US 200901 18236A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0118236A1 Erion et al. (43) Pub. Date: May 7, 2009

(54) NOVEL PHOSPHORUS-CONTAINING Publication Classification THYROMMETCS (51) Int. Cl. (76) Inventors: Mark D. Erion, Del Mar, CA (US); gt. 5% CR Hongjian Jiang, San Diego, CA A6II 3/662 CR (US); Serge H. Boyer, San Diego, ( .01) CA (US) C07F 9/59 (2006.01) A6IP5/4 (2006.01) Correspondence Address: 9."66 :08: STERNE KESSLER GOLDSTEIN & FOX P.L. L.C 9 9 C07F 9/58 (2006.01) 1100 NEW YORKAVENUE, N.W. C07F 9/38 (2006.01) WASHINGTON, DC 20005 (US) (52) U.S. Cl...... 514/89;568/15: 514/130; 514/119; 564/15: 514/114: 546/22:568/12: 514/110; (21) Appl. No.: 10/580,134 436/5O1 (22) PCT Filed: Nov. 19, 2004 (57) ABSTRACT The present invention relates to compounds of phosphonic (86). PCT No.: PCT/USO4/39024 acid containing T3 mimetics, Stereoisomers, pharmaceuti S371 (c)(1) cally acceptable salts, co-crystals, and prodrugs thereof and (2), (4).te: May 30, 2007 pharmaceutically acceptable salts and co-crystals of the pro s 9 drugs, as well as their preparation and uses for preventing and/or treating metabolic diseases such as obesity, NASH, Related U.S. Application Data hypercholesterolemia and hyperlipidemia, as well as associ (60) Provisional application No. 60/523,830, filed on Nov. ated conditions such as atherosclerosis, coronary heart dis 19, 2003, provisional application No. 60/598.524, ease, impaired glucose tolerance, metabolic syndromex and filed on Aug. 3, 2004. diabetes. Patent Application Publication US 2009/0118236 A1

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NOVEL PHOSPHORUS-CONTAINING gland and specific regions of the hypothalamus as well as the THYROMMETCS developing brain and inner ear. In the rat and mouse liver, TRB-1 is the predominant isoform (80%). The TR isoforms FIELD OF THE INVENTION found in human and rat are highly homologous with respect to their amino acid sequences which suggest that each serves a 0001. The present invention is directed toward phosphonic specialized function. acid-containing compounds that are thyroid receptor ligands, 0006 TSH is an anterior pituitary hormone that regulates pharmaceutically acceptable salts, and to prodrugs of these thyroid hormone production. TSH formation and secretion is compounds as well as their preparation and uses for prevent in turn regulated by the hypothalamic thyrotropin releasing ing and/or treating metabolic diseases Such as obesity, NASH, factor (TRF). TSH controls the uptake of iodide by the thy hypercholesterolemia and hyperlipidemia as well as associ roid, the Subsequent release of iodinated thyronines from ated conditions such as atherosclerosis, coronary heart dis thyroglobulin (e.g., T3, T4) as well as possibly the intrapitu ease, impaired glucose tolerance and diabetes. The invention itary conversion of circulating T4 to T3. Compounds that is also related to the liver specific delivery of thyroid receptor mimic T3 and T4 can negatively regulate both TSH and TRF ligands and the use of these compounds for the prevention and secretion resulting in suppression of TSH levels and treatment of diseases responsive to modulation of T3-respon decreased levels of T3 and other iodinated thyronines. Nega sive genes in the liver. tive regulation of TSH is postulated based on co-transfection and knockout studies (Abel et al., J. Clin. Invest. 104, 291 BACKGROUND 300, (1999)) to arise through activation of the thyroid receptor 0002 The following description of the background is pro TRB, possibly the isoform TRB-2, which is highly expressed vided to aid in understanding, but is not admitted to be, or to in the pituitary. describe, prior art. All publications and their cited references 0007. The most widely recognized effects of THs are an are incorporated by reference in their entirety. increase in metabolic rate, oxygen consumption and heat 0003) Thyroid hormones (TH) are synthesized in the thy production. T3 treatment increases oxygen consumption in roid in response to thyroid stimulating hormone (TSH), isolated perfused liver and isolated hepatocytes. (Oh, et al., J. which is secreted by the pituitary gland in response to various Nutr. 125(1): 112-24 (1995); Oh, et al., Proc. Soc. Exp. Biol. stimulants (e.g., thyrotropin-releasing factor (TRF) from the Med. 207(3): 260-7 (1994)) Liver mitochondria from hyper hypothalamus). Thyroid hormones are iodinated O-aryl thyroid rats exhibit increased oxygen consumption (Carreras, tyrosine analogues excreted into the circulation primarily as et al., Am J Physiol Heart Circ Physiol. 281 (6):H2282-8 T4. T4 is rapidly deiodinated in the liver and kidney by (2001) and higher activities of enzymes in the oxidative path thyroxine 5'-deiodinase to T3, which is the most potent TH. ways (Dummler et al., Biochem J 317(3):913-8 (1996), T3 is metabolized to inactive metabolites via a variety of Schmehl, et al., FEBS Lett. 375(3):206-10 (1995), Harper et pathways, including pathways involving deiodination, glucu al., Can J. Physiol Pharmacol. 72(8):899-908 (1994)). Con ronidation, Sulfation, deamination, and decarboxylation. versely, mitochondria from hypothyroid rats show decreased Most of the metabolic pathways reside in the liver. oxygen consumption. Increased metabolic rates are associ 0004 THs have profound physiological effects in animals ated with increased mitochondrialgenesis and the associated and humans. Hyperthyroidism is associated with increased 2- to 8-fold increase in mitochondrial mRNA levels. Some of body temperature, general nervousness, weight loss despite the energy produced from the increased metabolic rate is increased appetite, muscle weakness and fatigue, increased captured as ATP (adenosine 5'-triphosphate), which is stored bone resorption and enhanced calcification, and a variety of or used to drive biosynthetic pathways (e.g., gluconeogen cardiovascular changes, including increased heart rate, esis, lipogenesis, lipoprotein synthesis). Much of the energy, increased stroke Volume, increased cardiac index, cardiac however, is lost in the form of heat (thermogenesis), which is hypertrophy, decreased peripheral vascular resistance, and associated with an increase in mitochondrial proton leak pos increased pulse pressure. Hypothyroidism is generally asso sibly arising from TH-mediated effects on mitochondrial ciated with the opposite effects. membrane, uncoupling proteins, enzymes involved in the 0005. The biological activity of THs is mediated largely inefficient sn-glycerol 3-phosphate shuttle Such as mitochon through thyroid hormone receptors (TRs). TRs belong to the drial sn-glycerol 3-phosphate dehydrogenase (mGPDH), receptor Superfamily known as nuclear receptors, which, and/or enzymes associated with proton leakage such as the along with its common partner, the retinoid X receptor, form adenine nucleotide transporter (ANT), Na/K-ATPase, heterodimers that act as ligand-inducible transcription fac Cat-ATPase and ATP synthase. tors. Like other nuclear receptors, TRS have a ligand binding 0008 THs also stimulate metabolism of cholesterol to bile domain and a DNA binding domain and regulate gene expres acids. Hypertyroidism leads to decreased plasma cholesterol sion through ligand-dependent interactions with DNA levels, which is likely due to increased hepatic LDL receptor response elements (thyroid response elements, TREs). Cur expression. Hypothyroidism is a well-established cause of rently, the literature shows that TRs are encoded by two hypercholesterolemia and elevated serum LDL. L-T3 is distinct genes (IRC. and TRB), which produce several iso known to lower plasma cholesterol levels. The effects of T3 forms through alternative splicing (Williams, Mol Cell Biol. are attributed to TRB since TRB-deficient mice are resistant to 20022):8329-42 (2000): Nagaya, et al. Biochem Biophy's Res T3-induced reduction in cholesterol levels. The effects on Commun 226(2):426-30 (1996)). The major isoforms that cholesterol levels have been postulated to result from direct have so far been identified are TRO-1, TRC-2, TRB-1 and effects on LDL receptor expression, enzymes involved in TRB-2. TRO-1 is ubiquitously expressed in the rat with high conversion of cholesterol to bile acids such as the rate-limit est expression in skeletal muscle and brown fat. TRB-1 is also ing enzyme cholesterol 7C.-hydroxylase (CYP7A) and/or ubiquitously expressed with highest expression in the liver, possibly enzymes involved in cholesterol synthesis such as brain and kidney. TRB-2 is expressed in the anterior pituitary HMG CoA reductase. In addition, THs are known to affect US 2009/011 8236 A1 May 7, 2009

