EP1891080A2 - Neue phosphorhaltige thyromimetika - Google Patents

Neue phosphorhaltige thyromimetika

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Publication number
EP1891080A2
EP1891080A2 EP06760469A EP06760469A EP1891080A2 EP 1891080 A2 EP1891080 A2 EP 1891080A2 EP 06760469 A EP06760469 A EP 06760469A EP 06760469 A EP06760469 A EP 06760469A EP 1891080 A2 EP1891080 A2 EP 1891080A2
Authority
EP
European Patent Office
Prior art keywords
optionally substituted
alkyl
group
aryl
atoms
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06760469A
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English (en)
French (fr)
Inventor
Mark D. Erion
Hongjian Jiang
Serge H. Boyer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Metabasis Therapeutics Inc
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Metabasis Therapeutics Inc
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Publication date
Priority claimed from US11/137,773 external-priority patent/US7514419B2/en
Application filed by Metabasis Therapeutics Inc filed Critical Metabasis Therapeutics Inc
Publication of EP1891080A2 publication Critical patent/EP1891080A2/de
Withdrawn legal-status Critical Current

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    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
    • C07F9/65517—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
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    • C07F9/30—Phosphinic acids R2P(=O)(OH); Thiophosphinic acids, i.e. R2P(=X)(XH) (X = S, Se)
    • C07F9/32—Esters thereof
    • C07F9/3205—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
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    • C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
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    • C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
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    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
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    • C07F9/40—Esters thereof
    • C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
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    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/44—Amides thereof
    • C07F9/4403—Amides thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4407—Amides of acyclic saturated acids which can have further substituents on alkyl
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    • C07F9/28—Phosphorus compounds with one or more P—C bonds
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    • C07F9/44—Amides thereof
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    • C07F9/44—Amides thereof
    • C07F9/4461—Amides thereof the amide moiety containing a substituent or a structure which is considered as characteristic
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    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
    • C07F9/657181—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative

Definitions

  • T3 is metabolized to inactive metabolites via a variety of pathways, including pathways involving deiodination, glucuronidation, sulfation, deamination, and decarboxylation. Most of the circulating T4 and T3 is eliminated through the liver.
  • THs have profound physiological effects in animals and humans.
  • Hyperthyroidism is associated with increased body temperature, general nervousness, weight loss despite increased appetite, muscle weakness and fatigue, increased bone resorption and enhanced calcification, and a variety of cardiovascular changes, including increased heart rate, increased stroke volume, increased cardiac index, cardiac hypertrophy, decreased peripheral vascular resistance, and increased pulse pressure. Hypothyroidism is generally associated with the opposite effects.
  • Lp(a) is a hepatic acute phase protein that promotes the binding of LDL to cell surfaces independent of LDL receptors. Accordingly, Lp(a) is thought to provide supplementary cholesterol to certain cells, e.g., cells involved in inflammation or repair. Lp(a) is an independent risk factor for premature atherosclerosis. Lp(a) is synthesized in the liver.
  • TH therapy is reported to stimulate hepatic gluconeogenesis. Enzymes specific to gluconeogenesis and important for controlling the pathway and its physiological role of producing glucose are known to be influenced by TH therapy. Phosphoenolpyruvate carboxykinase (PEPCK) is upregulated by TH (Park et al, J. Biol. Chem. 274:211 (1999)) whereas others have found that glucose 6-phosphatase is upregulated (Feng et al., MoI. Endocrinol. 14:947 (2000)). TH therapy is also associated with reduced glycogen levels.
  • PEPCK Phosphoenolpyruvate carboxykinase
  • FIG. 1b depicts the dose response of serum cholesterol levels to
  • Figure 3 a depicts the effect of Compound 17 on the weight of the heart in cholesterol fed rats.
  • Figure 3b depicts the effect of Compound 7 on the weight of the heart in cholesterol fed rats.
  • Figure 4a depicts the effect of Compound 17 on cardiac GPDH activity in cholesterol fed rats.
  • Figure 4b depicts the effect of Compound 7 on cardiac GPDH activity in cholesterol fed rats.
  • Figure 5 depicts the dose response of serum cholesterol levels to
  • 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 diastereomeric enriched mixtures, and individual stereoisomers of the compounds of Formula I, II, III, VIII, and X and prodrugs thereof.
  • Carbocyclic aryl groups are groups which have 6-14 ring atoms wherein the ring atoms on the aromatic ring are carbon atoms.
  • Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and polycyclic or fused compounds such as optionally substituted naphthyl groups.
  • -aralkyl refers to an alkylene group substituted with an aryl group. Suitable aralkyl groups include benzyl, picolyl, and the like, and may be optionally substituted. "Heteroarylalkyl” refers to an alkylene group substituted with a heteroaryl group.
  • acyl refers to -C(O)R where R is alkyl, heterocycloalkyl, or aryl.
  • -carboxylamido refers to -CONR 2 where each R is independently hydrogen or alkyl.
  • halogen refers to -F, -Cl, -Br and -I.
  • sulphonyl or “sulfonyl” refers to -SO 2 R, where R is H, alkyl, aryl, aralkyl, or heterocycloalkyl.
  • alkenyl refers to unsaturated groups which have 2 to 12 atoms and contain at least one carbon-carbon double bond and includes straight-chain, branched-chain and cyclic groups. Alkenyl groups may be optionally substituted. Suitable alkenyl groups include allyl. "1 -alkenyl” refers to alkenyl groups where the double bond is between the first and second carbon atom. If the 1 -alkenyl group is attached to another group, e.g., it is a W substituent attached to the cyclic phosphonate, it is attached at the first carbon.
  • 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 atom. If the 1 -alkynyl group is attached to another group, e.g., it is a W substituent attached to the cyclic phosphonate, it is attached at the first carbon.
  • aryloxyalkyl- refers to an alkyl group substituted with an aryloxy group.
  • alkylthio- refers to the group alkyl-S-.
  • R and R 1 include -H, alkyl, aryl, aralkyl, and heterocycloalkyl.
  • acylalkyl refers to an alkyl-C(O)-alk-, where “alk” is alkylene.
  • heteroarylalkyl refers to an alkylene group substituted with a heteroaryl group.
  • surrogates of carboxylic acid refers to groups that possess near equal molecular shapes and volumes as carboxylic acid and which exhibit similar physical and biological properties.
  • examples of surrogates of carboxylic acid include, but are not limited to, tetrazole, 6-azauracil, acylsulphonamides, thiazolidinedione, hydroxamic acid, oxamic acid, malonamic acid, and carboxylic acid amides.
  • the ratio of the compound of the present invention to co-crystal former or solvent may be specified as stoichiometric or non-stoichiometric. 1:1, 1.5:1, 1:1.5, 2:1, 1:2, and 1:3 ratios of APLco-crystal former/solvent are examples of stoichiometric ratios.
  • patient means an animal.
  • Prodrugs must undergo some form of a chemical transformation to produce the compound that is biologically active or is a precursor of the biologically active compound, hi some cases, the prodrug is biologically active, usually less than the drug itself, and serves to improve drug efficacy or safety through improved oral bioavailability, and/or pharmacodynamic half-life, etc.
  • Prodrug forms of compounds may be utilized, for example, to improve bioavailability, improve subject acceptability such as by masking or reducing unpleasant characteristics such as bitter taste or gastrointestinal irritability, alter solubility such as for intravenous use, provide for prolonged or sustained release or delivery, improve ease of formulation, or provide site-specific delivery of the compound.
  • Prodrugs are described in The Organic Chemistry of Drug Design and Drag Action, by Richard B.
  • esters are possible in which a cyclic alkyl ring is formed. These esters have been shown to generate phosphorus-containing nucleotides inside cells through a postulated sequence of reactions beginning with deesterification and followed by a series of elimination reactions ⁇ e.g., Freed et al, Biochem. Pharm, 35:3193-3198 (1989)).
  • alkyloxycarbonyloxymethyl esters as shown in formula A, where 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 ⁇ -lactam antibiotics (Nishimura et ah, J. Antibiotics 40(l):Sl-90 (1987); for a review see Ferres, H., Drugs of Today, 19:499 (1983)). More recently Cathy, M. S. et al.
  • R is -H, alkyl, aryl, alkylaryl, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino, or cycloalkyl.
  • Y is -H, alkyl, aryl, alkylaryl, alkoxy, acyloxy, halogen, amino, alkoxycarbonyl, hydroxy, cyano, and heterocycloalkyl.
  • prodrugs of Formula E-3 are an example of "optionally substituted heterocycloalkyl where the cyclic moiety contains a carbonate or thiocarbonate.”
  • Propyl phosphonate proesters can also be used to deliver drugs into hepatocytes. These proesters may contain a hydroxyl and hydroxyl group derivatives at 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 oxygens of the phosphonate can be esterified.
  • prodrugs are possible based on literature reports such as substituted ethyls, for example, bis(trichloroethyl)esters as disclosed by McGuigan, et al, Bioorg Med. Chem. Lett. 3:1207-1210 (1993), and the phenyl and benzyl combined nucleotide esters reported by Meier, C. et al, Bioorg. Med. Chem. Lett. 7:99-104 (1997).
  • substituted ethyls for example, bis(trichloroethyl)esters as disclosed by McGuigan, et al, Bioorg Med. Chem. Lett. 3:1207-1210 (1993), and the phenyl and benzyl combined nucleotide esters reported by Meier, C. et al, Bioorg. Med. Chem. Lett. 7:99-104 (1997).
  • spot- 14 refers to a 17 kilodalton protein expressed in lipogenic tissues and is postulated to play a role in thyroid hormone stimulation of lipogenesis. (Campbell, MC et al, Endocrinology /0:1210 (2003).
  • CPT- 1 refers to carnitine palmitoyltransferase- 1.
  • nephrotic syndrome refers to a condition of heavy glomerular proteinuria which is associated with hyperlipidemia, increased risk of cardiovascular disease, and deterioration of renal function.
  • the nephrotic dyslipidemia is marked by hypercholesterolemia, hypertriglyceridemia, and elevated plasma concentration and impaired clearance of LDL, VLDL, and IDL.
  • Atherogenic dyslipidemia blood fat disorders — mainly high triglycerides and low HDL cholesterol — that foster plaque buildups in artery walls
  • Insulin resistance or glucose intolerance the body can't properly use insulin or blood sugar
  • thyroid responsive element refers to an element that usually consists of directly repeated half-sites with the consensus sequence AGGTCA. (Harbers et al, Nucleic Acids Res. 24(12):2252-2259 (1996)). TREs contain two half-sites of the AGGTCA motif which can be arranged as direct repeats, inverted repeats, or everted repeats.
  • 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 "significant” or “statistically significant” means a result (i.e. experimental assay result) where the p-value is ⁇ 0.05 (i.e. the chance of a type I error is less than 5%) as determined by an art-accepted measure of statistical significance appropriate to the experimental design. [0185] All references cited herein are incorporated by reference in their entirety.
  • phosphonic acids were thought to be a poor replacement for carboxylic acids based on differences in geometry, size, and charge. Phosphonic acids can also show reduced binding affinities against enzymes that utilize or bind the analogous carboxylic acid. Phosphonic acids can 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 thought to be important for binding and activation of T3 responsive genes. The carboxylic acid may also be important in the transport and distribution of these compounds through various transport proteins. Transport proteins can enhance transport of certain compounds, particularly negatively charged compounds, to the nucleus. .
