-, and -NRV-; when Y and Y 'both 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 (O) -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 'both are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] qC (0) ORy, -C (Rx) 2C (0) 0Ry, - [C (Rz) 2] qC (0) ) SRy, and -cycloalkylene-C (0) 0Ry; 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 (Rz) 2-0-C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-S-C (0) Ry, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] qC (0) 0Ry, -C (Rx) 2C (0) 0Ry, - [C (Rz) 2 ] qC (0) SRy, and -cycloalkylene-C (0) 0Ry; or when Y and Y 'are independently selected from -0- and -NRV-, then R11 and R11 together form a cyclic group comprising -alkyl-SS-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 hydrogen, hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom that is 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 or carbon replaced by hydrogen, and the cyclic group is fused to a group aryl in the beta position and gamma to the 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 or carbon substituted by hydrogen and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, bonded to one of the carbon atoms that is three atoms of a Y bonded to phosphorus; or together Z and W are connected by means of 3-5 additional atoms to form a cyclic group, characterized in that 0-1 atoms are heteroatoms and the remaining atoms are carbon or carbon replaced by hydrogen, and V can 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 or carbon substituted by hydrogen, and V can 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, -SCORy, -SC02Ry, -NHCOR2, -NHC02Ry, -CH2NHaril, - (CH2) q-0R2, and - (CH2) q-SRz; q is an integer 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 that consists of -H, and alkyl, or together Rx and Rx form a cycloalkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the conditions that: a) V, Z,, W are not all -H; and b) 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. 8. The compound according to any of claims 5-7, characterized in that D is selected from the group consisting of a bond and -CH2-. 9. The compound according to any of claims 5-7, characterized in that A is selected from the group consisting of -NH-, -NMe-, -0-, and -S-. The compound according to any of claims 5-7, characterized in that B is selected from the group consisting of -CH-, -CMe-, and -N-. 11. A compound of Formula III: characterized in that: G is selected from the group consisting of -Se and CH2 linked to any of -0-, -S-, -Se-, -S (= 0) -, -S (= 0) 2-, -CH2 -, -CF2-, -CHF-, -C (0) -, -CH (OH) -, -NH-, and -N (C? -C4 alkyl) -; or G is R50-R51 wherein; R50-R51 together are -C (R52) = C (R52) - or alternatively R50 and R51 are independently selected from 0, S and -CH (R53) -, with the proviso that at least one R50 and R51 is -CH (R53) -, and when one of R50 and R51 is 0 or S, then R53 is R54; R54 is hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl; R53 is selected from hydrogen, halogen, hydroxyl, mercapto, C1-C4 alkyl, C2-C alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; R 52 is selected from hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; 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) mC (Rb) (NRbRc) ~, -C (O) (CRa2) ra-, - (CRa2) mC (0) -, - (CRb2) -0- (CRb2) - (CRa2) p -, - (CRb2) -S- (CRb2) - (CRa2) p-, - (CRb2) -N (Rc) - (CRb2) - (CRa2) p-, - (CRa2) p- (CRb2) -O - (CRb2) -, - (CRa2) p- (CRb2) -S- (CRb2) -, - (CRa2) p- (CRb2) -N (Rc) - (CRb2) - and - (CH2) pC (0 ) N (Rb) C (Ra2) -; 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-optionally substituted C 1 -C 4 alkyl, -OCF 3, -OCHF 2, -OCH 2 F, -S- alkyl Optionally substituted C? -C4, -NRbRc, optionally substituted C2-C4 alkenyl, and optionally substituted C2-C4 alkynyl; with the proviso that when one Ra is linked to C through an atom of 0, S, or N, then the other Ra linked to the same C is a hydrogen, or 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 and C 1 -C 4 alkyl optionally substituted, -C (0) - optionally substituted C? -C4alkyl, 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-C3 alkyl, optionally substituted C2-C alkenyl, optionally substituted C2-C4 alkynyl, -CF3, -CHF2, -CH2F, -0CF3, -0CHF2, -0CH2F, -0- optionally substituted C? -C3 alkyl, and cyano; R 8 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 4 alkyl, -S- optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, -CF 3 , -CHF2, -CH2F, -0CF3, -0CHF2, -0CH2F, -0- optionally substituted C1-C3 alkyl, hydroxy, - (CRa2) aryl, (CRa2) cycloalkyl, - (CRa2) heterocycloalkyl, -C (0) aril, C (0) cycloalkyl, -C (0) heterocycloalkyl, -C (0) alkyl and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -CHF2, -CH2F, -0CF3, -OCHF2, -0CH2F, cyano, optionally substituted-C12-C12 alkyl, C2-alkenyl Ci2 optionally substituted, optionally substituted C2-Ci2-alkynyl, optionally substituted - (CRa2) maryl, - (CRa2) optionally substituted cycloalkyl, - (CRa) optionally substituted -heterocycloalkyl, -C (Rb) = C (Rb) -aryl, - C (Rb) = C (Rb) -cycloalkyl, - C (Rb) = C (Rb) -heterocycloalkyl, -C = C (aryl), -C = C (cycloalkyl), -C = C (heterocycloalkyl), - (CRa2) n (CRb2) NRfRg, -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 12 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl, optionally substituted (CR 2) naryl, - (CR 2) n Optionally substituted cycloalkyl, - (CRb2) n-heterocycloalkyl optionally substituted, 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 2 alkynyl 2, optionally substituted (CRa 2), - ( CRa2) n Optionally substituted cycloalkyl, and - (CRa2) n -heterocycloalkyl optionally substituted; R f and R g are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 2 alkyl, optionally