levels of other lipoproteins linked to atherosclerosis. THs therapy has also been associated with bone loss. With these stimulate apo AI and the secretion of apo AI in HDL while side effects, the medical community has tended to use thy reducing apo AII. Accordingly, one would expect T3 and T3 roxine at low doses as an adjunct to dietary treatments. At mimetics to inhibit the atherosclerotic process in the choles these doses, TH has little effect on body weight or BMR. terol fed animal. 0015 The effectiveness of T3 to induce weight loss may 0009 THs simultaneously increase de novo fatty acid syn be attenuated by defects in TH action. In comparison to nor thesis and oxidation through effects on enzymes such as ACC, mal animals, higher T3 doses were required in ob/ob mice to FAS, and spot-14. THs increase circulating free fatty acids affect oxygen consumption, which was only observed in (FFA) levels in part by increasing production of FFAs from muscle, with no changes in liver and BAT. (Oh, et al., J. Nutr. adipose tissue via TH-induced lipolysis. In addition, THS 125(1): 112-24 (1995); Oh, et al., Proc. Soc. Exp. Biol. Med. increase mitochondrial enzyme levels involved in FFA oxi 207(3): 260-7 (1994)). These effects were at least partially dation, e.g., carnitine palmitoyltransferase 1 (CPT-1) and attributed to decreased uptake of T3 by the liver. enzymes involved in energy storage and consumption. 0016 T3 analogues have been reported. Many were 0010. The liver represents a major target organ of THs. designed for use as cholesterol-lowering agents. Analogues Microarray analysis of hepatic gene expression from livers of that lower cholesterol and various lipoproteins (e.g., LDL hypothyroid mice and mice treated with T3 showed changes cholesterol and Lp(a)) without generating adverse cardiac in mRNA levels for 55 genes (14 positively regulated and 41 effects have been reported (e.g., Underwood, et al. Nature negatively regulated) (Feng, et al. Mol. Endocylinol. 14(7): 324: 425-9 (1986)). In some cases the improved therapeutic 947-55 (2000). Others have estimated that approximately 8% profile is attributed to increased specificity for the TR-B of the hepatic genes are regulated by T3. Many of these genes wherein other cases it may be due to enhanced liver distribu are important to both fatty acid and cholesterol synthesis and tion. (Stanton, et al., Bioorg. Med. Chem. Lett. 10(15): 1661-3 metabolism. T3 is also known to have other effects in liver, (2000): Dow et al., Bioorg. Med. Chem. Lett., 13(3): 379-82 including effects on carbohydrates through increased glyco (2003)). genolysis and gluconeogenesis and decreased insulin action. 0017 T3 and T3 mimetics are thought to inhibit athero 0011. The heart is also a major target organ of THs. THs Sclerosis by modulating the levels of certain lipoproteins lower systemic vascular resistance, increase blood Volume known to be independent risk factors or potential risk factors and produce inotropic and chronotropic effects. Overall TH of atherosclerosis, including low density lipoprotein (LDL)- results in increased cardiac output, which may suggest that T3 cholesterol, high density lipoprotein (HDL)-cholesterol, or T3 mimetics might be of use to treat patients with compro apoAI, which is a major apoprotein constituent of high den mised cardiac function (e.g., patients undergoing coronary sity lipoprotein (HDL) particles and lipoprotein (a) or Lp(a). artery bypass grafting (CABG) or cardiac arrest) (U.S. Pat. 0018. Lp(a) is an important risk factor, elevated in many No. 5,158,978). The changes in cardiac function are a result patients with premature atherosclerosis. Lp(a) is considered of changes in cardiac gene expression. Increased protein Syn highly atherogenic (de Bruinet al., J. Clin. Endo. Metab., 76, thesis and increased cardiac organ weight are readily 121-126 (1993)). In man, Lp(a) is a hepatic acute phase observed in T3-treated animals and represent the side effect protein that promotes the binding of LDL to cell surfaces of T3 that limits therapeutic use. TRB knockout mice exhibit independent of LDL receptors. Accordingly, Lp(a) is thought high TSH and T4 levels and increased heart rate suggesting to provide Supplementary cholesterol to certain cells, e.g., that they retain cardiac sensitivity and therefore that the car cells involved in inflammation or repair. Lp(a) is an indepen diac effects are via TRO. TRO. knockouts exhibit reduced dent risk factor for premature atherosclerosis. Lp(a) is syn heart rates. thesized in the liver. 0012 THs also play a role in the development and function 0019 Apollipoprotein AI or apoAI is the major component of brown and white adipose tissue. Both TRC. and TRB are of HDL, which is an independent risk factor of atherosclero expressed in brown adipose tissue (BAT). THs induce differ sis. apoAI is thought to promote the efflux of cholesterol from entiation of white adipose tissue (WAT) as well as a variety of peripheral tissues and higher levels of HDL (or apoAI) result lipogenic genes, including ACC, FAS, glucose-6-phosphate in decreased risk of atherosclerosis. dehydrogenase and spot-14. Overall THS play an important 0020 Hyperthyroidism worsens glycemic control in type role in regulating basal oxygen consumption, fat stores, lipo 2 diabetics. TH therapy is reported to stimulate hepatic glu genesis and lipolysis (Oppenheimer, et al., J. Clin. Invest. coneogenesis. Enzymes specific to gluconeogenesis and 87(1): 125-32 (1991)). important for controlling the pathway and its physiological 0013 TH has been used as an antiobesity drug for over 50 role of producing glucose are known to be influenced by TH years. In the 1940s TH was used alone, whereas in the 1950s therapy. Phosphoenolpyruvate carboxykinase (PEPCK) is it was used in combination with diuretics and in the 1960s in upregulated by TH (Park et al., J. Biol. Chem., 274, 211 combination with amphetamines. Hyperthyroidism is associ (1999)) whereas others have found that glucose 6-phos ated with increased food intake but is also associated with an phatase is upregulated (Feng et al., Mol. Endrocrinol., 14,947 overall increase in the basal metabolic rate (BMR). Hyper (2000)).TH therapy is also associated with reduced glycogen thyroidism is also associated with decreased body weight (ca. levels. 15%) whereas hypothyroidism is associated with a 25-30% 0021 TH therapy results in improved non insulin stimu increase in body weight. Treating hypothyroidism patients lated and insulin stimulated glucose utilization and decreased with T3 leads to a decrease in body weight for most patients insulin resistance in the muscle of ob?ob mice. (Oh et al., J. but not all (17% of the patients maintain weight). Nutri, 125, 125 (1995)). 0014. The effectiveness of TH treatment is complicated by 0022. There is still a need for novel thyromimetics that can the need for Supraphysiological doses of T3 and the associ be used to modulate cholesterol levels, to treat obesity, and ated side effects, which include cardiac problems, muscle other metabolic disorders especially with reduced undesir weakness and excess erosion of body mass. Long-term able effects. US 2009/011 8236 A1 May 7, 2009

BRIEF DESCRIPTION OF THE DRAWINGS

0023 FIG. 1a. Depicts the binding of T3 to the TRC.1 Formula I receptor using a homologous displacement reaction. R3 R2 0024 FIG. 1b. Depicts the binding of T3 to the RB1 recep tor using a homologous displacement reaction. 0025 FIG.1c. Depicts the binding of Compound 17 to the TRC.1 receptor using a heterologous displacement reaction. 0026 FIG. 1d. Depicts the binding of Compound 17 to the R4 R1 TRB1 receptor using a heterologous displacement reaction. Formula II 0027 FIG. 1e. Depicts the binding of Compound 7 to the R3 R2 B D-X TRC.1 receptor using a heterologous displacement reaction. 0028 FIG. 1f. Depicts the binding of Compound 7 to the s TRB1 receptor using a heterologous displacement reaction. R5 G A 0029 FIG. 2a. Depicts the dose response of serum cho lesterol levels to Compound 17 in cholesterol fed rats. R4 R1 0030 FIG. 2b. Depicts the dose response of serum cho Formula III lesterol levels to Compound 7 in cholesterol fed rats. R3 R2 T-X 0031 FIG.3a. Depicts the effect of Compound 17 on the weight of the heart in cholesterol fed rats. 0032 FIG. 3b. Depicts the effect of Compound 7 on the weight of the heart in cholesterol fed rats. -)- \ / 0033 FIG. 4a. Depicts the effect of Compound 17 on R4 R1 R7 cardiac GPDH activity in cholesterol fed rats. Formula VIII 0034 FIG. 4b. Depicts the effect of Compound 7 on car R3 R8 R2 R6 diac GPDH activity in cholesterol fed rats. 0035 FIG. 5. Depicts the dose response of serum choles terol levels to Compound 13-1-cis in cholesterol-fed rats. -- T-X SUMMARY OF THE INVENTION R4 R9 R1 R7 0036. The present invention relates to phosphonic acid containing compounds that bind to thyroid receptors in the 0038. Some of the compoundsp of Formula I, II, III, and liver. Activation of these receptors results in modulation of VIII have asymmetric centers, thus included in the present gene expression of genes regulated by thyroid hormones. The invention are racemic mixtures, enantiomerically enriched present invention also relates to pharmaceutically acceptable mixtures, diastereomeric mixtures, including diastereomeric salts and co-crystals, prodrugs, and pharmaceutically accept enriched mixtures, and individual stereoisomers of the com able salts and co-crystals of these prodrugs of these com pounds of Formula I, II, III and VIII and prodrugs thereof. pounds. The compounds can be used to treat diseases and disorders including metabolic diseases. In one aspect, the DEFINITIONS phosphonic acid-containing compounds are useful for 0039. As used herein, the following terms are defined with improving efficacy, improving the therapeutic index, e.g., the following meanings, unless explicitly stated otherwise. decreasing non-liver related toxicities and side effects, or for 0040 T groups that have more than one atom are read from improving liver selectivity, i.e., increasing distribution of an left to right wherein the left atom of the T group is connected active drug to the liver relative to extrahepatic tissues and to the phenyl group bearing the R' and R groups, and the more specifically increasing distribution of the an active drug right atom of the T group is linked to the phosphorus atom in to the nucleus of liver cells relative to the nucleus of extrahe X. For example, when T is —O—CH2— or—N(H)C(O)—it patic tissue cells (including heart, kidney and pituitary). Pro means -phenyl-O CH-P(O)YR''Y'R'' and -phenyl-N drugs of the phosphonic acid-containing compounds are use (H)C(O) P(O)YR''Y'R''. ful for increasing oral bioavailability and sustained delivery 0041. The term “alkyl refers to a straight or branched or of the phosphosphonic acid-containing compounds. cyclic chain hydrocarbon radical with only single carbon 0037. In another aspect, the present invention relates to carbon bonds. Representative examples include methyl, compounds of Formula I, II, III, and VIII The compounds of ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert Formula I, II, III, and VIII may be an active form or a prodrug butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, and cyclohexyl, thereof. Further included are pharmaceutically acceptable all of which may be optionally substituted. Alkyl groups are salts, including but not limited to acid addition salts and C1-C12. physiological salts, and co-crystals of said compounds of 0042. The term “aryl refers to aromatic groups which Formula I, II, III, and VIII. Further included in the present have 5-14 ring atoms and at least one ring having a conjugated invention are prodrugs of compounds of Formula I, II, III, and pielectron system and includes carbocyclic aryl, heterocyclic VIII that are active forms, and pharmaceutically acceptable aryl and biaryl groups, all of which may be optionally Sub salts, including but not limited to acid addition salts and stituted. physiological salts, and co-crystals thereof. Further included 0043 Carbocyclic aryl groups are groups which have 6-14 are methods of making and using the compounds of the ring atoms wherein the ring atoms on the aromatic ring are present invention. carbon atoms. Carbocyclic aryl groups include monocyclic US 2009/011 8236 A1 May 7, 2009 carbocyclic aryl groups and polycyclic or fused compounds (a) R is aryl and R is hydrogen, alkyl, aralkyl, heterocy Such as optionally Substituted naphthyl groups. cloalkyl, or aryl, and (b) R is aralkyl and R' is hydrogen, 0044 Heterocyclic aryl or heteroaryl groups are groups aralkyl, aryl, alkyl or heterocycloalkyl. which have 5-14 ring atoms wherein 1 to 4 heteroatoms are 0054) The term “acyl” refers to C(O)R where R is alkyl, ring atoms in the aromatic ring and the remainder of the ring heterocycloalkyl, or aryl. atoms being carbonatoms. Suitable heteroatoms include oxy 0055. The term “carboxy esters' refers to C(O)OR gen, Sulfur, nitrogen, and selenium. Suitable heteroaryl where R is alkyl, aryl, aralkyl, cyclic alkyl, or heterocy groups include furanyl, thienyl, pyridyl, pyrrolyl. N-lower cloalkyl, all optionally substituted. alkylpyrrolyl pyridyl-N-oxide, pyrimidyl, pyrazinyl, imida 0056. The term “carboxyl refers to C(O)OH. Zolyl, and the like, all optionally substituted. 0057 The term “oxo” refers to —O in an alkyl or hetero 0045. The term “biaryl' represents aryl groups which have cycloalkyl group. 5-14 atoms containing more than one aromatic ring including 0058. The term “amino” refers to NRR' where Rand R' both fused ring systems and aryl groups substituted with other are independently selected from hydrogen, alkyl, aryl, aralkyl aryl groups. Such groups may be optionally substituted. Suit and heterocycloalkyl, all except Hare optionally substituted; able biaryl groups include naphthyl and biphenyl. and R and R' can form a cyclic ring system. 0046. The term “optionally substituted” or “substituted” includes groups substituted by one to six substituents, inde 0059. The term “-carboxylamido” refers to CONR pendently selected from lower alkyl, lower aryl, lower where each R is independently hydrogen or alkyl. aralkyl, lower cyclic alkyl, lower heterocycloalkyl, hydroxy, 0060. The term '-sulphonylamido’ or '-sulfonylamido' lower alkoxy, lower aryloxy, perhaloalkoxy, aralkoxy, lower refers to —S(=O)NR2 where each R is independently heteroaryl, lower heteroaryloxy, lower heteroarylalkyl, lower hydrogen or alkyl. heteroaralkoxy, azido, amino, halo, lower alkylthio, oXo, 0061. The term “halogen' or “halo” refers to - F - C1, lower acylalkyl, lower carboxy esters, carboxyl, -carboxa —Brand —I. mido, nitro, lower acyloxy, lower aminoalkyl, lower alky 0062. The term “alkylaminoalkylcarboxy' refers to the laminoaryl, lower alkylaryl, lower alkylaminoalkyl, lower group alkyl-NR-alk-C(O)—O— where “alk” is an alkylene alkoxyaryl, lower arylamino, lower aralkylamino, Sulfonyl, group, and R is a H or lower alkyl. lower-carboxamidoalkylaryl, lower-carboxamidoaryl, lower 0063. The term “sulphonyl' or “sulfonyl refers to hydroxyalkyl, lower haloalkyl, lower alkylaminoalkylcar —SOR, where R is H, alkyl, aryl, aralkyl, or heterocy boxy-, lower aminocarboxamidoalkyl-, cyano, lower alkoxy cloalkyl. alkyl, lower perhaloalkyl, and lower arylalkyloxyalkyl. 0064. The term “sulphonate” or “sulfonate” refers to 0047. “Substituted aryl” and “substituted heteroaryl —SOOR, where R is —H, alkyl, aryl, aralkyl, or heterocy refers to aryland heteroaryl groups substituted with 1-3 sub cloalkyl. stituents. These Substituents are selected from the group con 0065. The term “alkenyl refers to unsaturated groups sisting of lower alkyl, lower alkoxy, lower perhaloalkyl, halo, which have 2 to 12 atoms and contain at least one carbon hydroxy, and amino. carbon double bond and includes Straight-chain, branched 0048. The term “-aralkyl refers to an alkylene group sub chain and cyclic groups. Alkenyl groups may be optionally stituted with an aryl group. Suitable aralkyl groups include substituted. Suitable alkenyl groups include allyl. “1-alk benzyl, picolyl, and the like, and may be optionally Substi enyl refers to alkenyl groups where the double bond is tuted. “Heteroarylalkyl refers to an alkylene group substi between the first and second carbon atom. If the 1-alkenyl tuted with a heteroaryl group. group is attached to another group, e.g., it is a W Substituent 0049. The term “alkylaryl-” refers to an aryl group substi attached to the cyclic phosphonate, it is attached at the first tuted with an alkyl group. “Lower alkylaryl-” refers to such carbon. groups where alkyl is lower alkyl. 0066. The term “alkynyl refers to unsaturated groups 0050. The term “lower referred to herein in connection which have 2 to 12 atoms and contain at least one carbon with organic radicals or compounds respectively defines Such carbon triple bond and includes straight-chain, branched as with up to and including 10, in one aspect up to and chain and cyclic groups. Alkynyl groups may be optionally including 6, and in another aspect one to four carbon atoms. substituted. Suitable alkynyl groups include ethynyl. “1-alky Such groups may be straight chain, branched, or cyclic. nyl refers to alkynyl groups where the triple bond is between 0051. The term “cyclic alkyl or “cycloalkyl refers to the first and second carbon atom. If the 1-alkynyl group is alkyl groups that are cyclic of 3 to 10 carbonatoms, and in one attached to another group, e.g., it is a W substituent attached aspectare 3 to 6 carbon atoms Suitable cyclic groups include to the cyclic phosphonate, it is attached at the first carbon. norbornyl and cyclopropyl. Such groups may be substituted. 0067. The term “alkylene' refers to a divalent straight 0052. The term “heterocyclic”, “heterocyclic alkyl or chain, branched chain or cyclic Saturated aliphatic group. In "heterocycloalkyl refer to cyclic groups of 3 to 10 atoms, and one aspect the alkylene group contains up to and including 10 in one aspect are 3 to 6 atoms, containing at least one het atoms. In another aspect the alkylene chain contains up to and eroatom, in a further aspect are 1 to 3 heteroatoms. Suitable including 6 atoms. In a further aspect the alkylene groups heteroatoms include oxygen, Sulfur, and nitrogen. Heterocy contains up to and including 4 atoms. The alkylene group can clic groups may be attached through a nitrogen or through a be either straight, branched or cyclic. carbonatom in the ring. The heterocyclic alkyl groups include 0068. The term “acyloxy' refers to the ester group unsaturated cyclic, fused cyclic and Spirocyclic groups. Suit —O—C(O)R, where R is H, alkyl, alkenyl, alkynyl, aryl, able heterocyclic groups include pyrrolidinyl, morpholino, aralkyl, or heterocycloalkyl. morpholinoethyl, and pyridyl. 0069. The term "aminoalkyl-” refers to the group NR 0053. The terms “arylamino” (a), and “aralkylamino” (b). alk- wherein “alk” is an alkylene group and R is selected from respectively, refer to the group —NRR' wherein respectively, —H, alkyl, aryl, aralkyl, and heterocycloalkyl. US 2009/011 8236 A1 May 7, 2009