  • the present Inventors discovered that the compounds of the present invention are effective in activating thyroid hormone responsive genes and for the uses described herein, such as lowering cholesterol, even for compounds of the present invention that bind to the thyroid hormone receptors with reduced affinity as compared to the corresponding carboxylic acid derivative. Still further surprisingly, the present Inventors discovered that the compounds of the present invention have a high enough tissue selectivity and have a therapeutic index great enough to be efficacious in treating the diseases and disorders described herein while avoiding undesired side-effects involving the heart.
  • the phosphonic acid- or phosphonic acid monoester- containing compounds, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs used in these methods cause at least a 50%, 2 fold, 3 fold, 4 fold, 6 fold or 8 fold increase or decrease in the expression of one or more thyroid hormone-responsive genes. Changes in gene expression can be detected in cells or in vivo. Prodrugs of the phosphonic acid- or phosphonic acid monoester-containing compounds can increase cellular uptake but in some cases are poorly converted to the phosphonic acid or monoester due to low levels of the enzymes required for the conversion.
  • the liver is a major target organ of thyroid hormone with an estimated
  • T3 mimetics in these methods would minimize effects on thyroid function, thyroid production of circulating iodinated thyronines such as T3 and T4, and/or the ratio of T3 to T4.
  • the compounds or the present invention distribute more readily to the liver and result in pharmacological effects at doses that do not adversely affect thyroid function, thyroid production of circulating iodinated thyronines such as T3 and T4, and/or the ratio of T3 to T4.
  • the phosphonic acid- or phosphonic acid monoester-containing thyromimetics and their prodrugs and salts are useful for significantly lowering cholesterol levels without having a significant effect on TSH levels, hi another embodiment, the compounds of the present invention significantly lower cholesterol levels without lowering TSH levels by more than 30%, 25%, 20%, 15%, 10%, or 5%.
  • Mitochondria are the fuel source for all cellular respiration.
  • the synthesis of new mitochondria is a complex process which requires over 1000 genes (Goffart et al, Exp. Physiol. 88(l):33-40 (2003)).
  • the mechanisms which control mitochondrial biogenesis are not well defined, but are known to include exercise (Jones et al, Am. J. Physiol. Endocrinol. Metab. 284(1): ⁇ 96- 101 (2003)), overexpression of PGC-I (Lehman et al, J. CHn. Invest. 106(7):847-56 (2000)) or AMP activated protein kinase (Bergeron et al, Am. J. Physiol Endocrinol.
  • phosphonic acid- or phosphonic acid monoester- containing thyromimetics and their prodrugs and salts may be used to cause weight loss or prevent weight gain without side effects. It may be advantageous to use compounds that result in high liver specificity (Examples F and G).
  • compounds that result in increased levels of genes associated with oxygen consumption, e.g., GPDH (Example B) are particularly useful in weight loss and controlling weight gain.
  • compounds that show weight loss at doses that do not affect cardiac function e.g., heart rate, force of systolic contraction, duration of diastolic relaxation, vascular tone, or heart weight, may be particularly useful in weight loss and controlling weight gain.
  • compounds that cause weight loss without affecting thyroid function, thyroid production of circulating iodinated thyronines such as T3 and T4, and/or the ratio of T3 to T4 are particularly useful.
  • Compounds of this invention while they mimic T3, result in preferential activation of liver T3 genes, are not expected to increase lipolysis in peripheral tissues which is expected to avoid the T3-induced higher circulating levels of free fatty acids and their effects on increasing gluconeogenesis flux and decreasing insulin sensitivity. Increased hepatic insulin sensitivity will decrease PEPCK and glucose 6-phosphatase gene expression thus reducing gluconeogenesis. TR activation in the liver should also decrease liver fat content, which in turn is expected to improve diabetes and steatohepatitis ⁇ e.g., NASH), thus providing another use for the compounds of the present invention.
  • TH therapy results in increased energy expenditure. Increased energy expenditure can result in increased weight loss, which in turn can result in improved glycemic control. Diet and exercise are often used initially to treat diabetics. Exercise and weight loss increase insulin sensitivity and improve glycemia. Thus, further uses of the compounds of the present invention include increasing energy expenditure, increasing insulin sensitivity and improving glycemia.
  • 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 disclosed herein, e.g., lowering cholesterol, and the dose at which a significant effect on a property or function, as disclosed herein (e.g., heart rate), is observed, is at least 50 fold, 100 fold, 200 fold, 300 fold, 400 fold, 500 fold, 600 fold, 700 fold, 800 fold, 900 fold, 1000 fold, 2000 fold, 3000 fold, 4000 fold, 5000 fold, 6000 fold, 7000 fold, 8000 fold, 9000 fold or at least 10000 fold.
  • a therapeutic index defined as the difference between the dose at which a significant effect is observed for a use disclosed herein, e.g., lowering cholesterol, and the dose at which a significant effect on a property or function, as disclosed herein (e.g., heart rate), is observed, is at least 50 fold, 100 fold, 200 fold, 300 fold, 400 fold, 500 fold, 600 fold, 700 fold, 800 fold, 900
  • Examples of said use disclosed herein includes but is not limited to reducing lipid levels, increasing the ratio of HDL to LDL or apoAI to LDL, reducing weight or preventing weight gain, maintaining or improving glycemic control, lowering blood glucose levels, increasing mitochondrial biogenesis, increasing expression of PGC-I, AMP activated protein kinase or nuclear respiratory factor, inhibiting 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, thyroid disease, thyroid cancer, depression, glaucoma, cardiac arrhythmias, heart failure, and osteoporosis.
  • a disease or disorder selected from the group consisting of atherosclerosis, hypercholesterolemia, hyperlipidemia, obesity, fatty liver
  • cardiac property/function examples include but are not limited to cardiac hypertrophy (heart weight to body weight ratio), heart rate, and various hemodynamic parameters, including systolic and diastolic arterial pressure, end systolic left ventricular pressure and maximal speeds of contraction and relaxation.
  • genes such as spot-14, FAS, mGPDH, CPT-I, and LDL receptor are monitored. Changes of >1.5 fold in two or more genes is considered proof that the compound modulates T3 -responsive genes in vivo.
  • Alternative methods for measuring changes in gene transcription include monitoring the activity or expression level of the protein encoded by the gene. For instance, in cases where the genes encode enzyme activities (e.g., FAS, mGPDH), direct measurements of enzyme activity in appropriately extracted liver tissue can be made using standard enzymological techniques. In cases where the genes encode receptor functions (e.g., the LDL receptor), ligand binding studies or antibody-based assays (e.g., Western blots) can be performed to quantify the number of receptors expressed.
  • the effect on cholesterol is determined using cholesterol fed animals such as normal rats and hamsters, or TRa " " knockout mice. Cholesterol is measured using standard tests.
  • Compounds of the present invention were tested using the methods described in Example D and I. Hepatic glycogen levels are determined from livers isolated from treated animals. Compounds of the present invention were tested using the methods described in Examples D and E. Changes in energy expenditure are monitored by measuring changes in oxygen consumption (MVo )• A variety of methods are well described in the literature and include measurement in the whole animal using Oxymax chambers (U.S. Patent No. 6,441,015). Livers from treated rats can also be evaluated (Fernandez et ah, Toxicol. Lett.
  • Another aspect is 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.
  • Also provided are methods of reducing plasma lipid levels in an animal 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.
  • said compound is an active form, m another embodiment said compound is a prodrug.
  • said compound of Formula I, II, III, VIII, and X or a prodrug thereof comprises a stereocenter, is enantiomerically enriched or diastereomerically enriched, or a stereoisomer covered later.
  • said compound is administered as a racemic mixture.
  • said compound is administered as an enantiomerically enriched mixture.
  • said compound is a administered as a diastereomerically enriched mixture.
  • said compound is administered as an individual stereoisomer.
  • said compound is an active form.
  • said compound is a prodrug.
  • said compound of Formula I, II, III, VIII, and X or a prodrug thereof comprises a stereocenter.
  • said compound is administered as a racemic mixture.
  • said compound is administered as an enantiomerically enriched mixture.
  • said compound is administered as a diastereomeric mixture.
  • said compound is administered as an individual stereoisomer.
  • said methods of reducing cholesterol results in a lowering of total cholesterol.
  • said methods of reducing cholesterol results in a reduction of high density lipoprotein (HDL).
  • said methods of reducing cholesterol results in a reduction of low density lipoprotein (LDL).
  • said methods of reducing cholesterol results in a reduction of very low density lipoprotein (VLDL).
  • said LDL is reduced to a greater extent than said HDL.
  • said VLDL is reduced to a greater extent than said HDL.
  • said VLDL is reduced to a greater extent than said LDL.
  • the lipid is triglycerides, hi one embodiment said lipid is liver triglycerides, hi another embodiment said lipid is in the form of a lipoprotein, hi another embodiment said lipoprotein is Lp(a). hi another embodiment said lipoprotein is apoAII.
  • HDL to VLDL, LDL to VLDL, apoAl to LDL or apoAI to VLDL in an animal 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.
  • said compound is an active form.
  • said compound is a prodrug.
  • said compound of Formula I, II, III, VIII and X, or a prodrug thereof comprises a stereocenter.
  • said compound is administered as a racemic mixture.
  • said compound is administered as an enantiomerically enriched mixture.
  • said compound is administered as a diastereomeric mixture.
  • said compound is administered as an individual stereoisomer.
  • said compound is an active form, hi another embodiment said compound is a prodrug, hi another embodiment said compound of Formula I, II, III, VIII, and X or a prodrug thereof comprises a stereocenter.
  • said compound is administered as a racemic mixture.
  • said compound is administered as an enantiomerically enriched mixture.
  • said compound is a administered as a diastereomeric mixture, hi still another embodiment said compound is administered as an individual stereoisomer.
  • said compound is administered as a racemic mixture, hi another embodiment said compound is administered as an enantiomerically enriched mixture, hi another embodiment said compound is a administered as a diastereomeric mixture, hi still another embodiment said compound is administered as an individual stereoisomer.
  • Also provided are methods of reducing weight or preventing weight gain in an animal 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.
  • said compound is an active form.
  • said compound is a prodrug.
  • said compound of Formula I, II, III, VIII, and X or a prodrug thereof comprises a stereocenter.
  • said compound is administered as a racemic mixture.
  • said compound is administered as an enantiomerically enriched mixture.
  • said compound is a administered as a diastereomeric mixture.
  • said compound is administered as an individual stereoisomer.
  • Also provided are methods of preventing or treating obesity in an animal 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, hi one embodiment said compound is an active form.
  • Li another embodiment said compound is a prodrug, hi another embodiment said compound of Formula I, II, III, VIII, and X or a prodrug thereof comprises a stereocenter.
  • hi another embodiment said compound is administered as a racemic mixture.
  • said compound is administered as an enantiomerically enriched mixture, hi another embodiment said compound is a administered as a diastereomeric mixture, hi still another embodiment said compound is administered as an individual stereoisomer.
  • Also provided are methods of preventing or treating coronary heart disease in an animal 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, hi one embodiment said compound is an active form, hi another embodiment said compound is a prodrug, hi another embodiment said compound of Formula I, II, III, VIII, and X or a prodrug thereof comprises a stereocenter.
  • hi another embodiment said compound is administered as a racemic mixture
  • hi another embodiment said compound is administered as an enantiomerically enriched mixture
  • hi another embodiment said compound is a administered as a diastereomeric mixture.
  • said compound is administered as an individual stereoisomer.
  • Also provided are methods of maintaining or improving glycemic control in an animal being treated with a T3 mimetic 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.
  • said compound is an active form.
  • said compound is a prodrug.
  • Li another embodiment said compound of Formula I, II, III, VIII, and X or a prodrug thereof comprises a stereocenter.