substituted C 2 -C 20 alkenyl, optionally substituted C 2 -C 20 alkynyl, optionally substituted (C 2 -C 2) substituted, - (CRb2) optionally substituted cycloalkyl, and - (CRb2) nheterocycloalkyl optionally substituted, or Rf and Rg may together form a ring optionally substituted heterocyclic of 3-8 atoms containing 0-4 unsaturations, which may contain a second hetero group selected from the group consisting 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, -ORb, oxo, cyano, -CF 3, -CHF 2, CH 2 F, 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, optionally substituted C 1 -C 6 alkylcycloalkyl, and - (CRb2) optionally substituted n-heterocycloalkyl; or R3 and R8 are taken together with the carbon atoms to which they are bonded to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation in the ring to which R3 and R8 are linked , including 0 to 2 heteroatoms independently selected from -NRh-, -O-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms have to be separated by minus one carbon atom; or R8 and G are taken together with the carbon atoms to which they are bonded to form a ring optionally substituted which comprises -CH = CH-CH =, -N = CH-CH =, -CH = N-CH = or -CH = CH-N =; R5 is selected from the group consisting of -OH, -0 optionally substituted C6-C6 alkyl, -0C (0) Re, -0C (0) 0Rh ', -NHC (0) 0R, -0C (0) NH ( Rh), -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2R% -NHC (= S) NH (Rh), and -NHC (0) NH (Rh); or R3 and R5 are taken in conjunction with the carbons to which they are bonded to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation in the ring to which R3 and R5 are linked, including 0 to 2 heteroatoms independently selected from -NRh-, -0-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms have to be separated by at least a carbon atom; R7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, -0- C C-C4 alkyl, -0CF3, -0CHF2, -0CH2F, -CF3, -CHF2, -CH2F, cyano, -SH and -S - alkyl C? -C4; X is P (0) YR Y'Rn; Y and Y 'are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y 'both are -O-, R11 linked to -O- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, CH2-heterocycloalkyl optionally substituted wherein the cyclic portion contains a carbonate or thiocarbonate, -alkylaryl optionally substituted, -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 'both 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 (Rz) 2-0-C (0) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-S-C (0) Ry, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] qC (0) 0Ry, -C (Rx) 2C (0) 0Ry, - [C (Rz) 2 ] qC (0) SRy, and -cycloalkylene-C (0) 0Ry; or when Y and Y 'are independently selected from -0- and -NRV-, then R11 and R11 together form a cyclic group which it comprises -alkyl-S-S-alkyl-, or j 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 hydrogen, hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom that is 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 or carbon replaced by hydrogen, and the cyclic group is fused up to an aryl group in the beta position and Y-gamma 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 or carbon substituted by hydrogen and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, bonded to one of the carbon atoms which is of three atoms of a Y bonded 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 or carbon substituted by hydrogen, and V can 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 or carbon substituted by hydrogen, and V can be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHRz0H, -CHRz0C (0) Ry, -CHRzOC (S) Ry, -CHRzOC (S) ORy, -CHRzOC (0) SRy, -CHRz0C02Ry, -ORz, -SRZ, -CHRZN3 , -CH2aryl, -CH (aryl) OH, -CH (CH = CRz2) 0H, -CH (C = CRz) 0H, -Rz, -NRZ2 / -OCORy, -0C02Ry, -SC0Ry, -SC02Ry, -NHC0Rz, -NHC02Ry, -CH2NHaril, - (CH2) q-0Rz, and - (CH2) q-SRz; q is an integer 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 cycloalkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the conditions 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. 12. A compound of Formula III: characterized in that: G is selected from the group consisting of -O-, -S-, -Se-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF -, -C (O) -, -CH (OH) -, -NH-, and -N (C? -C4 alkyl) -, or CH2 linked to any of the above groups; or G is R50-R51 wherein; R50-R51 together are -C (R52) = C (R52) - or alternatively R50 and R51 are independently selected from 0, S and -CH (R53) -, with the proviso that at least one R50 and R51 is -CH (R53) -, and when one of R50 and R51 is 0 or S, then R53 is R54; R54 is hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl; R53 is selected from hydrogen, halogen, hydroxyl, mercapto, C 1 -C 4 alkyl, C 2 -C alkenyl, C 2 -C alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; R 52 is selected from hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; T is selected from the group consisting of - (CRa2)? -2-0- (CRa2)! - 2- and - (CH2) pC (0) N (Rb) C (Ra2) -; 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, -OCHF 2, -OCH 2 F, -S- alkyl Optionally substituted C? -C4, -NRbRc, optionally substituted C2-C4 alkenyl, and optionally substituted C2-C4 alkynyl; with the proviso that when one Ra is linked to C through an atom of O, S, or N, then the other Ra linked to the same C is a hydrogen, or 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 and 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 -C4-C4 alkyl, -S- optionally substituted C?