0070 The term “alkylaminoalkyl-” refers to the group I0089. The term “haloalkyl refers to an alkyl group sub alkyl-NR-alk- wherein each “alk” is an independently stituted with one halo. selected alkylene, and R is H or lower alkyl. “Lower alky (0090. The term “cyano” refers to -C=N. laminoalkyl-” refers to groups where the alkyl and the alky lene group is lower alkyl and alkylene, respectively. (0091. The term “nitro” refers to - NO. 0071. The term “arylaminoalkyl-refers to the group aryl 0092. The term “acylalkyl refers to an alkyl-C(O)-alk-, NR-alk- wherein “alk” is an alkylene group and R is —H. where “alk” is alkylene. alkyl, aryl, aralkyl, or heterocycloalkyl. In “lower arylami (0093. The term “aminocarboxamidoalkyl-” refers to the noalkyl-, the alkylene group is lower alkylene. group NR—C(O)—N(R)-alk- wherein R is an alkyl group or 0072 The term “alkylaminoaryl-” refers to the group H and “alk” is an alkylene group. "Lower aminocarboxami alkyl-NR-aryl- wherein “aryl' is a divalent group and R is doalkyl-” refers to such groups wherein “alk” is lower alky —H, alkyl, aralkyl, or heterocycloalkyl. In “lower alkylami lene. noaryl-, the alkyl group is lower alkyl. (0094. The term “heteroarylalkyl refers to an alkylene 0073. The term “alkoxyaryl- refers to an aryl group sub group Substituted with a heteroaryl group. stituted with an alkyloxy group. In “lower alkyloxyaryl-, the (0095. The term “perhalo” refers to groups wherein every alkyl group is lower alkyl. C—H bond has been replaced with a C-halo bond on an 0074 The term “aryloxyalkyl-” refers to an alkyl group aliphatic or aryl group. Suitable perhaloalkyl groups include Substituted with an aryloxy group. —CF and —CFC1. 0075. The term “aralkyloxyalkyl-” refers to the group 0096. The term “carboxylic acid moiety” refers to a com aryl-alk-O-alk- wherein “alk-' is an alkylene group. “Lower pound having a carboxylic acid group (-COOH), and salts aralkyloxyalkyl-” refers to such groups where the alkylene thereof, a carboxylic acid ester, or a carboxylic acid Surrogate. groups are lower alkylene. Suitable carboxylic acid surrogates include a tetrazole group, 0076. The term “alkoxy-” or “alkyloxy-” refers to the a hydroxamic acid group, a thiazolidinedione group, an acyl group alkyl-O-. Sulfonamide group, and a 6-azauracil; and prodrugs thereof. 0077. The term “alkoxyalkyl- or “alkyloxyalkyl-” refer Phosphonic acids and prodrugs thereof are not within the to the group alkyl-O-alk- wherein “alk” is an alkylene group. Scope of carboxylic acid Surrogates. In “lower alkoxyalkyl-, each alkyl and alkylene is lower 0097. The term “co-crystal as used herein means a crys alkyl and alkylene, respectively. talline material comprised of two or more unique Solids at 0078. The terms “alkylthio- and “alkylthio-” refer to the room temperature, each containing distinctive physical char group alkyl-S—. acteristics, such as structure, melting point and heats of 0079. The term “alkylthioalkyl-” refers to the group alkyl fusion. The co-crystals of the present invention comprise a 5-alk- wherein “alk” is an alkylene group. In “lower alkylth co-crystal former H-bonded to a compound of the present ioalkyl-” each alkyl and alkylene is lower alkyl and alkylene, invention. The co-crystal former may be H-bonded directly to respectively. the compound of the present invention or may be H-bonded to 0080. The term “alkoxycarbonyloxy- refers to alkyl-O an additional molecule which is bound to the compound of the C(O) O-. present invention. The additional molecule may be H-bonded 0081. The term “aryloxycarbonyloxy- refers to aryl-O to the compound of the present invention or bound ionically to C(O) O-. the compound of the present invention. The additional mol 0082. The term “alkylthiocarbonyloxy-” refers to alkyl ecule could also be a second API. Solvates of compounds of S C(O) O-. the present invention that do not further comprise a co-crystal 0083. The term "amido” refers to the NR group next to an former are not “co-crystals' according to the present inven acyl or sulfonyl group as in NR C(O) , RC(O) NR'—, tion. The co-crystals may however, include one or more sol NR S(=O), and RS(=O), NR-, where R and R' vate molecules in the crystalline lattice. That is, solvates of include —H, alkyl, aryl, aralkyl, and heterocycloalkyl. co-crystals, or a co-crystal further comprising a solvent or I0084. The term “carboxamido” refer to NR C(O)—and compound that is a liquid at room temperature, is included in RC(O) NR' , where R and R' include -H, alkyl, aryl, the present invention as a co-crystal. aralkyl, and heterocycloalkyl. The term does not include urea, 0098. The co-crystals may also be a co-crystal between a —NR C(O) NR-. co-crystal former and a salt of a compound of the present I0085. The terms “sulphonamido” or “sulfonamido” refer invention, but the compound of the present invention and the to NR S(=O) and RS(=O). NR'—, where Rand R' co-crystal former are constructed or bonded together through include —H, alkyl, aryl, aralkyl, and heterocycloalkyl. The hydrogen bonds. Other modes of molecular recognition may term does not include Sulfonylurea, —NR—S(—O)— also be present including, pi-stacking, guest-host complex NR ation and Vander Waals interactions. Of the interactions listed I0086. The term “carboxamidoalkylaryland “carboxami above, hydrogen-bonding is the dominant interaction in the doaryl” refers to an aryl-alk-NR'—C(O), and ar-NR'—C formation of the co-crystal, (and a required interaction (O)-alk-, respectively where “ar” is aryl, "alk” is alkylene, R' according to the present invention) whereby a non-covalent and R include H. alkyl, aryl, aralkyl, and heterocycloalkyl. bond is formed between a hydrogen bond donor of one of the 0087. The term "sulfonamidoalkylaryl and “sulfonami moieties and a hydrogen bond acceptor of the other. doaryl” refers to an aryl-alk-NR'—S(=O) , and 0099 Crystalline material comprised of solid compound ar-NR'—S(—O) , respectively where “ar is aryl, "alk” is of the present invention and one or more liquid solvents (at alkylene, R' and R include -H, alkyl, aryl, aralkyl, and room temperature) are included in the present invention as heterocycloalkyl. “solvates.” A “hydrate' is where the solvent is water. Other 0088. The term “hydroxyalkyl refers to an alkyl group forms of the present invention include, but are not limited to, substituted with one —OH. are anhydrous forms and de-Solvated Solvates. US 2009/011 8236 A1 May 7, 2009