  • said compound is administered as a racemic mixture.
  • said compound is administered as an enantiomerically enriched mixture, hi another embodiment said compound is administered as a diastereomeric mixture.
  • Also provided are methods of lowering blood glucose levels in an animal 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, hi one embodiment said compound is an active form, hi another embodiment said compound is a prodrug.
  • said compound of Formula I, II, III, VIII, and X or a prodrug thereof comprises a stereocenter.
  • said compound is administered as a racemic mixture, hi another embodiment said compound is administered as an enantiomerically enriched mixture.
  • said compound is a administered as a diastereomeric mixture, hi still another embodiment said compound is administered as an individual stereoisomer.
  • Also provided are methods of preventing or treating thyroid disease, thyroid cancer, depression, glaucoma, cardiac arrhythmias, heart failure, or osteoporosis in an animal 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.
  • said compound is an active form.
  • said compound is a prodrug, hi another embodiment said compound of Formula I, II, III, VIII, and X or a prodrug thereof comprises a stereocenter.
  • said compound is administered as a racemic mixture.
  • said compound is administered as an enantiomerically enriched mixture, hi another embodiment said compound is a administered as a diastereomeric mixture, hi still another embodiment said compound is administered as an individual stereoisomer.
  • Also provided are methods of increasing mitochondrial biogenesis in an animal 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, hi one embodiment said compound is an active form, hi another embodiment said compound is a prodrug, hi another embodiment said compound of Formula I, II, III, VIII, and X or a prodrug thereof comprises a stereocenter.
  • Also provided are methods of increasing expression of PGC-I, AMP activated protein kinase or nuclear respiratory factor in an animal 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.
  • said compound is an active form.
  • said compound is a prodrug.
  • said compound of Formula I, II, III, VIII, and X or a prodrug thereof comprises a stereocenter.
  • said compound is administered as a racemic mixture.
  • said compound is administered as an enantiomerically enriched mixture.
  • said compound is a administered as a diastereomeric mixture.
  • said compound is administered as an individual stereoisomer.
  • the compounds of the present invention may be either crystalline, amorphous or a mixture thereof.
  • Compositions comprising a crystalline form a compound of the present invention may contain only one crystalline form of said compound or more than one crystalline form.
  • the composition may contain two or more different polymorphs. The polymorphs
  • compositions herein having a base functional group are also included in the present invention.
  • Pharmaceutically acceptable acid addition salts refer to those salts which retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic acid or an organic acid to the free base.
  • Salts derived from inorganic acids include, but are not limited to, acistrate, hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, besylate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulphonate. bromide, fumarate, pamoate, glucouronate, hydroiodide, iodide, sulfate, xinofoate and chloride salts
  • the compound of Formula X is a compound of Formula I wherein G is -O-, T is -(CH 2 ) 0 - 4 -, R 1 and R 2 are independently halogen, alkyl of 1 to 3 carbons, and cycloalkyl of 3 to 5 carbons, R 3 is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 7 carbons, R 4 is hydrogen, and R 5 is -OH, then X is not -P(O)(OH) 2 or -P(O)(O-lower alkyl) 2 .
  • Ar 1 and Ar 2 are aryl groups
  • G is an atom or group of atoms that links Ar 1 and Ar 2 through a single C, S, Se, O, or N atom or through two C atoms or through one C and one S atom or through one C and one O atom, wherein C and N are substituted;
  • the compound has a Ki ⁇ 15OnM.
  • Another embodiment includes a pharmaceutical composition comprising the compound and a at least one excipient.
  • the pharmaceutical composition has a bioavailability of at least 15%.
  • the compound is crystalline.
  • the pharmaceutical composition is a unit dose.
  • the invention relates to a compound of Formula I:
  • R 54 is hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
  • R 53 is selected from hydrogen, halogen, hydroxyl, mercapto, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, Ci-C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; and
  • Each R a is independently selected from the group consisting of hydrogen, optionally substituted -Ci-C 4 alkyl, halogen, -OH, optionally substituted -0-C 1 -C 4 alkyl, -OCF 3 , -OCHF 2 , -OCH 2 F, optionally substituted -S-Ci-C 4 alkyl, -NR b R c , optionally substituted -C 2 -C 4 alkenyl, and optionally substituted -C 2 -C 4 alkynyl; with the proviso that when one R a is attached to C through an O, S, or N atom, then the other R a attached to the same C is a hydrogen, or attached via a carbon atom;
  • Each R b is independently selected from the group consisting of hydrogen and optionally substituted -C 1 -C 4 alkyl;
  • R 1 and R 2 are each independently selected from the group consisting of halogen, optionally substituted -Ci-C 4 alkyl, optionally substituted -S-Ci-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 , -OCHF 2 , -OCH 2 F, optionally substituted -0-C 1 -C 3 alkyl, and cyano;
  • Each R d 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 -(CR b 2 ) n aryl, optionally substituted -(CR b 2 ) n cycloalkyl, optionally substituted
  • 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 12 alkenyl, optionally substituted -C 2 -C 12 alkynyl, optionally substituted -(CR b 2 ) n aryl, optionally substituted -(CR b 2 ) n cycloalkyl, and optionally substituted -(CR b 2 ) n heterocycloalkyl, or R f and R s may together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsarurations, which may contain a second heterogroup selected from the group of O, NR C , and S, wherein said optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting of optionally substituted -Ci -C 4 alkyl, -OR b , oxo, cyan
  • Y and Y' are each independently selected from the group consisting of-0-, and -NR V -; when Y and Y' are both -0-, R 11 attached to -O- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, -C(R Z ) 2 OC(O)NR Z 2 , -NR z -C(0)-R y , -C(R z ) 2 -0C(0)R y , -C(R z ) 2 -0-C(0)0R y , -C(R z ) 2 0C(0)SR y , -alkyl-S-C(O)R y , -alkyl-S-S-alky
  • Z is selected from the group consisting of -CHR 2 OH, -CHR 2 OC(O)R 5 ',
  • Each R 2 is selected from the group consisting of R y and -H;
  • Each R y is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl;
  • Each R x is independently selected from the group consisting of -H, and alkyl, or together R x and R x form a cycloalkyl group;
  • Each R v is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the provisos that: a) V, Z, W, W are not all -H; and b) when Z is -R z , 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 said prodrugs.
  • the invention relates to a compound of Formula I:
  • G, T, k, m, n, p, R a , R b , R c , R 1 , R 2 , R 3 , R 4 , R d , R e , R f , R g , R h , R 5 , X, V, W, W, Z, q, R z , R y , R x , and R v are as defined above;
  • Y and Y' are each independently selected from the group consisting of-O-, and -NR V -; when Y and Y' are both -O-, R 11 attached to -O- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, -C(R Z ) 2 OC(O)NR Z 2 , -NR z -C(O)-R y , -C(R z ) 2 -OC(O)R y , -C(R z ) 2 -O-C(O)OR y , -C(R z ) 2 OC(O)SR y , -alkyl-S-C(O)R y , -alky
  • R 11 attached to -NR V - is independently selected from the group consisting of -H, -[C(R z ) 2 ] q -C00R y , -C(R ⁇ 2 COOR 3 ', -[C(R z ) 2 ] q -C(O)SR y , and -cycloalkylene-COOR y
  • R 1 and R 2 are independently chosen from the group consisting of hydrogen, halogen, -C 1 -C 4 alkyl, R 3 is -C(O)NR 25 R 26 , -CH 2 -NR 25 R 26 , -NR 25 -C(O)R 26 , -OR 27 , R 28 , or R 29 ⁇ -o
  • R 4 is hydrogen, halogen, cyano or alkyl
  • R 5 is -OH
  • R 25 and R 26 are each independently selected from the group consisting of hydrogen, aryl, heteroaryl, alkyl, cycloalkyl, aralkyl or heteroaralkyl
  • R 27 is aryl, heteroaryl, alkyl, aralkyl, or heteroaralkyl
  • R 28 is aryl, heteroaryl, or cycloalkyl
  • R 29 is hydrogen, aryl, heteroaryl, alkyl, aralkyl, heteroaralkyl, then X is not -P(O)(OH) 2 , or -P(O)(O-lower alkyl) 2 ; b) when G is -0-, -S-, -Se-, -S(O)-, -S(O) 2 -, -CH 2 -, -CF 2 -, -C(O)-, -NH-
  • A is selected from the group consisting of -NR 1 -, -O-, and -S-;
  • R 1 is selected from the group consisting of hydrogen, -C(O)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
  • R 54 is hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
  • R 53 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
  • 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, -(CR a 2 )-, and -C(O)-;
  • Each R a is independently selected from the group consisting of hydrogen, optionally substituted -C 1 -C 4 alkyl, halogen, -OH, optionally substituted -0-C 1 -C 4 alkyl, -OCF 3 , -OCHF 2 , -OCH 2 F, optionally substituted -S-C 1 -C 4 alkyl, -NR b R c , optionally substituted -C 2 -C 4 alkenyl, and optionally substituted -C 2 -C 4 alkynyl; with the proviso that when one R a is attached to C through an O, S, or N atom, then the other R a attached to the same C is a hydrogen, or attached via 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, optionally substituted -S-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 , -OCHF 2 , -OCH 2 F, optionally substituted -0-C 1 -C 3 alkyl, and cyano;
  • R is selected from the group consisting of hydrogen, halogen, optionally substituted -C 1 -C 4 alkyl, optionally substituted -S-C 1 -C 3 alkyl, optionally substituted -C 2 -C 4 alkenyl, optionally substituted -C 2 -C 4 alkynyl, -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -OCH 2 F, optionally substituted -0-C 1 -C 3 alkyl, hydroxy, -(CR a 2 )aryl, -(CR a 2 )cycloalkyl, -(CR a 2 )heterocycloalkyl, -C(O)aryl, -C(O)cycloalkyl, -C(O)heterocycloalkyl, -C(O)alkyl and cyano;
  • Each R d 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 -Ci 2 alkynyl, optionally substituted -(CR b 2 ) n aryl, optionally substituted -(CR b 2 ) n cycloalkyl, optionally substituted
  • Each R e is selected from the group consisting of optionally substituted -Ci-Ci 2 alkyl, optionally substituted -C 2 -Ci 2 alkenyl, optionally substituted -C 2 -C 12 alkynyl, optionally substituted -(CR a 2 ) n aryl, optionally substituted -(CR a 2 ) n cycloalkyl, and optionally substituted -(CR a 2 ) n heterocycloalkyl;
  • R and R g are each independently selected from the group consisting of hydrogen, optionally substituted -Ci-Ci 2 alkyl, optionally substituted -C 2 -Ci 2 alkenyl, optionally substituted -C 2 -Ci 2 alkynyl, optionally substituted -(CR b 2 ) n aryl, optionally substituted -(CR b 2 ) n cycloalkyl, and optionally substituted -(CR b 2 ) n heterocycloalkyl, or R f and R s may 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, NR C , and S, wherein said optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting of optionally substituted -Ci-C 4 alkyl, -OR b , oxo, cyan
  • Each R h is selected from the group consisting of optionally substituted -Ci-Ci 2 alkyl, optionally substituted -C 2 -C 12 alkenyl, optionally substituted -C 2 -Ci 2 alkynyl, optionally substituted -(CR b 2 ) n aryl, optionally substituted -(CR b 2 ) n cycloalkyl, and optionally substituted -(CR b 2 ) n heterocycloalkyl; or
  • R 3 and R 8 are taken together along with the carbon atoms to which they are attached to form an optionally substituted ring of 5 to 6 atoms with 0- 2 unsaturations, not including the unsaturation on the ring to which R 3 and R 8 are attached, including 0 to 2 heteroatoms independently selected from -NR h -, -O-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom; or
  • R 3 and R 5 are taken together along with the carbons they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R 3 and R 5 are attached, including O to 2 heteroatoms independently selected from -NR h -, -0-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom;
  • X is P(O)YR 11 Y 5 R 11 ;
  • Y and Y' are each independently selected from the group consisting of-0-, and -NR V -; when Y and Y' are both -0-, R 11 attached to -O- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, -C(R Z ) 2 OC(O)NR Z 2 , -NR z -C(0)-R y , -C(R z ) 2 -0C(0)R y , -C(R z ) 2 -0-C(0)0R y , -C(R z ) 2 OC(O)SR y , -alkyl-S-C(O)R y , -alkyl-S-S-al
  • V, W, and W are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-alkynyl; or together V and Z are connected via an additional 3-5 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 attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or or together V and Z are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon or carbon substituted by hydrogen
  • Each R z is selected from the group consisting of R y and -H;
  • Each R y is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl;
  • Each R x is independently selected from the group consisting of -H, and alkyl, or together R x and R x form a cycloalkyl group;
  • Each R v is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the provisos that: a) V, Z, W, W are not all -H; and b) when Z is -R z , 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 said prodrugs.