-C3 alkyl, optionally substituted C2-C alkenyl, optionally substituted C2-C4 alkynyl , -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, -O-C-C3 alkyl optionally substituted, and cyano; R8 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 4 alkyl, -S- optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, -CF 3, -CHF 2, -CH 2 F, -OCF 3, -OCHF2, -OCH2F, -0- optionally substituted C? -C3 alkyl, hydroxy, - (CRa2) aryl, (CRa2) cycloalkyl, - (CRa2) heterocycloalkyl, -C (0) aryl, C (0) cycloalkyl, - C (0) heterocycloalkyl, -C (0) alkyl and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -CHF2, -CH2F, -0CF3, -0CHF2, -0CH2F, cyano, optionally substituted -C1 -C2 alkyl, alkenyl- C2-Ci2 optionally substituted, optionally substituted alkynyl-C -Ci2, optionally substituted - (CRa2) aryryl, - (CRa2) optionally substituted cycloalkyl, - (CRa2) mheterocycloalkyl optionally substituted, -C (Rb) = C (Rb) -aryl , -C (Rb) = C (Rb) -cycloalkyl, -C (Rb) = C (Rb) -heterocycloalkyl, -C = C (aryl), -C = C (cycloalkyl), -C = C (heterocycloalkyl), - (CRa2) n (CRb2) NRfRg, -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 2 -C 2 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl 2, optionally substituted (CR 2) 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 1 -C 2 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl, optionally substituted (CRa 2) naryl, - (CRa 2) n Optionally substituted cycloalkyl, and - (CRa 2) n -heterocycloalkyl optionally substituted; R f and R g are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 2 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl 2, - (CR 2) optionally substituted naryl, - (CRb2) optionally substituted n-cycloalkyl, and optionally substituted - (CRb2) nheterocycloalkyl, or Rf and Rg can together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, which may contain a second heterogroup 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 -C1-C4 alkyl, -ORb, oxo, cyano , -CF3, -CHF2, -CH2F, optionally substituted phenyl, and -C (0) 0Rh; Each Rh 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, optionally substituted (CR 2) nCycloalkyl, and - ( CRb2) optionally substituted n-heterocycloalkyl; or R3 and R8 are taken together with the carbon atoms to which they are bonded to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation in the ring to which R3 and R8 are linked , including 0 to 2 heteroatoms independently selected from -NRh-, -O-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms have to be separated by minus one carbon atom; or R8 and G are taken together with the carbon atoms to which they are bonded to form an optionally substituted ring comprising -CH = CH-CH =, -N = CH-CH =, -CH = N-CH = or -CH = CH-N =; R5 is selected from the group consisting of -OH, -O optionally substituted C6-C6 alkyl, -OC (0) Re, -OC (0) ORh ', -NHC (0) ORh, -OC (0) NH ( Rh), -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2Re, -NHC (= S) NH (Rh), and -NHC (O) NH (Rh); or R3 and R5 are taken together with the carbons to which they are bonded to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, without include the unsaturation in the ring to which R3 and R5 are linked, including 0 to 2 heteroatoms independently selected from -NRh-, -0-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms must be separated by at least one carbon atom; R7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, -O- C C-C4 alkyl, -0CF3, -0CHF2, -0CH2F, -CF3, -CHF2, -CH2F, cyano, -SH and -S -alkyl C? -C4; X is P (0) YRnY'Rn; Y and Y 'are each independently selected from the group consisting of -O-, and -NRV-; when Y and Y 'both are -0-, 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 (O) -Ry, -C (R2) 2-OC (0) Ry, -C (R2) 2- 0-C (0) ORy, -C (Rz) 20C (O) SRy, -alkyl-SC (O) Ry, -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; when Y and Y 'both are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (R2) 2] q-COORy, -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 an optionally substituted carbonate or thiocarbonate, -alkylaryl, -C (Rz) 2OC (O) NRZ2, -NRZ-C (0) -Ry, -C (Rz) 2-OC (0) Ry, -C (R2) 2-0-C (O) 0Ry, -C (Rz) 20C (0) SRy, -alkyl-SC (O) Ry, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] qC (O) ORy, -C (Rx) 2C (O) 0Ry, - [C (Rz) 2 ] qC (0) SRy, and -cycloalkylene-C (0) ORy; or when Y and Y 'are independently selected from -0- and -NRV-, then R11 and R11 together form a cyclic group comprising -alkyl-S-S-alkyl-, or together R11 and R11 are the group: where: V, W, and W are independently selected from the group which consists 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 hydrogen, hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom that is 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, characterized in that 0-1 atoms are heteroatoms and the remaining atoms are carbon or carbon replaced by hydrogen, and the cyclic group is fused to a group aryl in the beta position and gamma to the 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 or carbon substituted by hydrogen and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, bonded to one of the carbon atoms which is three atoms of a Y linked 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 or carbon substituted by hydrogen, and V can 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 or carbon substituted by hydrogen, and V can 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, -SCORy, -SC02Ry, -NHCOR2, -NHC02Ry, -CH2NHaril, - (CH2) q-ORz, and - (CH2) q-SRz; q is an integer 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 cycloalkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the conditions that: a) V, Z, W, W are not all -H; and b) 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. 