0100. The ratio of the compound of the present invention formation to produce the compound that is biologically active to co-crystal former or solvent may be specified as Stoichio or is a precursor of the biologically active compound. In some metric or non-stoichiometric. 1:1, 1.5:1, 1:1.5, 2:1, 1:2, and cases, the prodrug is biologically active, usually less than the 1:3 ratios of API:co-crystal former/solvent are examples of drug itself, and serves to improve drug efficacy or safety Stoichiometric ratios. through improved oral bioavailability, and/or pharmacody 0101 The term “binding' means the specific association namic half-life, etc. Prodrug forms of compounds may be of the compound of interest to the thyroid hormone receptor. utilized, for example, to improve bioavailability, improve One method of measuring binding in this invention is the Subject acceptability Such as by masking or reducing unpleas ability of the compound to inhibit the association of 'I-T3 ant characteristics such as bitter taste orgastrointestinal irri with a mixture of thyroid hormone receptors using nuclear tability, alter solubility such as for intravenous use, provide extracts or purified or partially purified thyroid hormone for prolonged or Sustained release or delivery, improve ease receptor (for example, alpha or beta) in a heterologous assay. of formulation, or provide site-specific delivery of the com 0102 The term “energy expenditure” means basal or rest pound. Prodrugs are described in The Organic Chemistry of ing metabolic rate as defined by Schoeller et al., J Appl Drug Design and Drug Action, by Richard B. Silverman, Physiol. 53(4):955-9 (1982). Increases in the resting meta Academic Press, San Diego, 1992. Chapter 8: “Prodrugs and bolic rate can be also be measured using increases in O. Drug delivery Systems’ pp. 352-401; Design of Prodrugs, consumption and/or CO efflux and/or increases in organ or edited by H. Bundgaard, Elsevier Science, Amsterdam, 1985; body temperature. Design of Biopharmaceutical Properties through Prodrugs 0103) The phrase “therapeutically effective amount and Analogs, Ed. by E. B. Roche, American-Pharmaceutical means an amount of a compound or a combination of com Association, Washington, 1977; and Drug Delivery Systems, pounds that ameliorates, attenuates or eliminates one or more ed. by R. L. Juliano, Oxford Univ. Press, Oxford, 1980. of the symptoms of a particular disease or condition or pre 0108. The term "phosphonate prodrug” refers to com vents, modifies, or delays the onset of one or more of the pounds that breakdown chemically or enzymatically to a symptoms of a particular disease or condition. phosphonic acid group in vivo. As employed herein the term 0104. The term “pharmaceutically acceptable salt includes, but is not limited to, the following groups and com includes salts of compounds of Formula I and its prodrugs binations of these groups: derived from the combination of a compound of this invention 0109 Acyloxyalkyl esters which are well described in the and an organic or inorganic acid or base. Suitable acids literature (Farquhar et al., J. Pharm. Sci., 72: 324-325 include acetic acid, adipic acid, benzenesulfonic acid, (1983)). (+)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methane 0110. Other acyloxyalkyl esters are possible in which a Sulfonic acid, citric acid, 1.2-ethanedisulfonic acid, dodecyl cyclic alkyl ring is formed. These esters have been shown to Sulfonic acid, fumaric acid, glucoheptonic acid, gluconic generate phosphorus-containing nucleotides inside cells acid, glucuronic acid, hippuric acid, hydrochloride hemietha through a postulated sequence of reactions beginning with nolic acid, HBr, HCl, HI, 2-hydroxyethanesulfonic acid, lac deesterification and followed by a series of elimination reac tic acid, lactobionic acid, maleic acid, methanesulfonic acid, tions (e.g., Freed et al., Biochem. Pharm., 38: 3193-3 198 methylbromide acid, methyl suffinic acid, 2-naphthalene (1989)). Sulfonic acid, nitric acid, oleic acid, 4,4'-methylenebis 3-hy 0111. Another class of these double esters known as alky droxy-2-naphthalenecarboxylic acid, phosphoric acid, loxycarbonyloxymethyl esters, as shown informula A, where polygalacturonic acid, Stearic acid, Succinic acid, Sulfuric R is alkoxy, aryloxy, alkylthio, arylthio, alkylamino, andary acid, Sulfosalicylic acid, tannic acid, tartaric acid, terphthalic lamino; R', and R" are independently —H, alkyl, aryl, alky acid, and p-toluenesulfonic acid. laryl, and heterocycloalkyl have been studied in the area of B-lactam antibiotics (Nishimura et al., J. Antibiotics, 40(1): 0105. The term “patient’ means an animal. 81-90 (1987); for a review see Ferres, H., Drugs of Today, 19: 0106. The term “animal' includes birds and mammals, in 499 (1983)). More recently Cathy, M.S., et al. (Abstract from one embodiment a mammal, including a dog, cat, cow, horse, AAPS Western Regional Meeting, April, 1997) showed that goat, sheep, pig or human. In one embodiment the animal is a these alkyloxycarbonyloxymethyl ester prodrugs on (9-(R)- human. In another embodiment the animal is a male. In 2-phosphonomethoxy)propyladenine (MPA) are bioavail another embodiment the animal is a female. able up to 30% in dogs. 0107 The term “prodrug as used herein refers to any compound that when administered to a biological system generates a biologically active compound as a result of spon taneous chemical reaction(s), enzyme catalyzed chemical reaction(s), and/or metabolic chemical reaction(s), or a com bination of each. Standard prodrugs are formed using groups attached to functionality, e.g., HO , HS HOOC RN associated with the drug, that cleave in vivo. Standard prodrugs include but are not limited to carboxylate esters where the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxy 0112 wherein R. R', and R" are independently H, alkyl, carbonyloxyalkyl as well as esters of hydroxyl, thiol and aryl, alkylaryl, and alicyclic; (see WO 90/08155; WO amines where the group attached is an acyl group, an alkoxy 90/10636). carbonyl, aminocarbonyl; phosphate or Sulfate. The groups 0113. Other acyloxyalkyl esters are possible in which a illustrated are exemplary, not exhaustive, and one skilled in cyclic alkyl ring is formed such as shown informula B. These the art could prepare other known varieties of prodrugs. Such esters have been shown to generate phosphorus-containing prodrugs of the compounds of Formula I, fall within this nucleotides inside cells through a postulated sequence of Scope. Prodrugs must undergo some form of a chemical trans reactions beginning with deesterification and followed by a US 2009/011 8236 A1 May 7, 2009

series of elimination reactions (e.g. Freed et al., Biochem. Pharm., 38: 3193-3 198 (1989)). Formula D X O Formula B | O O O-P- Y X- X R. R" R OYa O R OYa O /N /N 0119 wherein X and Y are independently —H, alkyl, O R O aryl, alkylaryl, alkoxy, acyloxy, hydroxy, cyano, nitro, perhaloalkyl, halo, or alkyloxycarbonyl; and R' and R" are independently —H, alkyl, aryl, alkylaryl, halogen, OX-d and cyclic alkyl. 0.120. Thio-containing phosphonate proesters may also be 0114 wherein R is —H, alkyl, aryl, alkylaryl, alkoxy, useful in the delivery of drugs to hepatocytes. These proesters aryloxy, alkylthio, arylthio, alkylamino, arylamino, or contain a protected thioethyl moiety as shown in formula E. cycloalkyl. One or more of the oxygens of the phosphonate can be esteri fied. Since the mechanism that results in de-esterification 0115. Another class of these double esters known as alky requires the generation of a free thiolate, a variety of thiol loxycarbonyloxymethyl esters, as shown informula A, where protecting groups are possible. For example, the disulfide is R is alkoxy, aryloxy, alkylthio, arylthio, alkylamino, andary reduced by a reductase-mediated process (Puech et al., Anti lamino; R', and R" are independently —H, alkyl, aryl, alky viral Res. 22: 155-174 (1993)). Thioesters will also generate laryl, and heterocycloalkyl have been studied in the area of free thiolates after esterase-mediated hydrolysis Benzaria, et B-actam antibiotics (Nishimura et al., J. Antibiotics, 40(1): al., J. Med. Chem., 39(25): 4958-65 (1996)). Cyclic analogs 81-90 (1987); for a review see Ferres, H., Drugs of Today, 19: are also possible and were shown to liberate phosphonate in 499 (1983)). More recently Cathy, M.S., et al. (Abstract from isolated rat hepatocytes. The cyclic disulfide shown below AAPS Western Regional Meeting, April, 1997) showed that has not been previously described and is novel. these alkyloxycarbonyloxymethyl ester prodrugs on (9-((R)- 2-phosphonomethoxy)propyladenine (PMPA) are bioavail Formula E able up to 30% in dogs. 0116. Aryl esters have also been used as phosphonate pro S O drugs (e.g., DeLambert et al., J. Med. Chem. 37(7): 498-511 71 S N-1No ! D: (1994); Serafinowska et al., J. Med Chem. 38(8): 1372-9 S O (1995). Phenyl as well as mono and poly-substituted phenyl proesters have generated the parent phosphonic acid in stud ies conducted in animals and in man (Formula C). Another I0121 wherein Z is alkylcarbonyl, alkoxycarbonyl, aryl approach has been described where Y is a carboxylic ester carbonyl, aryloxycarbonyl, or alkylthio. ortho to the phosphate (Khamnei et al., J. Med. Chem. 39: 0.122 Other examples of suitable prodrugs include 4109-15 (1996)). proester classes exemplified by Biller and Magnin (U.S. Pat. No. 5,157,027); Serafinowska et al., J. Med. Chem., 38(3): 1372-9 (1995); Starrett et al., J. Med. Chem, 37: 1857 (1994); Formula C Martin et al. J. Pharm. Sci. 76: 180 (1987); Alexander et al., Collect. Czech. Chem. Commun, 59: 1853 (1994); and EP 0 632 048 A1. Some of the structural classes described are optionally Substituted, including fused lactones attached at the omega position (formulae E-1 and E-2) and optionally substituted 2-oxo-1,3-dioxolenes attached through a methyl 0117 wherein Y is —H, alkyl, aryl, alkylaryl, alkoxy, ene to the phosphorus oxygen (formula E-3) such as: acyloxy, halogen, amino, alkoxycarbonyl, hydroxy, cyano, and heterocycloalkyl. E-1 0118 Benzyl esters have also been reported to generate the parent phosphonic acid. In some cases, using Substituents at the para-position can accelerate the hydrolysis. Benzyl analogs with 4-acyloxy or 4-alkyloxy group Formula D. O X= H, OR or O(CO)R or O(CO)OR can generate the 4-hy | droxy compound more readily through the action of enzymes, - 0-- e.g., oxidases, esterases, etc. Examples of this class of pro Omega O drugs are described in Mitchell et al., J. Chem. Soc. Perkin 3-phthalidyl Trans. 12345 (1992); WO 91/19721. US 2009/011 8236 A1 May 7, 2009