  • the invention relates to a compound of Formula II:
  • A, B, R, R b , G, D, R a , R 1 , R 2 , R 8 , R 3 , R 4 , R d , ,R e , R f , R s , R h , R 5 , X, V, W, W, Z, q, R z , R y , R x , and R v are defined as above;
  • Each R z is selected from the group consisting of R y and -H;
  • Each R y is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl;
  • Each R v is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the provisos that: a) V, Z, W, W are not all -H; and b) when Z is -R z , 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 said prodrugs.
  • the invention relates to a compound of Formula III:
  • R 54 is hydrogen, halogen, Ci-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
  • R 53 is selected from hydrogen, halogen, hydroxyl, mercapto, Ci-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
  • 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;
  • Each R c is independently selected from the group consisting of hydrogen and optionally substituted -C 1 -C 4 alkyl, optionally substituted -C(O)-C 1 -C 4 alkyl, and -C(O)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 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 , -OCHF 2 , -OCH 2 F, optionally substituted -0-C 1 -C 3 alkyl, and cyano;
  • R f and R g are each independently selected from the group consisting of hydrogen, optionally substituted -Ci-Ci 2 alkyl, optionally substituted -C 2 -C 12 alkenyl, optionally substituted -C 2 -C 12 alkynyl, optionally substituted -(CR b 2 ) n aryl, optionally substituted -(CR b 2 ) n cycloalkyl, and optionally substituted -(CR b 2 ) n heterocycloalkyl, or R f and R g may 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, NR C , and S, wherein said optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting of optionally substituted -C 1 -C 4 alkyl, -OR b , oxo,
  • Each R h 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 -(CR b 2 ) n aryl, optionally substituted -(CR b 2 ) n cycloalkyl, and optionally substituted -(CR b 2 ) n heterocycloalkyl; or
  • R 3 and R 8 are taken together along with the carbon atoms to which they are attached to form an optionally substituted ring of 5 to 6 atoms with 0- 2 unsaturations, not including the unsaturation on the ring to which R 3 and R 8 are attached, including 0 to 2 heteroatoms independently selected from -NR h -, -O-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom; or
  • R 3 and R 5 are taken together along with the carbons they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R 3 and R 5 are attached, including O to 2 heteroatoms independently selected from -NR h -, -0-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom;
  • R 7 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, -0-Ci-C 4 alkyl, -OCF 3 , -OCHF 2 , -OCH 2 F, -CF 3 , -CHF 2 , -CH 2 F, cyano, -SH and -S-Ci-C 4 alkyl;
  • Y and Y' are each independently selected from the group consisting of-O-, and -NR V -; when Y and Y' are both -O-, R 11 attached to -O- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl,
  • R 11 attached to -NR V - is independently selected from the group consisting of -H, -[C(R z ) 2 ] q -C(O)OR y , -C(R x ) 2 C(O)OR y , -[C(R z ) 2 ] q -C(O)SR
  • Each R x is independently selected from the group consisting of -H, and alkyl, or together R x and R x form a cycloalkyl group;
  • Each R v is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the provisos that: a) V, Z, W, W are not all -H; and b) when Z is -R z , 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 said prodrugs.
  • the invention relates to a compound of Formula III:
  • G, T, k, m, n, p, R a , R b , R c , R 1 , R 2 , R 8 , R 3 , R 4 , R d , R e , R f , R g , R h , R 5 , R 7 , X, V, W, W, Z, q, R z , R y , R x , and R v are defined as above;
  • T is -A-B- where A is selected from the group consisting of -NR b -, -0-, -CH 2 - and -S- and B is selected from the group consisting of a bond and substituted or unsubstituted C 1 -C 3 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
  • R 54 is hydrogen, halogen, Ci-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl;
  • 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;
  • Each R a is independently selected from the group consisting of hydrogen, optionally substituted -C 1 -C 4 alkyl, halogen, -OH, optionally substituted -0-C 1 -C 4 alkyl, -OCF 3 , -OCHF 2 , -OCH 2 F, optionally substituted -S-C 1 -C 4 alkyl, -NR b R c , optionally substituted -C 2 -C 4 alkenyl, and optionally substituted -C 2 -C 4 alkynyl; with the proviso that when one R a is attached to C through an O, S, or N atom, then the other R a attached to the same C is a hydrogen, or attached via a carbon atom;
  • Each R b is independently selected from the group consisting of hydrogen and optionally substituted -C 1 -C 4 alkyl;
  • Each R c is independently selected from the group consisting of hydrogen and optionally substituted -C 1 -C 4 alkyl, optionally substituted -C(O)-C 1 -C 4 alkyl, and -C(O)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, optionally substituted -S-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 , -OCHF 2 , -OCH 2 F, optionally substituted -0-C 1 -C 3 alkyl, and cyano; with the proviso that at least one of R 1 and R 2 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, optionally substituted -S-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 , -OCHF 2 , -OCH 2 F, optionally substituted-O-Ci-C 3 alkyl, hydroxy, -(CR a 2 )aryl, -(CR a 2 )cycloalkyl, -(CR a 2 )heterocycloalkyl, -C(O)aryl, -C(O)cycloalkyl, -C(O)heterocycloalkyl, - C(O)alkyl and cyano; or R 6 and T are taken together along with
  • R 1 is selected from the group consisting of hydrogen, -C(O)C 1 -C 4 alkyl, -C 1 -C 4 alkyl, and -C 1 -C 4 -RTyI; or
  • R 1 and R 7 are taken together along with the carbons to which they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R 1 and R 7 are attached, including O to 2 heteroatoms independently selected from -NR h -, -0-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom; t is an integer from 3-6; - Ill -
  • r and s are integers from 0-5;
  • R f and R s are each independently selected from the group consisting of hydrogen, optionally substituted -C J -C I2 alkyl, optionally substituted -C 2 -C 12 alkenyl, optionally substituted -C 2 -Ci 2 alkynyl, optionally substituted -(CR b 2 ) n aryl, optionally substituted -(CR b 2 ) n cycloalkyl, and optionally substituted -(CR b 2 ) n heterocycloalkyl, or R f and R g may together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, said heterocyclic ring may contain a second heterogroup within the ring selected from the group consisting of O, NR C , and S, wherein said optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting of optionally substituted -C 1 -C 4 alkyl, -
  • R 3 and R 8 are taken together along with the carbon atoms to which they are attached to form an optionally substituted ring of 5 to 6 atoms with 0- 2 unsaturations, not including the unsaturation on the ring to which R and R are attached, including 0 to 2 heteroatoms independently selected from -NR h -, -O-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom; or
  • R 3 and R 5 are taken together along with the carbons they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R 3 and R 5 are attached, including O to 2 heteroatoms independently selected from -NR h -, -0-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom;
  • Y and Y' are each independently selected from the group consisting of-0-, and -NR V -; when Y and Y' are both -0-, R 11 attached to -O- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, -C(R Z ) 2 OC(O)NR Z 2 , -NR z -C(O)-R y , -C(R z ) 2 -OC(O)R y , -C(R z ) 2 -O-C(O)OR y , -C(R z ) 2 OC(O)SR y , -alkyl-S-C(O)R y , -alkyl-
  • V, W, and W are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-alkynyl; or together V and Z are connected via an additional 3-5 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 attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or together V and Z are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon or carbon substituted by hydrogen,
  • Each R z is selected from the group consisting of R y and -H;
  • Each R x is independently selected from the group consisting of -H, and alkyl, or together R x and R x form a cycloalkyl group;
  • Each R v is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the provisos that: a) V, Z, W, W are not all -H; and b) when Z is -R z , 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 said prodrugs.
  • the invention relates to a compound of Formula VIII:
  • G, T, k, m, n, p, R a , R b , R c , R 1 , R 2 , R 6 , R 7 , R ⁇ R 3 R 4 , R 5 , R 8 , R 9 , R d , R e , R f , R g , R h , X, V, W, W, Z, q, R z , R y , R x , and R v are defined as above;
  • Y and Y' are each independently selected from the group consisting of-O-, and -NR V -; when Y and Y' are both -O-, R 11 attached to -O- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, -C(R Z ) 2 OC(O)NR Z 2 , -NR z -C(0)-R y , -C(R z ) 2 -OC(O)R y , -C(R z ) 2 -O-C(O)OR y , -C(R z ) 2 OC(O)SR y , -alkyl-S-C(O)R y , -alkyl-
  • G, T, k, m, n, p, R a , R b , R°, R 1 , R 2 , R 6 , R 7 , R, R 3 , R 4 , R 5 , R 8 R 9 , R d , R e , R f , R g , R h , X, V, W, W, Z, q, R z , R y , R x , and R v are defined as above;
  • Y and Y' are each independently selected from the group consisting of-O-, and -NR v s when Y and Y' are both -O-, R 11 attached to -O- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl,
  • R 11 attached to -NR V - is independently selected from the group consisting of -H, -[C(R z ) 2 ] q -C(O)OR y , -C(R x ) 2 C(O)OR y , -[C(R z ) 2 ] q -C(O)SR y , and -cycloalkylene-COOR y ; when Y is -O- and Y' is NR V , then R 11 attached to -O- is independently selected from
  • R 4 is hydrogen, halogen, cyano or alkyl
  • R 5 is -OH
  • R 25 and R 26 are each independently selected from the group consisting of hydrogen, aryl, heteroaryl, alkyl, cycloalkyl, aralkyl or heteroaralkyl
  • R is aryl, heteroaryl, alkyl, aralkyl, or heteroaralkyl
  • R 28 is aryl, heteroaryl, or cycloalkyl
  • R 29 is hydrogen, aryl, heteroaryl, alkyl, aralkyl, heteroaralkyl, then X is not -P(O)(OH) 2 , or -P(O)(O-lower alkyl) 2 ; b) when G is -O-, -S-, -Se-, -S(O
  • R 50 and R 51 is oxygen and the other is -CH(R 54 )-, wherein R 54 is hydrogen, halogen, C 1 , C 2 , C 3 , or C 4 alkyl, C 2 , C 3 or C 4 alkenyl, C 2 , C 3 or C 4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl.