13. A compound of Formula III: characterized in that: G is selected from the group consisting of -O-, -S-, -Se-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF -, -C (O) -, -CH (OH) -, -NH-, and -N (C? -C alkyl) -, or CH2 linked to any of the above groups; or G is R50-R51 wherein; R50-R51 together are -C (R52) = C (R52) - or alternatively R50 and R51 are independently selected from O, S and -CH (R53) -, with the proviso that at least one R50 and R51 is -CH (R53) -, and when one of R50 and R51 is 0 or S, then R53 is R54; R54 is hydrogen, halogen, C 1 -C 4 alkyl, C 4 C 4 alkenyl, C 2 -C 4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl; R53 is selected from hydrogen, halogen, hydroxyl, mercapto, C-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C?-C4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; R 52 is selected from hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; 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) nC (Rb) (NRbRc) -, -C (O) (CRa2) m-, - (CRa2) mC (0) -, - (CRb2) -0- (CRb2) - (CRa2) p -, - (CR2) -S- (CRb2) - (CRa2) p-, - (CRb2) -N (Rc) - (CRb2) - (CRa2) p-, - (CRa2) p- (CRb2) -0 - (CRb2) -, - (CRa2) p- (CRb2) -S- (CRb2) -, - (CRa2) p- (CRb2) -N (Rc) - (CRb2) - and - (CH2) PC (0 ) N (Rb) C (Ra2) -; 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, C 1 -C 4 -alkyl optionally substituted, halogen, -OH, -O- optionally substituted C? -C4 alkyl, -OCF3, -OCHF2, -OCH2F, -S- optionally substituted C? -C4 alkyl, -NRbRc, optionally substituted C2-C4 alkenyl, and optionally substituted C2-C4 alkynyl; with the proviso that when one Ra is linked to C through an atom of 0, S, or N, then the other Ra linked to the same C is a hydrogen, or 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 and optionally substituted C 1 -C alkyl, -C (0) -alkyl optionally substituted C 4 -C, and -C (0) H; R 1 and R 2 are each independently selected from the group consisting of halogen, optionally substituted C 1 -C 4 alkyl, optionally substituted -S-C? -C 3 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl , -CF3, -CHF2, -CH2F, -0CF3, -OCHF2, -OCH2F, -O-C-C3 alkyl optionally substituted, and cyano; R 8 is selected from the group consisting of halogen, optionally substituted C 1 -C 4 alkyl, -S- optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, -CF 3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, -O- optionally substituted C? -C3 alkyl, hydroxy, - (CRa2) aryl, (CRa2) cycloalkyl, - (CRa2) heterocycloalkyl, -C (O) aryl, C (O) cycloalkyl, -C (O) heterocycloalkyl, -C (O) alkyl and cyano; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -CHF, -CH2F, -OCF3, -OCHF2, -OCHF, cyano, optionally substituted -C1 -C2 alkyl, alkenyl -C optionally substituted -Ci2, optionally substituted C2-Ci2 alkynyl, optionally substituted - (CRa2) maryl, - (CRa2) optionally substituted cycloalkyl, optionally substituted - (CRa2) mheterocycloalkyl, -C (Rb) = C (Rb) - aryl, -C (Rb) = C (Rb) -cycloalkyl, -C (Rb) = C (Rb) -heterocycloalkyl, -C = C (aryl), -C = C (cycloalkyl), -C = C (heterocycloalkyl) ), - (CRa2) n (CRb2) NRfRg, -ORd, -SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRfRg, -C (0) NRfRg, -C ( 0) ORh, -C (0) Re, -N (Rb) C (O) 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 -C 2 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl 2, optionally substituted - (CR 2) naryl, - (CR 2) optionally substituted cycloalkyl, - (CRb2) n-optionally substituted 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 2 alkynyl, optionally substituted (CRa 2) naryl, - (CRa 2) n Optionally substituted cycloalkyl, and - (CRa 2) n -heterocycloalkyl optionally substituted; R f and R g 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 C 1 -C 2 -C 2 -C 2 -C 2 -C 2 -C 2 -C 2 -C 2 -C 2 -C 2 -C 2 -C 2 -C 2 -C 2 - (CRb2) optionally substituted cycloalkyl, and - (CRb2) nheterocycloalkyl optionally substituted, or Rf and Rg can together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, which may contain a second heterogroup 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 , -CHF2, CH2F, optionally substituted phenyl, and -C (0) 0Rh; Each Rh 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 2, optionally substituted (CR 2) naryl, - (CRb2) optionally substituted cycloalkyl, and - (CRb2) nheterocycloalkyl optionally substituted; or R3 and R8 are taken together with the carbon atoms to which they are bonded to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation in the ring to which R3 and R8 are linked , including 0 to 2 heteroatoms independently selected from -NRh-, -O-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms have to be separated by minus one carbon atom; or R8 and G are taken together with the carbon atoms to which they are bonded to form an optionally substituted ring comprising -CH = CH-CH =, -N = CH-CH =, -CH = N-CH = or -CH = CH-N =; R5 is selected from the group consisting of -OH, -O optionally substituted C6-C6 alkyl, -OC (0) Re, -OC (0) ORh ', -NHC (0) ORh, -OC (0) NH ( Rh), -F, -NHC (0) Re, -NHS (= 0) Re, -NHS (= 0) 2Re, -NHC (= S) NH (Rh), and -NHC (O) NH (Rh); or R3 and R5 are taken in conjunction with the carbons to which they are bonded to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation in the ring to which R3 and R5 are linked, including 0 to 2 heteroatoms independently selected from -NRh-, -O-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms have to be separated by at least one carbon atom; R7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, -O-C-C4 alkyl, -OCF3, -OCHF2, -OCH2F, -CF3, -CHF2, -CH2F, cyano, -SH and -S - C-C4 alkyl; X is P (O) YR Y'Rn; Y and Y 'are each independently selected from the group consisting of -O-, and -NRV-; when Y and Y 'both 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) 20C (O) NRZ2, -NRZ-C (O) -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 'both 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) 