-continued E-2 Formula G O O

O --o R'' HN R" ) COR O- – R Formula H 2-oxotetrahydrofuran-5-yl CO-alkyl E-3 O

--, CO-alkyl o O R" | R R O-P- I0131 Cyclic phosphoramidates have also been studied as 2-oxo-4,5- phosphonate prodrugs because of their speculated higher sta didehydro-1,3- dioxolanemethyl bility compared to non-cyclic phosphoramidates (e.g., Star rett et al., J. Med. Chem., 37: 1857 (1994)). I0132) Another type of phosphoramidate prodrug was 0123 wherein R is —H, alkyl, cycloalkyl, or heterocy reported as the combination of S-acyl-2-thioethyl ester and cloalkyl; and phosphoramidate (Egron et al., Nucleosides & Nucleotides, 0.124 wherein Y is —H, alkyl, aryl, alkylaryl, cyano, 18,981 (1999)) as shown in Formula J: alkoxy, acyloxy, halogen, amino, heterocycloalkyl, and alkoxycarbonyl. Formula J O O 0.125. The prodrugs of Formula E-3 are an example of | “optionally substituted heterocycloalkyl where the cyclic -P-O moiety contains a carbonate or thiocarbonate.” S R 0126 Propyl phosphonate proesters can also be used to HN deliver drugs into hepatocytes. These proesters may contain a hydroxyl and hydroxyl group derivatives at the 3-position of )-coals the propyl group as shown in formula F. The R and X groups R can form a cyclic ring system as shown in formula F. One or more of the oxygens of the phosphonate can be esterified. I0133. Other prodrugs are possible based on literature reports such as substituted ethyls for example, bis(trichloro ethyl)esters as disclosed by McGuigan, et al., Bioorg Med. Formula F Chem. Lett., 3:1207-1210 (1993), and the phenyl and benzyl O combined nucleotide esters reported by Meier, C. et al., Bioorg Med. Chem. Lett. 7:99-104 (1997). I0134. Other prodrugs are possible based on literature 's---- reports such as substituted ethyls for example, bis(trichloro X ethyl)esters as disclosed by McGuigan, et al., Bioorg Med. Chem. Lett., 3:1207-1210 (1993), and the phenyl and benzyl Y. o combined nucleotide esters reported by Meier, C. et al., YX -- Bioorg Med. Chem. Lett. 7:99-104 (1997). O 0.135 The structure

O R6 V V/ 0127 wherein R is alkyl, aryl, heteroaryl; -PO X-( I0128 X is hydrogen, alkylcarbonyloxy, alkyloxycarbo V N nyloxy; and A I0129. Y is alkyl, aryl, heteroaryl, alkoxy, alkylamino, R6 W alkylthio, halogen, hydrogen, hydroxy, acyloxy, amino. 0130 Phosphoramidate derivatives have been explored as has a plane of symmetry running through the phosphorus phosphate prodrugs (e.g., McGuigan et al., J. Med. Chem., oxygen double bond when R. R. V=W, and V and Ware 42: 393 (1999) and references cited therein) as shown in either both pointing up or both pointing down. The same is Formula G and H. true of structures where each - NR is replaced with —O—. US 2009/011 8236 A1 May 7, 2009

0136. The term “cyclic phosphonate ester of 1,3-propane 0.141. The structure above has an acyloxy substituent that diol”, “cyclic phosphonate diester of 1,3-propane diol”, “2 is three carbon atoms from a Y. and an optional Substituent, oxo 2, 1.3.2dioxaphosphonane”, “2 oxo 1.3.2diox —CH, on the new 6-membered ring. There has to be at least aphosphonane”, “dioxaphosphonane' refers to the following: one hydrogen at each of the following positions: the carbon attached to Z; both carbons alpha to the carbon labeled '3”; and the carbon attached to “OC(O)CH above. Q 9 0142. The phrase “together W and Ware connected via an additional 2-5 atoms to form a cyclic group, optionally con YV 6 ) taining 0-2 heteroatoms, and V must be aryl, Substituted aryl, O heteroaryl, or substituted heteroaryl' includes the following: 0.137 The phrase “together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally containing 1 heteroatom, Substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, oraryloxycarbonyloxy attached to a carbonatom that is three atoms from both Y groups attached to the phosphorus' includes the following:

0143. The structure above has V-aryl, and a spiro-fused cyclopropyl group for W and W". \ 1 / YOH 0144. The term "cyclic phosphon(amid)ate' refers to Y V W H O. Y V/ 0.138. The structure shown above (left) has an additional 3 -P Z carbon atoms that forms a five member cyclic group. Such V cyclic groups must possess the listed Substitution to be oxi Y H dized. W Wi 0.139. The phrase “together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally con (0145 where Y is independently - O - or - NR' . The taining one heteroatom, that is fused to an aryl group attached carbon attached to V must have a C-H bond. The carbon at the beta and gamma position to the Y attached to the attached to Z must also have a C H bond. phosphorus' includes the following: 0146 The naming of the compounds is done by having the ring bearing the groups RandR be a substituent on the ring bearing the R' and R groups. The naming of the prodrugs is done by having the diaryl system with its linker T (Formula I or III) or D (Formula II) be a substituent on the phosphorus atom contained in X. For example: 0147 (3-R'-5-R-4-(4'-R-3'-R-benzyl)phenoxymeth ylphosphonic acid represents the formula: R2 R3 0140. The phrase “together V and Ware connected via an additional 3 carbon atoms to form an optionally substituted R5 O Ri O 1n P p-h cyclic group containing 6 carbon atoms and Substituted with M \, one Substituent selected from the group consisting of O O-H hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said additional 3-R'-5-R-4-(4'-R-3'-R-phenoxy)phenoxymethylphos carbon atoms that is three atoms from a Y attached to the phonic acid represents the formula: phosphorus' includes the following: R2

R3 O

R5DO R 1N p-h US 2009/011 8236 A1 May 7, 2009 10

N-3-R'-5-R-4-(4-R-3'-R-phenoxy)phenyl)carbam 0150. The formula below shows another trans-stere oylphosphonic acid represents the formula: ochemistry.

R2 V V R3 O O osi?, 2 \"5 CY MI 5 ly/ O R R N P 0151. The terms "S-configuration”, “S-isomer' and “S-prodrug” refers to the absolute configuration S of carbon 2-(3-R'-5-R-4-(4'-R-3'-R-benzyl)phenoxy)methyl-4- C'. The formula below shows the S-stereochemistry. aryl-2-oxo-2,-1,3,2-dioxaphosphonane: V aH

3 o TV R Aryl SK 5 C \ 6 O R5 R 1N / 0152 The terms “R-configuration”, “R-isomer' and / Y, “R-prodrug” refers to the absolute configuration R of carbon C'. The formula below shows the R-stereochemistry. 2-(3-R'-5-R-4-(4'-R-3'-R-phenoxy)phenoxy)methyl-4- aryl-2-oxo-2a-1,3,2-dioxaphosphonane:

O '. I IIH R2 O 3 i S. 2 5 3 C PP R O Aryl O y R5 R 1n P 0153. The term “percent enantiomeric excess (% ee)' refers to optical purity. It is obtained by using the following / Y, formula: 0148. The term “cis' stereochemistry refers to the spatial relationship of the V group and the carbon attached to the x 100 = % R-96 S. phosphorus atom on the six-membered ring. The formula below shows a cis stereochemistry. 0154 where R is the amount of the R isomer and S is the amount of the S isomer. This formula provides the '% ee when R is the dominant isomer. (O155 The term “enantioenriched” or “enantiomerically enriched’ refers to a sample of a chiral compound that con sists of more of one enantiomer than the other. The extent to which a sample is enantiomerically enriched is quantitated by the enantiomeric ratio or the enantiomeric excess. 0156 The term “liver” refers to liver organ. 014.9 The term “trans' stereochemistry refers to the spa 0157. The term "enhancing refers to increasing or tial relationship of the V group and the carbon, attached to the improving a specific property. phosphorus atom, on the six-membered ring. The formula below shows a trans-stereochemistry. 0158. The term “liver specificity” refers to the ratio:

drug or a drug metabolite in liver tissue drug or a drug metabolite in blood or another tissue

as measured in animals treated with the drug or a prodrug. The ratio can be determined by measuring tissue levels at a spe cific time or may represent an AUC based on values measured at three or more time points. US 2009/011 8236 A1 May 7, 2009

0159. The term “phosphonic acid containing compounds' converts cholesterol to 7-alpha-hydroxycholesterol which is refers to compounds that contain POH or PO’. the first and rate-limiting step in the synthesis of bile acids. 0160 The term “inhibitor of fructose-1,6-biphosphatase' 0171 The term “apoAI refers to Apollipoprotein AI found or “FBPase inhibitor refers to compounds that inhibit in HDL and chylomicrons. It is an activator of LCAT and a FBPase enzyme activity and thereby block the conversion of ligand for the HDL receptor. fructose 1,6-bisphosphate, the substrate of the enzyme, to (0172. The term “mCPDH refers to mitochondrial glyc fructose 6-phosphate. These compounds have an ICso of erol-3-phosphate dehydrogenase. equal to or less than 50 uMonhuman liver FBPase measured 0173 The term “hypercholesterolemia' refers to presence according to the procedure found in U.S. Pat. No. 6,489,476. of an abnormally large amount of cholesterol in the cells and 0161 The term “increased or enhanced liver specificity' plasma of the circulating blood. refers to an increase in the liver specificity ratio in animals (0174. The term “hyperlipidemia' or “lipemia' refers to treated with a compound of the present invention and a con the presence of an abnormally large amount of lipids in the trol compound. In one embodiment the test compound is a circulating blood. phosphonic acid compound of the present invention and in (0175. The term “atherosclerosis' refers to a condition another embodiment the test compound is a prodrug thereof. characterized by irregularly distributed lipid deposits in the In one embodiment the control compound is a phosphonic intima of large and medium-sized arteries wherein Such acid compound of the present invention. In another embodi deposits provoke fibrosis and calcification. Atherosclerosis ment the control compound is the corresponding carboxylic raises the risk of angina, stroke, heart attack, or other cardiac acid derivative of the phosphonic acid test compound. or cardiovascular conditions. 0162 The term "enhanced oral bioavailability” refers to (0176) The term “obesity” refers to the condition of being an increase of at least 50% of the absorption of the dose of the obese. Being obese is defined as a BMI of 30.0 or greater; and parent drug, unless otherwise specified. In an additional extreme obesity is defined at a BMI of 40 or greater. “Over aspect the increase in oral bioavailability of the prodrug weight' is defined as a body mass index of 25.0 to 29.9 (This (compared to the parent drug) is at least 100%, that is a is generally about 10 percent over an ideal body weight) doubling of the absorption. Measurement of oral bioavailabil 0177. The term “coronary heart disease' or “coronary dis ity usually refers to measurements of the prodrug, drug, or ease' refers to an imbalance between myocardial functional drug metabolite in blood, plasma, tissues, or urine following requirements and the capacity of the coronary vessels to oral administration compared to measurements following supply sufficient blood flow. It is a form of myocardial systemic administration of the compound administered ischemia (insufficient blood supply to the heart muscle) orally. caused by a decreased capacity of the coronary vessels. 0163 The terms “treating or “treatment of a disease 0.178 The term "diabetes’ refers to a heterogeneous group includes a slowing of the progress or development of a disease of disorders that share glucose intolerance in common. It after onset or actually reversing some or all of the disease refers to disorders in which carbohydrate utilization is affects. Treatment also includes palliative treatment. reduced and that of lipid and protein enhanced; and may be 0164. The term “preventing includes a slowing of the characterized by hyperglycemia, glycosuria, ketoacidosis, progress or development of a disease before onset or preclud neuropathy, or nephropathy. ing onset of a disease. 0179 The term “non-insulin-dependent diabetes melli (0165. The term “thyroid hormone receptors” (TR) refers tus’ (NIDDM or type 2 diabetes) refers to a heterogeneous to intracellular proteins located in cell nuclei that, following disorder characterized by impaired insulin secretion by the the binding of thyroid hormone, stimulate transcription of pancreas and insulin resistance in tissues such as the liver, specific genes by binding to DNA sequences called thyroid muscle and adipose tissue. The manifestations of the disease hormone response elements (TREs). In this manner TR regu include one or more of the following: impaired glucose tol lates the expression of a wide variety of genes involved in erance, fasting hyperglycemia, glycosuria, increased hepatic metabolic processes (e.g., cholesterol homeostasis and fatty glucose output, reduced hepatic glucose uptake and glycogen acid oxidation) and growth and development in many tissues, storage, reduced whole body glucose uptake and utilization, including liver, muscle and heart. There are at least two forms dyslipidemia, fatty liver, ketoacidosis, microvascular dis of TR; TR alpha (on chromosome 17) and TR beta (on chro eases such as retinopathy, nephropathy and neuropathy, and mosome 3). Each of these isoforms also has two main iso macrovascular diseases such as coronary heart disease. forms: TR alpha-1 and TR alpha-2; and TR beta-1 and TR 0180. The term “impaired glucose tolerance (IGT) refers beta-2, respectively. TRs are high affinity receptors for thy to a condition known to precede the development of overt roid hormones, especially triiodothyronine. type 2 diabetes. It is characterized by abnormal blood glucose (0166 The term “ACC” refers to acetyl CoA carboxylase. excursions following a meal. The current criteria for the diag (0167. The term “FAS” refers to fatty acid synthase. nosis of IGT are based on 2-hplasma glucose levels posta 75 0168 The term "spot-14” refers to a 17 kilodalton protein g oral glucose test (144-199 mg/dL). Although variable from expressed in lipogenic tissues and is postulated to play a role population to population studied, IGT progresses to full in thyroid hormone stimulation of lipogenesis. (Campbell, M blown NIDDMata rate of 1.5 to 7.3% per year, with a mean Cet al., Endocriniology 10: 1210 (2003). of 3-4% per year. Individuals with IGT are believed to have a (0169. The term “CPT-1” refers to carnitine palmitoyl 6 to 10-fold increased risk in developing NIDDM. IGT is an transferase-1. independent risk factor for the development of cardiovascular (0170 The term “CYP7A” refers to Cholesterol 7-alpha disease. hydroxylase, which is a membrane-bound cytochrome P450 0181. The term “Non-Alcoholic SteatoHepatitis (NASH) enzyme that catalyzes the 7-alpha-hydroxylation of choles refers to an inflammatory condition of the liver characterized terol in the presence of molecular oxygen and NADPH-fer by fat accumulation, hepatocellular injury, and fibrosis or rihemoprotein reductase. This enzyme, encoded by CYP7, cirrhosis, and may affect 2-3 percent of adults in Western US 2009/011 8236 A1 May 7, 2009