  • R 50 and R 51 are sulphur and the other is -CH(R 54 )-, wherein R 54 is hydrogen, halogen, Ci, C 2 , C 3 , or C 4 alkyl, C 2 , C 3 or C 4 alkenyl, C 2 , C 3 or C 4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl.
  • both R 50 and R 51 are -CH(R 53 )-, wherein R 53 is selected from hydrogen, halogen, hydroxyl, mercapto, Cj, C 2 , C 3 , or C 4 alkyl, C 2 , C 3 or C 4 alkenyl, C 2 , C 3 or C 4 alkynyl, Ci, C 2 , C 3 , or C 4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio .
  • T is -CH 2 -.
  • T is selected from the group consisting of -(CR a 2 ) n -, -O(CR b 2 )(CR a 2 ) p -, -N(R c )(CR b 2 )(CR a 2 ) p -, -S(CR b 2 )(CR a 2 ) p -, -N(R b )C(O)-, and -CH 2 CH(NR c R b )-.
  • T is -CH 2 CH(NH 2 )-.
  • T is -N(H)C(O)-.
  • T is -OCH 2 -.
  • T is -O(CR b 2 )(CR a 2 ) n - or -NH(CR b 2 )(CR a 2 ) p -.
  • T is -S(CR b 2 )(CR a 2 ) n -.
  • T is -N(R c )(CR b 2 )(CR a 2 ) n -.
  • T is -N(R b )C(O)(CR a 2 ) n -.
  • T is -(CR a 2 ) n CH(NR b R c )-. In another aspect, T is -C(O)(CR a 2 ) m -. hi a further aspect, T is -(CR a 2 ) m C(O)-. hi another aspect, T is -(CR a 2 )C(O)(CR a 2 ) n -. In a further aspect, T is -(CR a 2 ) n C(O)(CR a 2 )-. In yet another aspect, T is -C(O)NH(CR b 2 )(CR a 2 ) p -.
  • T is -O(CR b 2 )(CR a 2 ) n - or -NH(CR b 2 )(CR a 2 ) p -.
  • T is -S(CR b 2 )(CR a 2 ) n -.
  • T is -N(R°)(CR b 2 )(CR a 2 ) n -. In another aspect, T is -N(R b )C(O)(CR a 2 ) n -. In a further aspect, T is -(CR a 2 ) n CH(NR b R c )-. In another aspect, T is -C(O)(CR a 2 ) m -. hi a further aspect, T is -(CR a 2 ) m C(O)-. In another aspect, T is -(CR a 2 )C(O)(CR a 2 )n-.
  • T is -(CR a 2 ) n C(O)(CR a 2 )-.
  • T is -C(O)NH(CR b 2 )(CR a 2 ) p -.
  • T is -(CR a 2 )i-2-O-(CR a 2 )i- 2 -.
  • A is -NH-, -NMe-, -O-, and -S-.
  • A is -NR 1 -.
  • A is -O-.
  • A is -S-.
  • B is selected from
  • B is -CH-, CMe-, and -N-.
  • B is -CR b -.
  • B is -N-.
  • k is 0. hi a further aspect, k is 1. hi an additional aspect, k is 2. hi a further aspect, k is 3. hi yet another aspect, k is 4. hi one aspect m is 0. hi a further aspect, m is 1. In an additional aspect, m is 2. hi a further aspect, m is 3. hi one aspect n is 0. hi a further aspect, n is 1. hi an additional aspect, n is 2. In one aspect, p is 0. hi another aspect, p is 1.
  • each R a is hydrogen with the proviso that when one R a is attached to C through an O, S, or N atom, then the other R a attached to the same C is a hydrogen, or attached via a carbon atom, hi another aspect, each R a is optionally substituted -C 1 -C 4 alkyl with the proviso that when one R a is attached to C through an O, S, or N atom, then the other R a attached to the same C is a hydrogen, or attached via a carbon atom.
  • each R a is halogen with the proviso that when one R a is attached to C through an O, S, or N atom, then the other R a attached to the same C is a hydrogen, or attached via a carbon atom.
  • each R a is -OH with the proviso that when one R a is attached to C through an O, S, or N atom, then the other R a attached to the same C is a hydrogen, or attached via a carbon atom.
  • each R a is optionally substituted -0-C 1 -C 4 alkyl with the proviso that when one R a is attached to C through an O, S, or N atom, then the other R a attached to the same C is a hydrogen, or attached via a carbon atom.
  • each R a is -OCF 3 , -OCHF 2 , or -OCH 2 F, with the proviso that when one R a is attached to C through an O, S, or N atom, then the other R a attached to the same C is a hydrogen, or attached via a carbon atom.
  • each R a is optionally substituted -S-C 1 -C 4 alkyl with the proviso that when one R a is attached to C through an O, S, or N atom, then the other R a attached to the same C is a hydrogen, or attached via a carbon atom.
  • each R a is -NR b R c with the proviso that when one R a is attached to C through an O, S, or N atom, then the other R a attached to the same C is a hydrogen, or attached via a carbon atom.
  • each R a is optionally substituted -C 2 -C 4 alkenyl with the proviso that when one R a is attached to C through an O, S, or N atom, then the other R a attached to the same C is a hydrogen, or attached via a carbon atom.
  • each R a is optionally substituted -C 2 -C 4 alkynyl with the proviso that when one R a is attached to C through an O, S, or N atom, then the other R a attached to the same C is a hydrogen, or attached via a carbon atom.
  • R b is hydrogen. In an additional aspect, R b is optionally substituted -C 1 -C 4 alkyl.
  • R c is hydrogen. In another aspect, R c is optionally substituted -C 1 -C 4 alkyl. In a further aspect, R c is optionally substituted -C(O)-C 1 -C 4 alkyl. In yet another aspect, R c is -C(O)H. [0294] For compounds of Formula I, in one aspect, R 1 and R 2 are each bromo.
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, alkyl of 1 to 3 carbons, and cycloalkyl of 3 to
  • R and R are independently halogen, alkyl of 1 to 3 carbons, and cycloalkyl of 3 to 5 carbons, hi 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 an additional 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.
  • R 1 and R 2 are each independently selected from the group consisting of halogen, -C 1 -C 4 alkyl, -CF 3 , -CHF 2 , -CH 2 F, and cyano.
  • R and R are each independently selected from the group consisting of iodo, bromo, chloro, methyl, and cyano.
  • R 1 and R 2 are each iodo.
  • R 1 and R 2 are both alkyl.
  • R 1 and R 2 are each methyl, hi a further aspect, R 1 and R 2 are each chloro.
  • R 1 and R 2 are each independently selected from the group consisting of iodo, bromo, chloro, and methyl, hi an additional aspect, R 1 and R 2 are each halogen, hi another aspect, R 1 and R 2 are not both halogen. In another aspect, R 1 and R 2 are each optionally substituted -C 1 -C 4 alkyl. hi a further aspect, R 1 and R 2 are each optionally substituted -S-C 1 -C 3 alkyl. hi another aspect, R 1 and R 2 are each optionally substituted -C 2 -C 4 alkenyl. In a further aspect, R 1 and R 2 are each optionally substituted -C 2 -C 4 alkynyl.
  • 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.
  • R 1 and R 2 are each halogen, hi another aspect, R 1 and R 2 are not both halogen.
  • R 1 and R 2 are each optionally substituted -C 1 -C 4 alkyl.
  • R 1 and R 2 are each optionally substituted -S-C 1 -C 3 alkyl.
  • R 1 and R 2 are each optionally substituted -C 2 -C 4 alkenyl.
  • R 1 and R 2 are each optionally substituted -C 2 -C 4 alkynyl.
  • R 1 and R 2 are each -CF 3 , -CHF 2 , or -CH 2 F.
  • R 1 and R 2 are each -OCF 3 , -OCHF 2 , or -OCH 2 F.
  • R 1 and R 2 are each optionally substituted-O-Q-Cs alkyl.
  • R 1 and R 2 are each cyano.
  • R and R 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.
  • 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.
  • R 1 and R 2 are each halogen.
  • R 1 and R 2 are not both halogen.
  • R , R , R , R , R , and R are each optionally substituted -C 1 -C 4 alkyl.
  • R 1 , R 2 , R 6 , R 7 , R 8 , and R 9 are each optionally substituted -S-C 1 -C 3 alkyl.
  • R 1 , R 2 , R 6 , R 7 , R 8 , and R 9 are each optionally substituted -C 2 -C 4 alkenyl.
  • R 1 , R 2 , R 6 , R 7 , R 8 , and R 9 are each optionally substituted -C 2 -C 4 alkynyl.
  • R 1 , R 2 , R 6 , R 7 , R 8 , and R 9 are each -CF 3 , -CHF 2 , or -CH 2 F. In a further aspect, R 1 , R 2 , R 6 , R 7 , R 8 , and R 9 are each -OCF 3 , -OCHF 2 , or -OCH 2 F. In another aspect, R 1 , R 2 , R 6 , R 7 , R 8 , and R 9 are each optionally substituted-O-Q-Qs alkyl. In a further aspect, R 1 , R 2 , R 6 , R 7 , R 8 , and R 9 are each cyano.
  • R 6 and T are taken together along with the carbons they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations including 0 to 2 heteroatoms independently selected from -NR 1 -, -O-, and -S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom; and X is attached to this ring to either a carbon or a nitrogen by either -(CR a 2 )- or -C(O)- or a bond if X is attached directly to a carbon atom.
  • R 6 and T are taken together along with the carbons they are attached to form a ring of 5 to 6 atoms containing 0 unsaturations. In another aspect, R 6 and T are taken together along with the carbons they are attached to form a ring of 5 to 6 atoms containing 1 unsaturation. R 6 and T are taken together along with the carbons they are attached to form a ring of 5 to 6 atoms containing 2 unsaturations.
  • 0 to 2 heteroatoms are -NR 1 -.
  • 0 to 2 heteroatoms are -O-.
  • 0 to 2 heteroatoms are -S-.
  • R 1 is hydrogen.
  • R 1 is -C(O)C 1 -C 4 alkyl.
  • R 1 is -C 1 -C 4 alkyl.
  • R 1 is -Cj-C 4 -aryl.
  • R 3 and R 4 are each hydrogen, hi another aspect, R 3 and R 4 are each halogen, hi a further aspect, R 3 and R 4 are each -CF 3 . In another aspect, R 3 and R 4 are each -OCF 3 . hi a further aspect, R 3 and R 4 are each cyano. In another aspect, R 3 and R 4 are each optionally substituted -C 1 -C 12 alkyl. hi a further aspect, R 3 and R 4 are each optionally substituted -C 2 -C 12 alkenyl. hi another aspect, R 3 and R 4 are each optionally substituted -C 2 -C 12 alkynyl.
  • R 3 and R 4 are each optionally substituted -(CR a 2 ) m aryl.
  • R 3 and R 4 are each optionally substituted -(CR a 2 ) m cycloalkyl.
  • R 3 and R 4 are each optionally substituted -(CR a 2 ) m heterocycloaUcyl.
  • R 4 is selected from the group consisting of hydrogen, halogen, -C 1 -C 4 alkyl, cyano and CF 3 .
  • R 4 is hydrogen, hi a further aspect, R 3 is selected from the group consisting of halogen, optionally substituted -C 1 -C 6 alkyl, -CF 3 , cyano, -C(O)NR 1 R 8 , optionally substituted -(CR a 2 ) n aryl, -SO 2 NR f R g , and -SO 2 R 6 .
  • R 3 is isopropyl or 4- fluorobenzyl.