2OC (O) NRz2, -NR2-C (0) ) -Ry, -C (R2) 2-OC (0) Ry, -C (R2) 2-0-C (O) ORy, -C (Rz) 2OC (O) SRy, -alkyl-S-C (O) Ry, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] qC (O) ORy, -C (Rx) 2C (O) ORy, - [C (Rz) 2 ] qC (0) SRy, and -cycloalkylene-C (O) ORy; or when Y and Y 'are independently selected from -0- and -NRV-, then R11 and R11 together form a cyclic group comprising -alkyl-S-S-alkyl-, 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, heteroaryl substituted, 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 hydrogen, hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom that is 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 or carbon replaced by hydrogen, and the cyclic group is fused to a group aryl in the beta position and gamma to the 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 or carbon substituted by hydrogen and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, bonded to one of the carbon atoms which is of three atoms of a Y bonded 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 they are heteroatoms and the remaining atoms are carbon or carbon substituted by hydrogen, and V can 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 or carbon substituted by hydrogen, and V can 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, -SCORy, -SC02Ry, -NHCOR2, -NHC02Ry, -CH2NHaril, - (CH2) q-ORz, and - (CH2) q-SRz; q is an integer 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 cycloalkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the conditions 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; and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs. 14. A compound of Formula III: characterized in that: G is selected from the group consisting of -O-, -S-, -Se-, -S (= 0) -, -S (= 0) 2-, -CH2-, -CF2-, -CHF -, -C (O) -, -CH (OH) -, -NH-, and -N (C? -C alkyl) -, or CH2 linked to any of the above groups; or G is R50-R51 wherein; R50-R51 together are -C (R52) = C (R52) - or alternatively R50 and R51 are independently selected from 0, S and -CH (R53) -, with the proviso that at least one R50 and R51 is -CH (R53) -, and when one of R50 and R51 is 0 or S, then R53 is R54; R54 is hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl; R53 is selected from hydrogen, halogen, hydroxyl, mercapto, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; R 52 is selected from hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; T is selected from the group consisting of - (CRa2) -, -CRb = CRb- (CRa2) n-, - (CRa2) n-CRb = CRb-, - (CRa2) -CRb = CRb- (CRa2) -, -0 (CRD2) (CRa2) n-, -S (CRB2) (CRa2) n-, -N (RC) (CR 2) (CRa -N (Rb) C (0) (CRa2) n-, - (CRd2) mC (Rü) (NR "RA", -C (O) (CRa2) ra-, - (CRa2) mC (O) -, - (CRb2) -O- (CRb2) - (CRa2) p-, - (CRb2) -S- (CRb2) (CRa2) p-, - (CRb2) -N (Rc) - (CRb2) - (CRa2) p-, - (CRa2) p- (CRb2) -O- (CR2) -, - (CRa2) p- ( CRb2) -S- (CRb2) -, - (CRa2) p- (CRb2) -N (Rc) - (CRb2) - and - (CH2) pC (0) N (RD) C (Ra2) -; 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, C-alkyl Optionally substituted -C4, halogen, -OH, -O- optionally substituted C? -C4 alkyl, -OCF3, -OCHF2, -OCH2F, -S-optionally substituted C? -C4 alkyl, -NRRc, C2-C alkenyl optionally substituted, and optionally substituted C2-C4 alkynyl; with the proviso that when one Ra is linked to C through an atom of O, S, or N, then the other Ra linked to the same C is a hydrogen, or 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 and optionally substituted C 1 -C 4 -alkyl, -C (O) -alkyl 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-C3 alkyl, optionally substituted C2-C alkenyl, optionally substituted C2-C4 alkynyl , -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, -O-C1-C3 alkyl optionally substituted, and cyano; R 8 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 4 alkyl, -S- optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, -CF 3 , -CHF2, -CH2F, -0CF3, -0CHF2, -OCH2F, -O- optionally substituted C? -C3 alkyl, hydroxy, - (CRa2) aryl, (CRa2) cycloalkyl, - (CRa2) heterocycloalkyl, -C (O aril, C (O) cycloalkyl, -C (O) heterocycloalkyl, -C (O) alkyl and cyano; R 4 is selected from the group consisting of hydrogen, halogen, -CF 3, -CHF 2, -CH 2 F, -OCF 3, -OCHF 2, -OCH 2 F, cyano, optionally substituted C 1 -C 2 alkyl, optionally substituted C 2 -C 2 alkenyl-Ci 2 , optionally substituted C2-C2-alkynyl-2, optionally substituted - (CRa2) maryl, optionally substituted - (CRa2) m-cycloalkyl, - (CRa2) mheterocycloalkyl optionally substituted, C (Rb) = C (Rb) -aryl, -C ( Rb) = C (Rb) -cycloalkyl, -C (Rb) = C (Rb) -heterocycloalkyl, -C = C (aryl), -C = C (cycloalkyl), -C = C (heterocycloalkyl), - (CRa2 ) n (CRb2) NRfRg, -ORd, -SRd, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRfRg, -C (0) NR £ Rg, -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 12 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl, optionally substituted (CR 2) naryl, - (CR 2) n Optionally substituted cycloalkyl, - (CRb2) n-heterocycloalkyl 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 20 alkenyl, C 2 -C 2 alkynyl optionally substituted, - (CRa2) optionally substituted, optionally substituted _ (CRa2) n-cycloalkyl, and optionally substituted - (CRa2) nheterocycloalkyl; R f and R g are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 2 alkyl, optionally substituted C 2 -C 2 alkenyl, optionally substituted C 2 -C 2 alkynyl 2, - (CR 2) optionally substituted naryl, - (CRb2) optionally substituted n-cycloalkyl, and optionally substituted - (CRb2) nheterocycloalkyl, or Rf and Rg can together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, which may contain a second heterogroup 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, -0Rb, oxo, cyano, -CF3, -CHF2, -CH2F, optionally