countries. NASH is preceded by non-alcoholic fatty liver 0199 Fasting glucose greater than or equal to 110 disease, or NAFLD, which is characterized by fat accumula mg/dL tion in the liver and mild liver injury. The pathogenesis of (0200. The term “thyroid responsive element” or “TRE” NASH is multifactorial. Insulin resistance as well as the refers to an element that usually consists of directly repeated resulting hyperinsulinemia may be important factors in the half-sites with the consensus sequence AGGTCA. (Harbers et accumulation of hepatocellular fat, whereas excess intracel al., Nucleic Acids Res. 24 (12): 2252-2259 (1996)). TREs lular fatty acids, oxidant stress, adenosine triphosphate deple contain two half-sites of the AGG TCA motif which can be tion, and mitochondrial dysfunction may be important causes arranged as direct repeats, inverted repeats, or everted of hepatocellular injury and the development of an inflam repeats. matory condition in the steatotic liver. NASH is frequently but 0201 The term “thyroid responsive genes' refers to genes not always associated with severe obesity and is intimately whose expression is affected by triiodothyronine (Menjo et related to clinical and biological markers of the insulin resis tance syndrome. The accumulation of fat in the liver is al., Thyroid 9(9):959-67 (1999); Helbing et al., Mol. Endo thought to contribute significantly to the development of crinol. 17(7): 1395-409 (2003)). hepatic insulin resistance. (0202) The term “TSH or “thyrotropin” refers to the thy 0182. The term “insulin resistance' is defined clinically as roid stimulating hormone. the impaired ability of a known quantity of exogenous or 0203 The term “atherogenic proteins’ refers to proteins endogenous insulin to increase whole body glucose uptake that induce, stimulate, enhance or prolongatherosclerosis and and utilization. As insulin regulates a wide variety of meta diseases related to atherosclerosis, including but not limited bolic processes in addition to glucose homeostasis (e.g., lipid to coronary heart disease. Atherogenic proteins include and protein metabolism), the manifestations of insulin resis apoAI and Lp(a). tance are diverse and include one or more of the following: (0204. The term “thyroid hormone, or TH' includes for glucose intolerance, hyperinsulinemia, a characteristic dys example natural iodinated thyronines from thyroglobulin lipidemia (high triglycerides; low high-density lipoprotein (e.g., T3, T4), as well as drugs such as Levothyroxine Sodium cholesterol, and Small, dense low-density lipoprotein choles which is the sodium salt a levorotatory isomer of T4 and a terol), obesity, upper-body fat distribution, fat accumulation commonly used drug as replacement therapy in hypothyroid in the liver (non-alcoholic fatty liver disease), NASH (non ism. Other uses include the treatment of simple nonendemic alcoholic steatohepatitis), increased hepatic glucose output, goiter, chronic lymphocytic thyroiditis and thyrotropin-de reduced hepatic glucose uptake and storage into glycogen, pendent thyroid carcinoma. Liothyronine Sodium is the hypertension, and increased prothrombotic and antifibrin sodium salt a levorotatory isomer of T3. Liotrix is a 4:1 olytic factors. This cluster of cardiovascular-metabolic mixture of levothyroxine and liothronine. Thyroid is a prepa abnormalities is commonly referred to as “The Insulin Resis ration derived from dried and defatted thyroid glands of ani tance Syndrome' or “The Metabolic Syndrome' and may mals. lead to the development of type 2 diabetes, accelerated ath (0205 The term “thyromimetic' or “T3 mimetic” as used erosclerosis, hypertension or polycystic ovarian syndrome. herein, is intended to cover any moiety which binds to a 0183. The Metabolic Syndrome” or “Metabolic Syn thyroid receptor and acts as an agonists, antagonists or partial dromeX' is characterized by a group of metabolic risk factors agonists/antagonist of T3. The thyromimetic may be further in one person. They include: specified as a, agonists, an antagonists, a partial agonists, or a 0.184 Central obesity (excessive fattissue in and around partial antagonist. The thyromimetics of the present invention the abdomen) presumably bind the T3 binding site and can inhibit T3 bind 0185. Atherogenic dyslipidemia (blood fat disorders— ing to a thyroid hormone receptor utilizing a heterologous mainly high triglycerides and low HDL cholesterol— displacement reaction. Thyromimetics of the present inven that foster plaque buildups in artery walls) tion that can produce one of or more of the effects mediated by 0186 Raised blood pressure (130/85 mmHg or higher) naturally occurring L-triiodothyronine in a target tissue or 0187. Insulin resistance or glucose intolerance (the cell would be considered an agonist or partial agonist. Thy body can't properly use insulin or blood Sugar) romimetics of the present invention that can inhibit one of 0188 Prothrombotic state (e.g., high fibrinogen or plas more of the effects mediated by naturally occurring L-tri minogen activator inhibitor -1 in the blood) iodothyronine in a target tissue or cell would be considered an 0189 Proinflammatory state (e.g., elevated high-sensi antagonist, partial agonist, or inverse agonist. tivity C-reactive protein in the blood) 0206. The term “metabolic disease' includes diseases and 0190. According to the present invention, “Metabolic conditions such as obesity, diabetes and lipid disorders such Syndrome” or “Metabolic Syndrome X is identified by the as hypercholesterolemia, hyperlipidemia, hypertriglyceri presence of three or more of these components: demia as well as disorders that are associated with abnormal 0191 Central obesity as measured by waist circumfer levels of lipoproteins, lipids, carbohydrates and insulin Such CCC. as metabolic syndrome X, diabetes, impaired glucose toler (0192 Men: Greater than 40 inches ance, atherosclerosis, coronary heart disease, cardiovascular 0193 Women: Greater than 35 inches disease. 0194 Fasting blood triglycerides greater than or equal 0207. The term “mitochondrial biogenesis” or “mitochon to 150 mg/dL drialgenesis” refers to the rate at which nascent mitochondria (0195 Blood HDL cholesterol: are synthesized. Mitochondrial biogenesis that occurs during (0196) Men: Less than 40 mg/dL cell replication provides enough new mitochondria for both (0197) Women: Less than 50 mg/dL the parent and daughter cells. Mitochondrial biogenesis that 0198 Blood pressure greater than or equal to 130/85 occurs in the absence of cell replication leads to an increase in mmHg the number of mitochondria within a cell. US 2009/011 8236 A1 May 7, 2009