  • R d is optionally substituted -C 1 -C 12 alkyl. In a further aspect, each R d is optionally substituted -C 2 -C 12 alkenyl. hi another aspect, each R d is optionally substituted -C 2 -C 12 alkynyl. hi a further aspect, each R is optionally substituted -(CR b 2 ) n aryl. hi another aspect, each R is optionally substituted -(CR b 2 ) n cycloalkyl. hi a further aspect, each R is optionally substituted -(CR b 2 ) n heterocycloalkyl. In another aspect, each R d is -C(0)NR f R g . [0303] For compounds of Formula I, II, III, and VIII, in an additional aspect,
  • R e is optionally substituted -C 1 -Ci 2 alkyl. In another aspect, R e is optionally substituted -C 2 -Ci 2 alkenyl. In a further aspect, R e is optionally substituted -C 2 -Ci 2 alkynyl. In another aspect, R e is optionally substituted -(CR a 2 ) n aryl. In a further aspect, R e is optionally substituted -(CR a 2 ) n cycloalkyl. In another aspect, R e is optionally substituted -(CR a 2 ) n heterocycloalkyl.
  • R f and R g are each hydrogen, hi an additional aspect, R f and R g are each optionally substituted -Ci-Ci 2 alkyl. In another aspect, R f and R g are each optionally substituted -C 2 -Ci 2 alkenyl. hi an additional aspect, R f and R s are each optionally substituted -C 2 -Ci 2 alkynyl. hi a further aspect, R f and R s are each optionally substituted -(CR b 2 ) n aryl.
  • R f and R g are each optionally substituted -(CR b 2 ) n cycloalkyl. In another aspect, R f and R g are each optionally substituted -(CR 2 ) n heterocycloalkyl.
  • the optionally substituted heterocyclic ring may be substituted with 1 substituent selected from the group consisting of optionally substituted -Ci-C 4 alkyl, -OR b , oxo, cyano, -CF 3 , -CHF 2 , -CH 2 F, optionally substituted phenyl, and -C(O)OR h .
  • 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(O)OR h .
  • the optionally substituted heterocyclic ring may be substituted with 3 substituents selected from the group consisting of optionally substituted -C 1 -C 4 alkyl, -OR b , oxo, cyano, -CF 3 , -CHF 2 , -CH 2 F, optionally substituted phenyl, and -C(O)OR 11 .
  • the optionally substituted heterocyclic ring may be substituted with 4 substituents selected from the group consisting of optionally substituted -C 1 -C 4 alkyl, -0R b , oxo, cyano, -CF 3 , -CHF 2 , -CH 2 F, optionally substituted phenyl, and -C(O)OR 11 .
  • R h is optionally substituted -Cj-C 12 alkyl.
  • R h is optionally substituted -C 2 -Ci 2 alkenyl.
  • R h is optionally substituted -C 2 -Ci 2 alkynyl.
  • R h is optionally substituted -(CR b 2 ) n aryl.
  • R h is optionally substituted -(CR b 2 ) n cycloalkyl.
  • R h is optionally substituted -(CR b 2 ) n heterocycloalkyl.
  • R 5 is selected from the group consisting of -OH, -OC(O)R 6 , -OC(O)OR 11 , -F, and -NHC(O)R 6 .
  • R 5 is -OH.
  • R 5 is optionally substituted -OCi-C 6 alkyl.
  • R 5 is -OC(O)R 6 .
  • R 5 is -OC(O)OR 11 .
  • R 5 is -NHC(0)0R h .
  • R 5 is -0C(0)NH(R h ).
  • R 5 is -F.
  • R 5 is -NHC(O)R 6 .
  • R 5 is -NHC(O)NH(R 11 ).
  • R 3 is iodo.
  • R 3 is -CH(OH)(4-fluoro ⁇ henyl).
  • X is selected from the group consisting of -PO 3 H 2 , -P(O)[-OCR z 2 OC(O)R y ] 2 , -P(O)[-OCR z 2 OC(O)OR y ] 2 , -P(O)[-N(H)CR z 2 C(O)OR y ] 2 , -P(O)[-N(H)CR z 2 C(O)OR y ][-OR ⁇ ], and -P(OX-OCH(V)CH 2 CH 2 O-], wherein V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl.
  • V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl.
  • X is selected from the group consisting of -PO 3 H 2 , -P(O)[-OCR z 2 OC(O)R y ] 2 , -P(O)[-OCR z 2 OC(O)OR y ] 2 , -P(O)[-Oalk-SC(O)R y ] 2 , -P(O)[-N(H)CR z 2 C(O)OR y ] 2 , -P(O)[-N(H)CR z 2 C(O)OR y ][-OR ⁇ ] and -P(O)[-OCH(V)CH 2 CH 2 O-], wherein V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl.
  • X is selected from the group consisting of -P(O)[-OCR z 2 OC(O)R y ] 2 , -P(O)[-OCR z 2 OC(O)OR y ] 2 ,
  • V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl.
  • V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl.
  • X is selected from the group consisting of -PO 3 H 2 , -P(O)[ ⁇ OCH 2 OC(O)-t-butyl] 2 , -P(O)[-OCH 2 OC(O)O-/-propyl] 2 ,
  • X is selected from the group consisting of -PO 3 H 2 , -P(O)[-OCH 2 OC(O)-t-butyl] 2 , -P(O)[-OCH 2 OC(O)O-z ' -propyl] 2 , -P(O)[-N(H)CH(CH 3 )C(O)OCH 2 CH 3 ] 2 , -P(O)C-N(H)C(CH 3 ) 2 C(O)OCH 2 CH 3 ] 2 ,
  • X is -PO 3 H 2 .
  • X is selected from the group consisting of -P(O)[-OCH 2 OC(OH-butyl] 2 and -P(O)[-OCH 2 OC(O)-?-propyl] 2 .
  • X is selected from the group consisting of -PO 3 H 2 , -P(O)[-OCH 2 OC(OH-butyl] 2 , -P(O)[-OCH 2 OC(O)O-i-propyl] 2 , -P(O)[-N(H)CH(CH 3 )C(O)OCH 2 CH 3 ] 2 ,
  • X is selected from the group consisting of -P(O)[-OCH 2 OC(O)O-ethyl] 2 and -P(O)[-OCH 2 OC(O)O-z ⁇ propyl] 2.
  • X is selected from the group consisting of -P(O)[-N(H)CH(CH 3 )C(O)OCH 2 CH 3 ] 2 and -P(O)[-N(H)C(CH 3 ) 2 C(O)OCH 2 CH 3 ] 2 .
  • X is -P(OX-OCH 2 CH 2 SC(O)Me] 2 .
  • X is selected from the group consisting of -P(OX-N(H)CH(CH 3 )C(O)OCH 2 CH 3 ]
  • this invention relates to Formulas I, II, III, or
  • Y and Y' are each independently selected from the group consisting of -O-, and -NR V -.
  • Y and Y' are each independently selected from the group consisting of -O-, and -NR V -; when Y and Y' are both -O- , R 11 attached to -O- is -H, alkyl.
  • Y and Y' are each independently selected from the group consisting of -O-, and -NR V ⁇ ; when Y and Y' are both -O- , R 11 attached to -O- is optionally substituted aryl.
  • Y and Y' are each independently selected from the group consisting of -O-, and -NR V -; when Y and Y' are both -O- , R 11 attached to -O- is optionally substituted heterocycloalkyl .
  • Y and Y' are each independently selected from the group consisting of -0-, and -NR V -; when Y and Y' are both -O- , R 11 attached to -O- is optionally substituted CH 2 -heterocycloakyl.
  • the cyclic moiety contains a carbonate or thiocarbonate.
  • the cyclic moiety contains optionally substituted -alkylaryl.
  • the cyclic moiety contains a -C(R Z ) 2 OC(O)NR Z 2 . In another aspect, the cyclic moiety contains -NR z -C(0)-R y . In another aspect, the cyclic moiety contains -C(R z ) 2 -OC(O)R y . In another aspect, the cyclic moiety contains -C(R z ) 2 -O-C(O)OR y . In a further aspect, the cyclic moiety contains -C(R z ) 2 OC(O)SR y . In another aspect, the cyclic moiety contains -alkyl-S-C(O)R y . In another aspect, the cyclic moiety contains -alkyl-S-S-alkylhydroxy. In a further aspect, the cyclic moiety contains -alkyl-S-S-alkylhydroxy.
  • Y and Y' are both -NR V -.
  • R 11 attached to -NR V - is -H.
  • R 11 attached to -NR V - is -[C(R z ) 2 ] q -C(0)0R y .
  • R 11 attached to -NR V - is -C(R x ) 2 C(O)OR y .
  • R 11 attached to -NR V - is -[C(R z ) 2 ] q -C(O)SR y .
  • R 11 attached to -NR V - is -cycloalkylene-C(O)OR y .
  • Y is -O- and Y' is NR V .
  • R 11 attached to -O- is -H.
  • R 11 attached to -O- is alkyl.
  • R 11 attached to -O- is optionally substituted aryl.
  • R 11 attached to -O- is optionally substituted heterocycloalkyl.
  • R 11 attached to -O- is optionally substituted CH 2 -heterocycloakyl.
  • the cyclic moiety contains a carbonate or thiocarbonate.
  • the cyclic moiety contains optionally substituted -alkylaryl.
  • the cyclic moiety contains -C(R Z ) 2 OC(O)NR Z 2 .
  • the cyclic moiety contains -NR z -C(0)-R y . In another aspect, the cyclic moiety contains -C(R Z ) 2 - OC(O)R y . In another aspect, the cyclic moiety contains -C(R z ) 2 -0-C(0)0R y . In a further aspect, the cyclic moiety contains -C(R z ) 2 OC(O)SR y . In another aspect, the cyclic moiety contains -alkyl-S-C(O)R y . m another aspect, the cyclic moiety contains -alkyl-S-S-alkylhydroxy. In a further aspect, the cyclic moiety contains -alkyl-S-S-alkylhydroxy.
  • Y is -O- and Y' is NR V
  • R 11 attached to -NR V - is -H.
  • R 11 attached to -NR V - is -[C(R z ) 2 ] q -COOR y .
  • R 11 attached to -NR V - is -CCR ⁇ COOR 7 .
  • Y' are independently selected from -O- and -NR V -, then R 11 and R 11 together form a cyclic group comprising -alkyl-S-S-alkyl-.
  • Y and Y' aarree iinnddeeppeendently selected from -O- and -NR V - and together R 1 ' and R 1 ' are the group:
  • V is hydrogen.
  • V is optionally substituted alkyl.
  • V is optionally substituted aralkyl.
  • V is heterocycloalkyl.
  • V is aryl.
  • V is substituted aryl.
  • V is heteroaryl.
  • V is substituted heteroaryl.
  • V is optionally substituted 1-alkenyl.
  • V is optionally substituted 1-alkynyl.
  • W is hydrogen.
  • W is optionally substituted alkyl.
  • W is optionally substituted aralkyl.
  • W is heterocycloalkyl.
  • W is aryl.
  • W is substituted aryl.
  • W is heteroaryl.
  • W is substituted heteroaryl.
  • W is optionally substituted 1-alkenyl.
  • W is optionally substituted 1-alkynyl.
  • W is hydrogen.
  • W is optionally substituted alkyl.
  • W is optionally substituted aralkyl.
  • W is heterocycloalkyl.
  • W is aryl.
  • W is substituted aryl.
  • W is heteroaryl.
  • W is substituted heteroaryl.
  • W is optionally substituted 1-alkenyl.
  • W is optionally substituted 1-alkynyl.
  • V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon.
  • the ring is substituted with hydroxyl attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus, hi another aspect, the ring is substituted with acyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus.