substituted phenyl, and -C (0) ORh; Each Rh 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 2, optionally substituted (CR 2) naryl, - (CR 2) n Optionally substituted cycloalkyl, and - (CRb 2) n -heterocycloalkyl optionally substituted; or R8 and G are taken together with the carbon atoms to which are linked to form an optionally substituted ring comprising -CH = CH-CH =, -N = CH-CH =, -CH = N-CH = or -CH = CH-N =; R3 and R5 are taken in conjunction with the carbons to which they are bonded to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation in the ring to which R3 and R5 are linked, including 0 to 2 heteroatoms independently selected from -NRh-, -O-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen then both heteroatoms must be separated by at least one atom of carbon; R 7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, -O- C 1 -C 4 alkyl, -OCF 3, -OCHF 2, -OCH 2 F, -CF 3, -CHF 2, -CH 2 F, cyano, -SH and -S - alkyl C? -C4; X is P (O) YRnY'Ru; Y and Y 'are each independently selected from the group consisting of -O-, and -NRV-; when Y and Y 'both 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 (R2) 2OC (O) NRZ2, -NRZ-C (O) -Ry, -C (R2) 2-OC (0) Ry, -C (R2) 2-0-C (0) ORy, -C (R2) 2OC (O) SRy, -alkyl-SC (O) Ry, -alkyl -SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; when Y and Y 'both are -NRV-, then R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (R2) 2] q-COORy, -C (Rx) 2COORy, - [ C (R2) 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) NRZ, -NR2-C (0) -Ry, -C (Rz) 2-OC (0) Ry, -C (RZ) 2-0-C (O) 0Ry, -C (Rz) 20C (O) SRy, -alkyl-S-C (0) Ry, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; and R11 linked to -NRV- is independently selected from the group consisting of -H, - [C (Rz) 2] qC (0) 0Ry, -C (Rx) 2C (0) 0Ry, - [C (Rz) 2 ] qC (0) SRy, and -cycloalkylene-C (0) 0Ry; or when Y and Y 'are independently selected from -0- and -NRV-, then R11 and R11 together form a cyclic group comprising -alkyl-S-S-alkyl-, 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 hydrogen, hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom that is 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 or carbon replaced by hydrogen, and the cyclic group is fused to a group aryl in the beta position and gamma to the 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 or carbon substituted by hydrogen and substituted with a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy , and aryloxycarbonyloxy, bonded to one of the carbon atoms that is three atoms of a Y bonded 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 or carbon substituted by hydrogen, and V can 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 or carbon substituted by hydrogen, and V can be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHRzOH, -CHRzOC (0) Ry, -CHRzOC (S) Ry, -CHR20C (S) ORy, -CHR20C (O) SRy, -CHR2OC02Ry, -ORz, -SRZ, -CHR2N3 , -CH2aryl, -CH (aryl) OH, -CH (CH = CR22) OH, -CH (C = CR2) 0H, -Rz, -NRZ2, -OCORy, -OC02Ry, -SCORy, -SC02Ry, -NHCORz, -NHC02Ry, -CH2NHaril, - (CH2) q-ORz, and - (CH2) q-SRz; q is an integer 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 cycloalkyl group; Each Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the conditions 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. 15. The compound according to any of claims 11-14, characterized in that R7 is selected from the group consisting of hydrogen, fluoro, chloro, amino, hydroxyl, and -0-CH3. 16. The compound according to any of claims 1, 5, or 11, characterized in that G is R50-R51. 17. The compound according to any of claims 2-4, 6, 7, or 12-14, characterized in that G it is selected from the group consisting of -O-, -CH2-, and R50-R51. 18. The compound according to any of claims 1, 3, 4, 10, 11, 13, or 14, 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-, -N (Rb) C (0) -, and -CH2C (Rb) (NRcRb) -. 19. The compound according to claim 18, characterized in that T is -O (CRb2) (CRa2) p- or -NH (CRb2) (CRa2) p-. 20. The compound according to any of claims 1-7 or 11-14, characterized in that R1 and R2 are the same and are selected from the group consisting of halogen, C? -C4 alkyl, -CF3, and cyano. 21. The compound according to claim 20, characterized in that R1 and R2 are both alkyl. 22. The compound according to any of claims 1-7 or 11-14, characterized in that R1 and R2 are different and are selected from the group consisting of halogen, C-C4 alkyl, -CF3, and cyano. 23. The compound according to claim 22, characterized in that R1 and R2 are not both halogen. The compound according to any of claims 1-7 or 11-14, characterized in that R 4 is selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, cyano and CF 3. 25. The compound according to claim 24, characterized in that R 4 is hydrogen. 26. The compound according to any of claims 1-3, characterized in that R6 and R7 are independently selected from the group consisting of hydrogen, halogen, C-alkyl, cyano and CF3. 27. The compound according to claim 26, characterized in that R6 and R7 are independently hydrogen, halogen, or methyl. 28. The compound according to any of claims 1-4, characterized in that R8 and R9 are independently selected from the group consisting of hydrogen, halogen, C-C4-alkyl, C-C4 alkylaryl, C (0) aryl, cyano and CF3. 29. The compound according to claim 28, characterized in that R8 and R9 are independently hydrogen, halogen, methyl, benzyl, and benzoate. 