0208. As used herein, the term “significant’ or “statisti receptor with sufficient affinity for receptor activity, it was not cally significant’ means a result (i.e. experimental assay known whether the compound would act as an agonist or result) where the p-value is s().05 (i.e. the chance of a type I antagonist of receptor activity; error is less than 5%) as determined by an art-accepted mea 0218 5. if the if the phosphonic acid containing T3 Sure of statistical significance appropriate to the experimental mimetic were transported across both the cellular membrane design. and the nuclear membrane of the liver cell, and bound to the 0209 All references cited herein are incorporated by ref TR receptor with sufficient affinity for receptor activation, erence in their entirety. and acted as an agonist of receptor activity, it was unknown whether the compound would have a high enough tissue DETAILED DESCRIPTION selectivity and have a therapeutic index great enough to be 0210. The present invention relates to methods of prevent efficacious in treating the diseases and disorders described ing or treating metabolic diseases with phosphonic acid con herein while avoiding undesired side-effects involving the taining compounds, pharmaceutically acceptable salts and heart. prodrugs thereof, and pharmaceutically acceptable salts of 0219. 6. finally, even if the if the phosphonic acid contain the prodrugs, where the phosphonic acid containing com ing T3 mimetic were transported across both the cellular pounds bind to a thyroid hormone receptor. membrane and the nuclear membrane of the liver cell, and 0211 Thyroid hormones and thyroid hormone mimetics bound to the TR receptor with sufficient affinity for receptor bind to thyroid hormone receptors in the nucleus of cells and activation, and acted as an agonist of receptor activity, and can change expression levels of genes encoding proteins that have a high enough tissue selectivity and have a therapeutic play an important role in metabolic diseases. Metabolic dis index great enough to be efficacious in treating the diseases eases that can be prevented or treated with thyroid hormone and disorders described herein while avoiding undesired side mimetics include obesity and lipid disorders such as hyperc effects involving the heart, it was not known if the phosphonic holesterolemia, hyperlipidemia, and hypertriglyderidemia as acid containing compounds of the present invention would be described in further detail below. Other metabolic diseases rapidly cleared from the blood by the kidneys thereby making that can be prevented or treated with thyroid hormone mimet the compound less useful as a drug compound. ics include NASH, diabetes, impaired glucose tolerance, and 0220 Thus, it was unexpected when the present Inventors insulin resistance. Conditions associated with these diseases, discovered that the phosphonic acid-T3 mimetic compounds Such as atherosclerosis, coronary artery disease, and heart of the present invention are capable of being effectively trans failure, can also be treated with these thyroid hormone recep ported across the cellular membrane into liver cells and across tor binding compounds. the nuclear membrane where they bind the thyroid receptors 0212 Prior to the discoveries of the present invention, and activate thyroid hormone responsive genes. Further, Sur phosphonic acids were thought to be a poor replacement for prisingly the present Inventors discovered that the com carboxylic acids based on differences in geometry, size, and pounds of the present invention bind to the thyroid receptors charge. Phosphonic acids can also show reduced binding with sufficient binding affinity to be effective inactivating the affinities against enzymes that utilize or bind the analogous receptors. Still further surprisingly, the present Inventors dis carboxylic acid. Phosphonic acids can also display differ covered that the compounds of the present invention act as ences in cellular and in vivo potency, oral bioavailability, agonists rather than antagonists and are thus effective in acti pharmacokinetics, metabolism, and safety. T3 and previously Vating thyroid hormone responsive genes and for the uses reported T3 mimetics contain a carboxylic acid thought to be described herein, such as lowering cholesterol. Still further important for binding and activation of T3 responsive genes. Surprisingly, the present Inventors discovered that the com The carboxylic acid may also be important in the transport pounds of the present invention are effective in activating and distribution of these compounds through various trans thyroid hormone responsive genes and for the uses described port proteins. Transport proteins can enhance transport of herein, such as lowering cholesterol, even for compounds of certain compounds, particularly negatively charged com the present invention that bind to the thyroid hormone recep pounds, to the nucleus. tors with reduced affinity as compared to the corresponding 0213 Prior to the discoveries of the present invention it carboxylic acid derivative. Still further surprisingly, the was therefore unclear whether replacement of a carboxylic present Inventors discovered that the compounds of the acid with a phosphonic acid would produce a compound that present invention have a high enough tissue selectivity and is effacious as a T3 mimetic because of the following: have a therapeutic index great enough to be efficacious in 0214) 1... it was not known whether a T3 mimetic with a treating the diseases and disorders described herein while phosphonic acid in place of the carboxylic acid would trans avoiding undesired side-effects involving the heart. ported into liver cell across the cellular membrane; 0221. It is well known that many phonphosic acids in the 0215 2. if the phosphonic acid containing T3 mimetic blood are quickly cleared by the kidneys thereby greatly were transported across the cellular membrane of liver cells, diminishing there usefulness as drugs in many cases. When it was not known whether the compound would be trans the Inventors of the present invention discovered that pro ported across the nuclear membrane into the nucleus; drugs of the compounds of the present invention were 0216 3. if the phosphonic acid containing T3 mimetic excreted into the blood stream as active phosphonic acids were transported across both the cellular membrane and the after being processed in the liver, it was not known whether nuclear membrane of the liver cell, it was not known if the the active compound would be quickly cleared by the kidneys compound would bind to the TR receptor with a great enough or whether the phosphonic acid would be re-absorbed or affinity to be effacious; transported into the liver. It was therefore unexpected when 0217. 4. if the phosphonic acid containing T3 mimetic the present Inventors discovered that the active phosphonic were transported across both the cellular membrane and the acid compounds of the present invention were not rapidly nuclear membrane of the liver cell, and bound to the TR cleared by the kidneys. It was also unexpected when the US 2009/011 8236 A1 May 7, 2009

present Inventors discovered that the active phosphonic acid lar uptake but in Some cases are poorly converted to the compounds of the present invention were re-absorbed or phosphonic acid due to low levels of the enzymes required for transported back into the liver. In fact, it was Surprisingly the conversion. Changes in gene expression in vivo require found that the liver was the main mode of clearance of com either the phosphonic acid of the invention to be taken up by pounds tested. the tissue following administration or for the prodrug remain intact after administration long enough to distribute to the 0222. In one aspect, the phosphonic acid containing com target organ and cell. Following distribution to the cell, pounds, pharmaceutically acceptable salts and prodrugs enzymes responsible for cleaving the prodrug must act on the thereof, and pharmaceutically acceptable salts of the pro prodrug and convert it to the phosphonic acid. The phospho drugs used in these methods bind to at least one thyroid nic acid must then be able to be transported to the nucleus. If hormone receptor with an Ki of s 100 nM relative to T3, or a portion of the phosphonic acid is excreted from the cell it s90 nM, s80 nM, f 70 nM, sG0 nM, is 50 nM, is 40 nM, must be retransported back across the cellular membrane and s30 nM, s20 nM, is 10 nM, is 50 nM, s1 nM, s0.5 nM. nuclear membrane. The prodrugs of the present invention that Thyroid hormone receptor binding is readily determined are activated in the liver and excreted by the liver as phospho using assays described in the literature. For example, nuclear nic acids compounds are retransported back across the cellu extracts from animal livers can be prepared according to the lar and nuclear membrane and into the nucleus. Despite the methods described by Yokoyama et al. (J. Med. Chem., 38: being excreted from the liver and having to be retransported 695-707 (1995)). Binding assays can also be performed using into the nucleus and despite having reduced potency, in vivo, purified thyroid hormone receptors. For example, using the the phosphonic acids and their prodrugs led to Suprisingly methods used by Chiellini et al. (Bioorg. Med. Chem., 10: potent biological activity. This Surprisingly high biological 333-346 (2002)) competition ligand binding affinities are activity is attributed to the ability of the compounds of the determined using IT3 and the human thyroid receptors present invention to modulate genes known to be regulated by TRO.1 and TRB1. The latter methods advantageously enable T3. For example, mGPDH increased >1.5-fold in the liver of determination of thyroid receptor selectivity. Methods an animal administered a 1 mg/kg dose of the drug. described in Example A were used to determine the binding of 0224. The liver is a major target organ of thyroid hormone compounds of this invention. with an estimated 8% of the hepatic genes regulated by thy 0223. In another aspect, the phosphonic acid containing roid hormone. Quantitative fluorescent-labeled cDNA compounds, pharmaceutically acceptable salts and prodrugs microarray hybridization was used to identify thyroid-re thereof, and pharmaceutically acceptable salts of the pro sponsive genes in the liver as shown in Table 1 below (Feng et drugs used in these methods cause at least a 50%, 2 fold, 3 al., Mol. Endocritol, 14:947-955 (2000)). Hepatic RNA from fold, 4 fold, 6 fold or 8 fold increase or decrease in the T3-treated and hypothyoid mice were used in the study. Thy expression of one or more thyroid hormone-responsive roid hormone treatment affected the expression of 55 genes genes. Changes in gene expression can be detected in cells or from the 2225 different mouse genes sampled with 14 in vivo. Prodrugs of the phosphonic acids can increase cellu increasing >2-fold and 41 decreasing >60%.

TABLE 1.

GENES REGULATED BY T3 List of Hepatie Genes Regulated by T3 Determined by cDNA Microarray Analyses

Function Accession Clone ID Genes No. Fold Carbohydrate and fatty acid metabolism, and insulin action 580906 Spot 14 gene X95279 8.8 523120 Glucose-6-phosphatase UOO445 3.8 615159 Carbonyl reductase (Cbr1) U31966 3.3 571409 Insulin-like growth factor binding protein 1 precursor X81579 3.0 481636 Fatty acid transport protein (FATP) U15976 1.8 550993 Cyp4a-10 X69296 O.3 583329 PHAS-II U75530 O.3 616283 Serine/threonine kinase (Akt2) U22445 O.3 583333 Putative transcription factor of the insulin gene X17500 O.3 533177 Nuclear-encoded mitochondrial acyltransferase L42996 O.2 608607 Glycerophosphate dehydrogenase O2655 O.3 Cell proliferation, Replication

614275 B61 U26.188 2.3 597868 BC-3 M90397 2.5 493127 Kinesin-like protein (Kip1p) AF13186S 2.0 582689 Chromodomain-helicase-DNA binding protein CHD-1 P4O2O1 0.4 524471 NfiB1-protein (exon 1-12) YO7685 O.3 516208 Putative ATP-dependent RNA helicase PL10 O4847 O.3 558121 Murine wikiSvariant in the kinase SS3216 O.1 573247 C11 protein X81624 O.3 522108 Thymic stromal stimulating factor D438.04 O.3 613942 Ubiquitin-activating enzyme E1 X D10576 O.3 US 2009/011 8236 A1 May 7, 2009 15

TABLE 1-continued

GENES REGULATED BY T3 List of Hepatic Genes Regulated by T3 Determined by cDNA Microarray Analyses Function Accession Clone ID Genes No. Fold Signal transduction 573046 B-2 Adrenergic receptor X15643 3.4 583258 Protein kinase C inhibitor (mPKCI) U6OOO1 2.1 616040 Inhibitory G protein of adenylate cyclase, C. chain M13963 O.3 583353 Terminal deoxynucleotidyltransferase O4123 O.3 550956 Rho-associated, coiled-coil forming protein kinase p160 U58513 O.2 582973 Protein kinase C, 0 type ABO11812 O.3 442989 Protein kinase 3 M94632 O.S 607870 Lamin A D13181 O.3 Glycoprotein synthesis 375144 C-2,3-Sialyltransferase D28941 481883 B-Galactoside C. 2,6-sialyltransferase D16106 Cellular immunity 615872 T-complex protein 1, d subunit P80315 618426 H-2 class I histocompatibility antigen Q61147 614012 FK506-binding protein (FKBP65) LO7063 604923 FK506-binding protein (FKBP23) AFO4O2S2 Cytoskeletal protein

374030 Myosin binding protein H (MyBP-H) U68.267 2.2 613905 AM2 receptor X67469 O.3 616518 Cytoskeletal B-actin XO3672 O.3 614948 Actin, C. cardiac M1SSO1 O.3 607364 Skeletal muscle actin M12866 O.3 597566 Capping protein a-subunit GS65961 O.3 483226 Actin, Y-enteric smooth muscle M26689 O.3 Others

552837 Major urinary protein 2 precursor M27608 3.9 521118 B-Globin ABO2O013 2.3 493218 C-Globin L75940 2.7 585883 Putative SH3-containing protein SH3P12 AFO786.67 O.3 615239 Membrane-type matrix metalloproteinase X83536 O.2 402408 ecel (endothelin-converting enzyme) W7861O O.2 635768 C-Adaptin P17426 O.3 634827 Glucose regulated protein 78 D7864.5 O.3 616189 Lupus la protein homolog LOO993 O.3 5883.37 EST AI6467S3 0.4 335579 Virus-like (VL30) retrotransposon BVL-1 X17124 O.3 557037 TGN38B DSOO32 O.3 597390 Mitochondrial genome LO7096 0.4 616563 Arylsulfatase A X73230 O.3