  • the ring is substituted with alkylthiocarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus. In another aspect, the ring is substituted with alkoxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus. Li a further aspect, the ring is substituted with aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus.
  • V and Z are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, that is fused to an aryl group at the beta and gamma position to the Y attached to the phosphorus.
  • V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent.
  • the substituent is hydroxyl that is attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus.
  • the substituent is acyloxy that is attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus.
  • the substituent is alkoxycarbonyloxy that is attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus.
  • the substituent is alkylthiocarbonyloxy that is attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus. In another aspect, the substituent is aryloxycarbonyloxy that is attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus.
  • Z and W are connected via an additional 3-5 atoms to form a cyclic group, wherein 0—1 atoms are heteroatoms and the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
  • W and W are connected via an additional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
  • Z is -CH 2 NHaTyI.
  • Z is -(CH 2 ) q -OR z .
  • Z is -(CH 2 ) q -SR z .
  • R 11 is not hydrogen, hi one aspect, q is 2. In a further aspect, q is 3.
  • R y is alkyl. hi another aspect, R y is aryl. hi a further aspect, R y is heterocycloalkyl. hi another aspect, R y is aralkyl. [0332] For compounds of Formula I, II, III, and VIII, in one aspect, R x is -H.
  • R x is alkyl. In yet another aspect, together R x and R x form a cycloalkyl group. [0333] For compounds of Formula I, II, III, and VIII, in one aspect, R v is -H.
  • R v is lower alkyl.
  • R v is acyloxyalkyl.
  • R v is alkoxycarbonyloxyalkyl.
  • R v is lower acyl.
  • V, W, and W are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-alkynyl; or together V and Z are connected via an additional 3-5 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 attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or together V and Z are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, that is fused to an aryl group
  • Each R z is selected from the group consisting of R y and -H;
  • Each R y is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; and
  • Each R v is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl.
  • V is optionally substituted aryl.
  • V is selected from the group consisting of 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 3 -fluorophenyl, pyrid-4-yl, ⁇ yrid-3-yl and 3,5-dichlorophenyl.
  • the relative stereochemistry between the V-group substituent and T on the dioxaphosphonane ring is cis.
  • the cis dioxaphosphonane ring has R stereochemistry at the carbon where V is attached.
  • the cis dioxaphosphonane ring has S stereochemistry at the carbon where V is attached.
  • R 11 is not hydrogen
  • X is -P(O)YR 11 Y", wherein Y" is -C 1 -C 6 alkyl.
  • Y is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • X is PO 2 H 2 , P(O)(OH)(R z ),
  • X is -P(O)(OH)(CH 3 ), -P(O)(OH)(CH 2 CH 3 ), -P(O)(OH)(isopropyl), or -P(O)(OH)(t-butyl).
  • V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl.
  • R 4 is not hydrogen.
  • G is selected from the group consisting of -O- and -CH 2 -; T is -OCH 2 -; R 1 and R 2 are each independently selected from the group consisting of iodo, bromo, chloro, methyl, and cyano; R 4 is selected from the group consisting of hydrogen, iodo, 4-chlorophenyl, and cyclohexyl; R 5 is selected from the group consisting of -OH and -OC(O)R 0 ; R 3 is selected from the group consisting of hydrogen, iodo, bromo, optionally substituted lower alkyl, optionally substituted -CH 2 aryl, optionally substituted -CH(OH)aryl, -C(O)-amido wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methypiperizinyl, morpholinyl, cyclo
  • G is -CH 2 -; T is -OCH 2 -; R 1 and R 2 are each methyl; R 4 is hydrogen; R 5 is -OH; R 3 is iso-proTpyl; and X is selected from the group consisting of -PO 3 H 2 , -P(O)[-OCR z 2 OC(O)R y ] 2 , -P(O)[-OCR z 2 OC(O)OR y ] 2 , -P(O)[-N(H)CR z 2 C(O)OR y ] 2 , -P(O)[-N(H)CR z 2 C(O)OR y ][OR e ] and -P(O)[-OCR z (aryl)CH 2 CH 2 O-] .
  • G is selected from the group consisting of -O- and -CH 2 -; T is -CH 2 -; R 1 and R 2 are each independently selected from the group consisting of iodo, bromo, chloro, methyl, and cyano; R is selected from the group consisting of hydrogen, iodo, 4-chlorophenyl, and cyclohexyl; R 5 is selected from the group consisting of -OH and -OC(O)R 6 ; R 3 is selected from the group consisting of hydrogen, iodo, bromo, optionally substituted lower alkyl, optionally substituted -CH 2 aryl, optionally substituted -CH(OH)aryl, -C(O)-amido wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methypiperizinyl, morpholinyl, cyclohex
  • R 4 is not hydrogen.
  • R 1 and R 2 are each chloro; R 4 is hydrogen; R 5 is -OH; R 3 is /-propyl; and X is selected from the group consisting of -PO 3 H 2 , -P(O)[ ⁇ OCR z 2 OC(O)R y ] 2 , -P(O)[-OCR 2 2 OC(O)OR y ] 2 ,
  • G is selected from the group consisting of -O- and -CH 2 -; T is -CH 2 CH 2 -; R 1 and R 2 are each independently selected from the group consisting of iodo, bromo, chloro, methyl, and cyano; R is selected from the group consisting of hydrogen, iodo, 4-chlorophenyl, and cyclohexyl; R 5 is selected from the group consisting of -OH and -OC(O)R 6 ; R 3 is selected from the group consisting of hydrogen, iodo, bromo, optionally substituted lower alkyl, optionally substituted ' -CH 2 aryl, optionally substituted -CH(OH)aryl, -C(O)-amido wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-methypiperizinyl, morpholinyl, cyclohe
  • G is -O-; T is -CH 2 CH 2 -; R 1 and R 2 are each chloro; R 4 is hydrogen; R 5 is -OH; R 3 is wo-propyl; and X is selected from the group consisting of -PO 3 H 2 , -P(O)[-OCR z 2 OC(O)R y ] 2 , -P(O)[-OCR z 2 OC(O)OR y ] 2 , -P(O)[-N(H)CR z 2 C(O)OR y ] 2 , -P(O)[-N(H)CR z 2 C(O)OR y ][OR e ] and -P(O)[-OCR z (aryl)CH 2 CH 2 O-] .
  • G is -O-; T is -CH 2 CH 2 -; R 1 and R 2 are each chloro; R 4 is hydrogen; R 5 is -OH; R 3 is iso- propyl; and X is selected from the group consisting of -PO 3 H 2 , -P(O)[-OCH 2 OC(OHbutyl] 2 , -P(O)[-OCH 2 OC(O)O-z-propyl] 2 , -P(O)[-N(H)CH(CH 3 )C(O)OCH 2 CH 3 ] 2 ,
  • G is -O-
  • T is -(CH 2 ) 0-4 -
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, alkyl of 1 to 3 carbons, and cycloalkyl of 3 to 5 carbons
  • R 3 is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 7 carbons
  • R 5 is -OH
  • R 4 is not hydrogen
  • G is -O-
  • G is -CH 2 -; T is -OCH 2 -; R 1 and R 2 are each methyl; R 4 is hydrogen; R 5 is -OH; R 3 is iso-p ⁇ opyl; and X is -P(O)YR 11 Y 5 R 11 ; wherein Y and Y' are each independently selected from -O- and -NR V -; together R 11 and R 11 are the group:
  • V, W, and W are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-alkynyl; or together V and Z are connected via an additional 3-5 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 attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or together V and Z are connected via an additional 3-5 atoms to form a cyclic group, wherein 0 - 1 atoms are heteroatoms and the remaining atoms are carbon, that is fused to an aryl group at the beta and gam
  • Each R z is selected from the group consisting of R y and -H;
  • Each R y is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl;
  • Each R v is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl.
  • V is aryl.
  • Z is hydrogen, W is hydrogen, and W is hydrogen.
  • V is 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 3 -fluorophenyl, pyrid-4-yl, pyrid-3-yl or 3,5-dichlorophenyl.
  • the relative stereochemistry between the substituents on the dioxaphosphonane ring is cis.
  • each R a is independently selected from the group consisting of hydrogen, optionally substituted -Ci-C 2 alkyl, halogen, -OH, optionally substituted -0-Ci-C 2 alkyl, -OCF 3 , optionally substituted -S-Ci-C 2 alkyl, -NR b R c , optionally substituted -C 2 alkenyl, and optionally substituted -C 2 alkynyl;
  • Each R b is independently selected from the group consisting of hydrogen, optionally substituted -Ci-C 2 alkyl;
  • Each R is selected from the group consisting of optionally substituted -Ci-C 6 alkyl, optionally substituted -C 2 -C 6 alkenyl, optionally substituted -C 2 -C 6 alkynyl, optionally substituted -(CR b 2 ) n phenyl, optionally substituted -(CR b 2 ) n monocyclic-heteroaryl, optionally substituted -(CR b 2 ) n -C 3 - C 6 -cycloalkyl, optionally substituted -(CR b 2 ) n -C 4 -C 5 -heterocycloalkyl, and -C(O)NR f R g ;
  • Each R e is selected from the group consisting of optionally substituted -Ci-C 6 alkyl, optionally substituted -C 2 -C 6 alkenyl, optionally substituted -C 2 -C 6 alkynyl, optionally substituted -(CR b 2 ) n phenyl, optionally substituted -(CR ⁇ n monocyclic-heteroaryl, optionally substituted -(CR b 2 ) n -C 3 -C 6 -cycloalkyl, optionally substituted
  • R f and R s are each independently selected from the group consisting of hydrogen, optionally substituted -C 1 -C 6 alkyl, optionally substituted -C 2 -C 6 alkenyl, optionally substituted -C 2 -C 6 alkynyl, optionally substituted -(CR b 2 ) n phenyl, optionally substituted -(CR b 2 ) n monocyclic- heteroaryl, optionally substituted -(CR b 2 ) n -C 3 -C 6 -cycloalkyl, optionally substituted -(CR b 2 ) n -C 4 -C 5 -heterocycloalkyl, or R f and R s may together form an optionally substituted heterocyclic ring, which may contain a second heterogroup selected from the group of O, NR b , and S, wherein said optionally substituted heterocyclic ring may be substituted with 0-2 substituents selected from the group consisting of
  • Each R h is optionally substituted -Ci-Cj 6 alkyl, optionally substituted -C 2 -Ci 6 alkenyl, optionally substituted -C 2 -Ci 6 alkynyl, optionally substituted -(CR b 2 ) n phenyl, optionally substituted -(CR b 2 ) n monocyclic- heteroaryl, optionally substituted ⁇ (CR b 2 ) n -C 3 -C 6 -cycloalkyl, optionally substituted -(CR b 2 ) n -C 4 -C 5 -heterocycloalkyl.
  • each R a is independently selected from the group consisting of hydrogen, methyl, fluoro, chloro, -OH, -0-CH 3 , -OCF 3 , -SCH 3 , -NHCH 3 , -N(CH 3 ) 2 ;
  • Each R is independently selected from the group consisting of hydrogen, and methyl
  • Each R c is independently selected from the group consisting of hydrogen, methyl, -C(O)CH 3 , -C(O)H;
  • Each R is selected from the group consisting of optionally substituted -Ci-C 4 alkyl, optionally substituted -C 2 -C 4 alkenyl, optionally substituted -C 2 -C 4 alkynyl, optionally substituted -(CH 2 ) n phenyl, optionally substituted -(CH 2 ) n monocyclic-heteroaryl, optionally substituted -(CH 2 ) n -C 3 -C 6 -cycloalkyl, optionally substituted
  • Each R e 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 ) n phenyl, optionally substituted -(CH 2 ) n monocyclic-heteroaryl, optionally substituted -(CH 2 ) n -C 3 -C 6 -cycloalkyl, optionally substituted
  • Each R 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 ) n phenyl, optionally substituted -(CH 2 ) n monocyclic- heteroaryl, optionally substituted -(CH 2 ) n -C 3 -C 6 -cycloalkyl, optionally substituted -(CH 2 ) n -C 4 -C 5 -heterocycloalkyl.