30. The compound according to any of claims 1, 2, 4, 5, 6, or 11-13, characterized in that R5 is selected from the group consisting of -OH, -OC (0) Re, -OC (0 ) ORh, -F, and -NHC (0) Re. 31. The compound according to claim 30, characterized in that R5 is -OH. 32. The compound according to any of claims 1, 2, 4, 5, 6, or 11-13, characterized in that R 3 is selected from the group consisting of halogen, optionally substituted C 1 -C 4 -alkyl, -CF 3, cyano, -C (0) NRfRg, - (CRa 2) optionally substituted naril, -S02NRfRg, and -S02Re. 33. The compound according to claim 32, characterized in that R3 is isopropyl or 4-fluorobenzyl. 34. The compound according to any of claims 1-7 or 11-14, characterized in that X is selected from the group consisting of -P03H2, -P (O) [-OCRz2OC (0) Ry] 2, -P ( O) [-OCRz2OC (0) ORy] 2, -P (O) [-N (H) CRz2C (0) ORy] 2, -P (O) [-N (H) CRZ2C (O) ORy] [-OR11], -P (O) [-OCH (V) CH2CH20-], -P (O) (OH) (ORe), -P (O) (ORe) (ORe), -P (O) [-OCRz2OC (O) Ry] (0Re), -P (O) [-OCRz2OC (O) ORy] (ORe), -P (O) [-N (H) CR22C (0) ORy] (ORe), and -P (O) (OH) (NH2) wherein V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl , and optionally substituted heteroaryl. 35. The compound according to claim 34, characterized in that 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 (0) OCH2CH3] 2, -P (O) [-N (H) CH (CH3) C (O) OCH2CH3] [3, 4-methylenedioxyphenyl], -P (O) [-N (H) C (CH3 ) 2C (0) OCH2CH3] [3, 4-methylenedioxyphenyl], -P (O) [-OCH (3-chlorophenyl) CH2CH20-], -P (O) [-OCH (pyrid-4- il) CH2CH20-], -P (O) (OH) (OCH3), -P (O) (OH) (OCH2CH3; -P (O) [[-OCH2OC (O) -t-butyl] (OCH3), -P (O) [[-OCH2OC (0) 0-i-propyl] (OCH3), -P (O) [[ -OCH (CH3) OC (O) -t-butyl] (OCH3), -P (O) [[-OCH (CH3) OC (0) 0-i-propyl] (OCH3), -P (O) [ [-N (H) CH (CH3) C (O) OCH2CH3] (OCH3), -P (O) [[-N (H) C (CH3) 2C (O) OCH2CH3] (OCH3), -p (0 ) [[-N (H) CH2C (0) OCH2CH3] (CH3) and -P (O) (OH) (NH2). 36. The compound according to any of claims 1-7 or 11-14, characterized in that Y and Y 'are each independently selected from -O- and -NRV-; together R11 and R11 are the group: 37. The compound in accordance with the claim 36, characterized in that V is aryl. 38. The compound in accordance with the claim 37, characterized in that Z is hydrogen, W is hydrogen, and W is hydrogen. 39. The compound in accordance with the claim 38, 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 and 3,5-dichlorophenyl. 40. The compound in accordance with the claim 39, characterized in that the relative stereochemistry between the substituent of group V and T in the ring is cis. 41. The compound in accordance with the claim 40, characterized in that the cis ring has the stereochemistry R on the carbon where the group V is linked. 42. The compound according to claim 40, characterized in that the cis ring has S stereochemistry at the carbon where the V group is linked. 43. A compound characterized in that it is selected from the group consisting of: Y and monomethyl ester thereof, and pharmaceutically acceptable salts and prodrugs of the monomethyl compounds and esters thereof. 44. A compound characterized in that it is selected from the group consisting of: Y and pharmaceutically acceptable salts thereof. 45. A compound characterized in that it is selected from the group consisting of: and monomethyl esters thereof and salts pharmaceutically acceptable and prodrugs of the monomethyl compounds and esters thereof. 46. A compound characterized in that it is selected from the group consisting of: 25 H3C X ^ .OH X. 20 25 H3C -A O.H 10 15 20 25 25 and pharmaceutically acceptable salts thereof. 47. The compound according to any of claims 1-7, 11-14, or 43-46, characterized in that it is in the form of a co-crystal. 48. A pharmaceutical composition characterized in that it comprises a therapeutically effective amount of the compound according to any of claims 1-7, 11-14, or 43-46. 49. The pharmaceutical composition according to claim 48, characterized in that it is a form selected from the group consisting of a controlled release composition, transdermal patch, tablet, hard capsule and soft capsule. 50. The pharmaceutical composition according to claim 48, characterized in that the pharmaceutical composition comprises a crystalline form of the compound. 51. The pharmaceutical composition according to claim 48, characterized in that it comprises a salt form of the compound. 52. The pharmaceutical composition according to claim 48, characterized in that it is administered orally in a unit dose of about 0.375 μg / kg to 3,375 mg / kg. 53. The pharmaceutical composition according to claim 48, characterized in that it is administered orally in a total dose daily 0.375 μg / kg / day up to about 3.75 mg / kg / day, equivalent of the free acid. 54. The use of phosphonic acid-containing compounds according to any of claims 1-7, 11-14 or 43-46 or a pharmaceutically acceptable salt thereof, or prodrugs thereof or pharmaceutically acceptable salts of the prodrugs in the manufacture of a medicament for preventing or treating a metabolic disease, wherein the phosphonic acid-containing compound binds to a thyroid receptor. 55. The use according to claim 54, wherein the phosphonic acid-containing compound is linked to a thyroid receptor with a Ki of < 1 μM. 56. The use according to claim 55, wherein the thyroid receptor is TRal. 57. The use according to claim 55, wherein the thyroid receptor is TRßl. 58. The use according to claim 55, wherein the phosphonic acid-containing compound is linked to a thyroid receptor with a Ki of < 100 nM. 59. The use according to claim 58, wherein the thyroid receptor is TRal. 60. The use according to claim 58, wherein the thyroid receptor is TRßl. 61. The use according to claim 54, wherein the metabolic disease is selected from the group consisting of obesity, hypercholesterolemia, hyperlipidemia, atherosclerosis, coronary heart disease and hypertension. 62. The use according to claim 61, wherein the metabolic disease is selected from the group consisting of obesity, hypercholesterolemia, and hyperlipidemia. 63. The use according to claim 62, wherein the metabolic disease is hypercholesterolemia. 64. The use according to claim 54, wherein the metabolic disease is fatty liver / steatosis, NAFLD, or NASH. 65. The use according to claim 54, wherein the metabolic disease is selected from the group consisting of impaired tolerance to glucose, diabetes and metabolic syndrome X. 66. The use according to claim 54, wherein the compound that contains fosfonico acid activates the receiver of the thyroid. 67. The use according to claim 66, in where the thyroid receptor is TRal. 68. The use according to claim 66, wherein the thyroid receptor is TRßl. 69. The use according to claim 54, wherein the phosphonic acid-containing compound increases the mRNA expression of a gene selected from the group consisting of the LDL ,, ACC, FAS, spot 14, CPT 1, CYP7A, apo AI, and mGPDH. 70. The use of a phosphonic acid-containing compound according to any of claims 1-7, 11-14, or 43-46, in the manufacture of a medicament for activating a thyroid receptor in an animal, wherein activation results in 50% or greater increase in mRNA expression of a gene selected from the group consisting of of the LDL receptor, ACC, FAS, spot 14, CPT 1, CYP7A, apo AI, and mGPDH. 71. The use according to claim 70, wherein the phosphonic acid-containing compound is linked to a thyroid receptor with a Ki of < 1 μM. 72. The use according to claim 71, wherein the phosphonic acid-containing compound is linked to a thyroid receptor with a Ki of < 100 nM. 73. A compound of Formula X: (Ar ^ -G-ÍAr2) -T-X characterized in that: Ar1 and Ar2 are aryl groups; G is an atom or group of atoms linked to Ar1 and Ar2 through a single atom C, S, Se, O, or N, or through two atoms where one atom is C and the other atom is C, S, or 0; T is an atom or group of atoms linked to Ar2 up to X through 1-4 contiguous atoms or is absent; X is a phosphonic acid or monoster of phosphonic acid or prodrug thereof; wherein the compound has a Ki of < 150 nM in relation to T3; with the conditions of the compound is not: b) c) or 74. A method for improving liver-to-heart selectivity of a thyromimetic compound of formula Y: (Arx) -G- (Ar2) -T-E characterized in that: Ar1 and Ar2 are aryl groups; G is an atom or group of atoms that are linked to Ar1 and Ar2 through a single atom C, S, Se, O, or N, or through two atoms where one atom is C and the other atom is C, S, or O; T is an atom or group of atoms linked to Ar2 up to E a through 1-4 contiguous atoms or is absent; E is selected from the group consisting of a group or functional portion with a pKa = 7.4, a carboxylic acid moiety or an atom or group of atoms containing an O or N that is linked to the hormone binding cavity of the thyroid of a TRa or TRβ, which comprises the step of replacing E with a phosphonic acid or monoester of phosphonic acid or prodrug thereof. 75. A method for increasing the therapeutic index of a thyromimetic compound of the formula Y: (Ar ^ -GAAr2) -T-E characterized in that: Ar1 and Ar2 are aryl groups; G is an atom or group of atoms that are linked to Ar1 and Ar2 through a single atom C, S, Se, O, or N, or through two atoms where one atom is C and the other atom is C, S, or O; T is an atom or group of atoms linked to Ar2 up to E through 1-4 atoms or is absent; E is selected from the group consisting of a functional group or moiety with a pKa = 7.4, a carboxylic acid moiety or an atom or group of atoms containing an O or N linking the thyroid hormone binding cavity of a TRa or TRβ, comprising the step of replacing E with a -P (0) (OH) 2 or prodrug thereof. 76. A method for designating a thyromimetic compound with improved selectivity of the liver against the heart comprising the steps of: Obtaining a molecular formula for a thyromimetic of the formula Y: (Arx) -G- (Ar2) -TE characterized in that: Ar1 and Ar2 they are aryl groups; G is an atom or group of atoms that are linked to Ar1 and Ar2 through a single atom C, S, Se, 0, or N, or through two atoms where one atom is C and the other atom is C, S, or O; T is an atom or group of atoms linked to Ar2 up to E through 1-4 contiguous atoms or is absent; E is selected from the group consisting of a functional group or moiety with a pKa = 7.4, a carboxylic acid moiety, or an atom or group of atoms containing an 0 or N that link the thyroid hormone binding cavity of a TRa or TRβ; comprising the step of replacing E with a phosphonic acid or monoester of phosphonic acid or prodrug thereof; and synthesizing a compound of Formula X wherein X is -P (O) (OH) 2 acid or prodrug thereof. 77. A method for designating a thyromimetic compound with an improved therapeutic index comprising the steps of: Obtain a molecular formula of a thyromimetic of the formula Y: (Ar ^ -G- (Ar2) -TE characterized because: Ar1 and Ar2 are aryl groups, G is an atom or group of atoms that are linked to Ar1 and Ar2 through a single atom C, S, Se, O, or N, or through two atoms where one atom is C and the other atom is C, S, or O; T is an atom or group of atoms bound to Ar2 through E through 1-4 atoms or is absent; E is selected from the group consisting of a functional group or moiety with a pKa = 7.4, a carboxylic acid moiety, or an atom or group of atoms containing O or N which binds the thyroid hormone binding cavity of a TRa or TRβ, comprising the step of replacing E with a phosphonic acid or phosphonic acid monoester or prodrug thereof, and synthesizing a compound of Formula X wherein X is -P (0) (OH) 2 acid or prodrug thereof.
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