  • G is selected from the group consisting of -O- and -CH 2 -; D is selected from the group consisting of a bond and -CH 2 -; 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-; R 1 and R 2 are each independently selected from the group consisting of halogen, -Cj-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 ; R 5 is selected from the group consisting of -OH, -OC(O)R e , -OC(O)OR h , -F, and -NHC(O)R 6 ; R 3 is selected from the group consisting of halogen, optionally substitute
  • V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl.
  • G is selected from the group consisting of -O- and -CH 2 ;
  • D is selected from the group consisting of a bond and -CH 2 -;
  • A is selected from the group consisting of -NH-, -NMe-, -0-, and -S-;
  • B is selected from the group consisting of -CH-, -CMe- and -N-;
  • R 1 and R 2 are each independently selected from the group consisting of iodo, bromo, chloro, methyl, and cyano;
  • R 4 is selected from the group consisting of hydrogen and halogen;
  • R 5 is selected from the group consisting of -OH and -OC(O)R 6 ;
  • R 3 is selected from the group consisting of halogen, optionally substituted -Cj-C 6 alkyl, optionally substituted -CH 2 aryl, optionally substituted -CH(OH)aryl, -C(O)-amido, -S(
  • G is -O-; D is a bond; A is -O-; B is selected from the group consisting of -CH- and -CMe-; R 1 and R 2 are each bromo; R is selected from the group consisting of hydrogen and iodo; R 5 is -OH; and R 3 is isopropyl.
  • R 1 and R 2 are each chloro, R 3 is ⁇ opropyl, R 7 is fluoro and R 5 is -OH, then R 4 is not hydrogen.
  • G is selected from the group consisting of oxygen, sulfur, sulfoxide, sulfonyl, -CH 2 -, -C(O)- and — NR b -;
  • T is -A-B- where A is selected from the group consisting of -NR b -, -0-, -CH 2 - and -S- and B is selected from the group consisting of a bond and substituted or unsubstituted C 1 -C 3 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
  • T is -N(H)C(O)-; G is -0-; R 1 and R 2 are each chloro; R 4 is hydrogen; R 5 is -OH; R 3 is -wo-propyl; R 7 is fluoro; X is selected from the group consisting of -PO 3 H 2 , -P(O)[-OCH 2 OC(OH-butyl] 2 ,
  • T is -OCH 2 -; G is -0-; R 1 and R 2 are each chloro; R 4 is hydrogen; R 5 is -OH; R 3 is wo-propyl; R 7 is fluoro; and X is selected from the group consisting of -PO 3 H 2 , -P(O)[-OCH 2 OC(O)-t-butyl] 2 ,
  • T is -CH 2 -;
  • R 1 and R 2 are each independently selected from the group consisting of iodo, bromo, chloro, methyl, and cyano;
  • R is selected from the group consisting of hydrogen and iodo;
  • R 5 is selected from the group consisting of -OH, and -OC(O)R e ;
  • T is -CH 2 -; G is -O-; R 1 and R 2 are each chloro; R 4 is hydrogen; R 5 is -OH; R 3 is z-propyl; R 7 is fluoro; and X is selected from the group consisting of -PO 3 H 2 , -P(O)[-OCH 2 OC(O)-t-butyl] 2 ,
  • T is -CH 2 CH 2 -;
  • R 1 and R 2 are each independently selected from the group consisting of iodo, bromo, chloro, methyl, and cyano;
  • R 4 is selected from the group consisting of hydrogen and iodo;
  • R 5 is selected from the group consisting of -OH and -OC(O)R 6 ;
  • T is -CH 2 CH 2 -; G is -O-; R 1 and R 2 are each chloro; R 4 is hydrogen; R 5 is -OH; R 3 is zso-propyl; R 7 is fluoro; and X is selected from the group consisting of -PO 3 H 2 , -P(O)[-OCH 2 OC(O)-t-butyl] 2 ,
  • T is -NHCH 2 -;
  • R 1 and R 2 are each independently selected from the group consisting of iodo, bromo, chloro, methyl, and cyano;
  • R 4 is selected from the group consisting of hydrogen and iodo;
  • R 5 is selected from the group consisting of -OH, and -OC(O)R e ;
  • T is -NHCH 2 -; G is -O-; R 1 and R 2 are each chloro; R 4 is selected from the group consisting of hydrogen and iodo R 5 is -OH; R 3 is wo-propyl; and R 7 is fluoro.
  • T is -NHCH 2 -; G is -O-; R 1 and R 2 are each bromo;
  • R 1 and R 2 are each bromo;
  • R 4 is selected from the group consisting of hydrogen and iodo
  • R 5 is -OH;
  • R 3 is wo-propyl;
  • R 7 is fluoro;
  • X is selected from the group consisting of -PO 3 H 2 , -P(O)[-OCH 2 OC(O)-t-butyl] 2 , -P(O)[-OCH 2 OC(O)O-z-propyl] 2 , -P(O)[-N(H)CH(CH 3 )C(O)OCH 2 CH 3 ] 2 , -P(O)[-N(H)C(CH 3 ) 2 C(O)OCH 2 CH 3 ] 2 , -P(O)[-N(H)CH(CH 3 )C(O)OCH 2 CH 3 ] [3,4-methylenedioxyphenyl], -P(O)[-N(H)C(CH 3
  • G is -O-; T is -CH 2 CH(NH 2 )-; R 1 and R 2 are each chloro; R 4 and R 8 are selected from the group consisting of hydrogen and iodo; R 5 is -OH; and R 3 is iodo.
  • G is -O-; T is -N(H)C(O)-; R 1 and R 2 are each chloro; R 4 and R 8 are hydrogen; R 5 is -OH; and R 3 is -CH 2 (4-fluorophenyl).
  • G is -O-; T is -OCH 2 -; R 1 and R 2 are each methyl; R 4 and R 8 are hydrogen; R 5 is -OH; and R 3 is ⁇ o-propyl.
  • G is -O-; T is -CH 2 -; R 1 and R 2 are each chloro; R 4 and R 8 are hydrogen; R 5 is -OH; and R 3 is zjo-propyl.
  • G is -O-; T is -CH 2 CH 2 -; R 1 and R 2 are each chloro; R and R 8 are hydrogen; R 5 is -OH; and R 3 is iso-propyl.
  • G is -0-
  • T is -(CH 2 ) O-4 -
  • R 1 and R 2 are independently halogen, alkyl of 1 to 3 carbons, and cycloalkyl of 3 to 5 carbons
  • R is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 7 carbons
  • R 4 is hydrogen
  • R 5 is -OH
  • X is not -P(O)(OH) 2 or -P(O)(O lower alkyl) 2 .
  • R 5 is -NHC(O)R 6 , -NHS(-0) 1-2 R e , -NHC(S)NH(R h ), or -NHC(0)NH(R h )
  • G is -0-; T is -CH 2 CH(NH 2 )-; R 1 and R 2 are each iodo; R 4 is selected from the group consisting of hydrogen and iodo; R 6 , R 7 , R 8 and R 9 are hydrogen; R 5 is -OH; and R 3 is iodo.
  • G is -0-; T is -N(H)C(O)-; R 1 and R 2 are each methyl; R 4 , R 6 , R 7 , R 8 and R 9 are hydrogen; R 5 is -OH; and R 3 is -CH(OH)(4-fluorophenyl).
  • G is -CH 2 -; T is -OCH 2 -; R 1 and R 2 are each methyl; R 4 , R 6 , R 7 , R 8 and R 9 are hydrogen; R 5 is -OH; and R 3 is isopropyl.
  • G is -0-; T is -CH 2 -; R 1 and R 2 are each chloro; R 4 , R 6 , R 7 , R 8 and R 9 are hydrogen; R 5 is -OH; and R 3 is ir ⁇ -pr ⁇ pyl.
  • the compound 1.3.6.7 from Formula V represents the compound of Formula V wherein V is 1, i.e., of group V is 1, i.e., of group -P(O)(OH) 2 ; V 2 is 3, i.e., of group -CH 2 -CH 2 -; V 3 is 6, i.e., of group methyl; and V 4 is 7, i.e., of group -SO 2 (4-fluorophenyl).

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EP06760469A 2005-05-26 2006-05-26 Neue phosphorhaltige thyromimetika Withdrawn EP1891080A2 (de)

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US11/137,773 US7514419B2 (en) 2003-11-19 2005-05-26 Phosphorus-containing thyromimetics
US72517005P 2005-10-06 2005-10-06
PCT/US2006/020607 WO2006128055A2 (en) 2005-05-26 2006-05-26 Novel phosphorus-containing thyromimetics

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WO2005051298A2 (en) 2003-11-19 2005-06-09 Metabasis Therapeutics, Inc. Novel phosphorus-containing thyromimetics
CA2606499C (en) 2005-05-26 2017-06-13 Metabasis Therapeutics, Inc. Thyromimetics for the treatment of fatty liver diseases
US20120046364A1 (en) 2009-02-10 2012-02-23 Metabasis Therapeutics, Inc. Novel Sulfonic Acid-Containing Thyromimetics, and Methods for Their Use
KR20190104524A (ko) 2016-11-21 2019-09-10 바이킹 테라퓨틱스 인코포레이티드 당원축적질환의 치료 방법
KR102600115B1 (ko) * 2017-06-05 2023-11-09 바이킹 테라퓨틱스 인코포레이티드 섬유증 치료를 위한 조성물
EP3768690A4 (de) * 2018-03-22 2021-11-24 Viking Therapeutics, Inc. Kristalline formen und verfahren zur herstellung kristalliner formen einer verbindung
CN113423684A (zh) 2018-12-12 2021-09-21 速通医疗公司 新型拟甲状腺素药
WO2020118564A1 (en) * 2018-12-12 2020-06-18 Autobahn Therapeutics, Inc. Novel thyromimetics
CA3130371A1 (en) 2019-03-01 2020-09-10 Autobahn Therapeutics, Inc. Novel thyromimetics
CN112300211B (zh) * 2019-07-26 2023-12-08 广东东阳光药业股份有限公司 一种作为甲状腺激素β受体激动剂的化合物及其用途
GB2603330B (en) * 2019-08-19 2023-08-09 Hepagene Therapeutics Hk Ltd Heterocyclic THR-B receptor agonist compound and preparation method and use therefor
CN110726801A (zh) * 2019-10-31 2020-01-24 山东泰星新材料股份有限公司 一种监测烷基次膦酸反应状态的方法
CN113336792A (zh) 2020-02-18 2021-09-03 甘莱制药有限公司 一种环状膦酸酯化合物的制备方法
US11752161B2 (en) 2020-03-27 2023-09-12 Gannex Pharma Co., Ltd. Pharmaceutical compositions, method of making and method of using thereof
CN114315902A (zh) * 2020-09-30 2022-04-12 甘莱制药有限公司 一种甲状腺激素β受体激动剂的晶体及其制备方法和用途
CN114763363A (zh) * 2021-01-12 2022-07-19 上海喀露蓝科技有限公司 磷酸或磷酸酯类衍生物及其制备方法和其在医药上的用途
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