0225 Genes reported to be affected by thyroid hormone 0227 Thyroid-responsive genes in the heart are not as well are identified using a variety oftechniques include microarray described as the liver but could be determined using similar analysis. Studies have identified genes that are affected by T3 techniques as described by Feng et al. Many of the genes and T3 mimetics that are important in metabolic diseases. described to be affected in the heart are the same as described 0226 T3-responsive genes in the liver include genes affecting lipogenesis, including spot 14, fatty acid transport above for the liver. Common genes evaluated include mito protein, malic enzyme, fatty acid synthase (Blennemann etal, chondrial sn-glycerol 3-phosphate dehydrogenase (mG Mol Cell Endocrinol. 110(1-2):1-8 (1995)) and CYP4A. PDH), and myosin heavy and light chains (Danzi et al., Thy HMG CoA reductase and LDL receptor genes have been roid. 12(6):467-72 (2002)). identified as affecting cholesterol synthesis and as being 0228 Compounds used in the methods bind to thyroid responsive to T3. CPT-1 is a T3 responsive gene involved in receptors and produce a change in some hepatic gene expres fatty acid oxidation. Genes affecting energy expenditure, Sion. Evidence for agonist activity is obtained using standard including mitochondrial genes Such as mitochondrial assays described in the literature. One assay commonly used sn-glycerol 3-phosphate dehydrogenase (mGPDH), and/or entails a reporter cell assay wherein cells, e.g., HeLa cells, enzymes associated with proton leakage such as the adenine Hek293 cells, chinese ovary cells, are transfected with an nucleotide transporter (ANT), Na"/K"-ATPase, Ca"-AT expression vector for human TRO.1 or TRB1 and subse Pase and ATP synthase are also T3 responsive genes. T3 quently with a reporter vector encoding a secreted form of responsive genes affecting glycogenolysis and gluconeogen alkaline phosphatase containing whose expression is under esis, include glucose 6-phosphatase and PEPCK. the control of a thyroid hormone response element. Agonist US 2009/011 8236 A1 May 7, 2009 activity is measured by exposing the cells to the compounds, significant decrease in T4, or significant change in the ratio of especially phosphonic acid prodrugs of the compounds that T3 to T4 is observed, is at least 50 fold, 100 fold, 200 fold,300 are cleaved to the phosphonic acid by cell homogenates, fold, 400 fold, 500 fold, 600 fold, 700 fold, 800 fold,900 fold, followed by determining alkaline phosphatase activity in the 1000 fold, 2000 fold, 3000 fold, 4000 fold, 5000 fold, 6000 cell culture medium using a chemiluminescent assay (Grover fold, 7000 fold, 8000 fold, 9000 fold or at least 10000 fold. In et al., Proc. Natl. Acad. Sci. U.S.A., 100(17): 10067-72 one embodiment, rather than a significant amount, the (2003)). amount of change in T3 or T4 is a decrease selected from; at 0229. In one aspect, the phosphonic acid thyromimetics least 5%, 10%, 15%, 20%, 25% or at least 30% of circulating and their prodrugs and salts are useful in preventing or treat levels. ing arteriosclerosis by modulating levels of atherogenic pro 0234 Side effects associated with TH-based therapies teins, e.g., Lp(a), apoAI, apoAII, LDL, HDL. Clinically overt limit their use for treating obese patients and according to the hypothyroidism is associated with accelerated and premature Physician's Desk Reference (PDR) T3 is now contraindicated coronary atherosclerosis and Subclinical hypothyroidism is for patients with obesity. 3.5-dichloro-4-4-hydroxy-3-(1- considered a condition with an increased risk for these dis methylethyl)phenoxybenzeneacetic acid and other T3 eases (Vanhaelst et al. and Bastenie et al., Lancet 2 (1967)). mimetics are reported to result in weight loss in animals, e.g., 0230 T3 and T3 mimetics modulate atherogenic proteins rodent models and monkeys. Weight loss from these com in a manner that could prove beneficial for patients at risk to pounds may arise from their effects on the liver as well as develop atherosclerosis or have patients with atherosclerosis peripheral tissues. TH is known to have a multitude of effects or diseases associated with atherosclerosis. T3 and T3 mimet outside of the liver that could result in increased metabolism ics are known to decrease Lp(a) levels, e.g., in the monkey and weight loss. TH plays an important role in the develop with 3,5-dichloro-4-4-hydroxy-3-(1-methylethyl)phenoxy ment and function of brown and white adipose tissue. TH can benzeneacetic acid (Grover et al., Proc. Natl. Acad. Sci. U.S. induce WAT differentiation, proliferation and intracellular A., 100, 10067-10072 (2003)). In human hepatoma cells, the lipid accumulation. THinduces lipogenic genes in WAT Such T3 mimetic CGS23425 (4-4-hydroxy-3-(1-methylethyl) as glucose-6-phosphate dehydrogenase, fatty acid synthase phenoxy-3,5-dimethylphenylaminoloxo acetic acid) and spot-14. TH also regulates lipolysis in fat to produce increased apoAI expression via thyroid hormone receptor weight loss in a coordinated manner, i.e., lipolysis in fat to activation (Taylor et al., Mol. Pharm., 52, 542-547 (1997)). free fatty acids followed by free fatty acid utilization in tis 0231. Thus in one aspect, the phosphonic acid containing Sues, e.g., liver, muscle and heart. thyromimetics, their salts and prodrugs can be used to treator 0235 Weight loss through administration of liver-specific prevent atherosclerosis, coronary heart disease and heart fail T3 analogues requires that the increased oxygen consumption ure because Such compounds are expected to distribute to the in the liver resulting from T3 is sufficient to result in net whole liver (Examples F and H) and modulate the expression and body energy expenditure. The liver's contribution to energy production of atherogenic proteins. expenditure is estimated to be 22% based on oxygen con 0232. In another aspect, the phosphonic acid containing sumption measurements. (Hsu, Aetal. Am J Clin Nutr. 77(6): thyromimetics and their prodrugs and salts are useful for 1506-11 (2003)). Thus, the compounds of the present inven preventing and/or treating metabolic diseases such as obesity, tion may be used to maintain or reduce weight in an animal. hypercholesterolemia and hyperlipidemia and conditions 0236 Mitochondria are the fuel source for all cellular Such as atherosclerosis, coronary heart disease, heart failure respiration. The synthesis of new mitochondria is a complex without affecting thyroid function, thyroid production of cir process which requires over 1000 genes (Goffart et al., Exp culating iodinated thyronines such as T3 and T4, and/or the Physiol. Jan. 88(1):33-40 (2003)). The mechanisms which ratio of T3 to T4. Compounds previously reported that con control mitochondrial biogenesis are not well defined, but are tain a carboxylic acid moiety, e.g., GC-1 (4-4-hydroxy-3- known to include exercise (Jones et al., Am J Physiol Endo (1-methylethyl)phenyl)methyl-3,5-dimethylphenoxyacetic crinol Metab. 2003 Jan. 284(1):E96-101), overexpression of acid) (Trost et al., Endocrinology, 141, 3057-3064 (2000)) PGC-1 (Lehman et al., J Clin Invest. 2000 Oct. 106(7):847 and 3,5-Dichloro-4-4-hydroxy-3-(1-methylethyl)phenoxy 56) or AMP activated protein kinase (Bergeron et al., Am J benzeneacetic acid (Grover et al., Proc. Natl. Acad. Sci. U.S. Physiol Endocrinol Metab. 2001 Dec. 281 (6):E1340-6). An A., 100, 10067-10072 (2003)) report that these TRB-selective increase in mitochondrial density leads to a greater rate of compounds dose-dependently lower cholesterol and TSH energy expenditure. Thyroid hormone has been shown to play levels. Effects on cholesterol and TSH occurat the same dose a key role in mitochondrial biogenesis by increasing expres or at doses stated to be not pharmacologically different (e.g., sion of nuclear respiratory factor-1 and PGC-1 (Weitzel et al., 2-fold). Exp Physiol. 2003 Jan. 88(1):121-8). 0233 Particularly useful T3 mimetics in these methods 0237 Compounds which increase the expression of would minimize effects on thyroid function, thyroid produc NRF-1 and/or PGC-1 could lead to an increase in mitochon tion of circulating iodinated thyronines such as T3 and T4. drial density within a cell. Such an increase would cause the and/or the ratio of T3 to T4. Unlike prior T3 mimetics, the cell to have a higher rate of energy expenditure. Methods to compounds or the present invention distribute more readily to analyze NRF-1 and PGC-1 include immunoblotting with spe the liver and result in pharmacological effects at doses that do cificantibodies, or analysis of mRNA levels. Compounds that not adversely affect thyroid function, thyroid production of caused increases in NRF-1 or PGC-1 would therefore lead to circulating iodinated thyronines such as T3 and T4, and/or the a greater energy expenditure. Even Small increases in energy ratio of T3 to T4. In one embodiment the compounds of the expenditure over long periods of time (weeks to years) could present invention have a therapeutic index, defined as the cause a decrease in weight under isocaloric circumstances. difference between the dose at which a significant effect is Further methods for assessing mitochondrial biogenesis observed for a use disclosed herein, e.g., lowering choles include the analysis of mitochondrial proteins such as cyto terol, and the dose at which a significant decrease in T3 or chrome c and cytochrome c oxidase, either by immunoblot US 2009/011 8236 A1 May 7, 2009

ting or analysis of mRNA levels. Mitochondrial density can sion in skeletal muscle and total amelioration of the hyperin also be measured by counting the number of mitochondria in Sulinemia, although plasma glucose levels were moderately electron micrographs. elevated (Torrance et al. Endocrinol., 138, 1204 (1997)). 0238. In one aspect, phosphonic acid containing thyromi Thus another embodiment of the present invention relates to metics and their prodrugs and salts may be used to cause the use of compounds of the present invention to prevent or weight loss or prevent weight gain withoutside effects. It may treat hyperinsulinemia. be advantageous to use compounds that result in high liver 0243 TH therapy results in increased energy expenditure. specificity. (Examples F and G) In one aspect, compounds Increased energy expenditure can result in increased weight that result in increased levels of genes associated with oxygen loss, which in turn can result in improved glycemic control. consumption, e.g., GPDH (Example B), are particularly use Diet and exercise are often used initially to treat diabetics. ful in weight loss and controlling weight gain. In another Exercise and weight loss increase insulin sensitivity and aspect, compounds that show weight loss at doses that do not improve glycemia. Thus, further uses of the compounds of the affect cardiac function, e.g., heart rate, force of systolic con present invention include increasing energy expenditure, traction, duration of diastolic relaxation, vascular tone, heart increasing insuling sensitivity and improving glycemia. weight may be particularly useful in weight loss and control 0244. In one aspect, the phosphonic acid containing com ling weight gain. In a further aspect, compounds that cause pounds of the present invention are useful form increasing weight loss without affecting thyroid function, thyroid pro levels of genes associated with gluconeogenesis (Example duction of circulating iodinated thyronines such as T3 and T4. B). In another aspect, the compounds of the present invention and/or the ratio of T3 to T4 are particularly useful. are useful for decreasing hepatic glycogen levels. Further, 0239 Besides their use in obesity and weight control, compounds of the present invention result in amelioration of phosphonic acid containing thyromimetics and their prodrugs hyperinsulinemia and/or decreased glucose levels in diabetic and salts may be used to treat diabetes and related conditions animal models at doses that do not affect cardiac function, like impaired glucose tolerance, insulin resistance and hyper e.g., heart rate, force of systolic contraction, duration of dias insulinemia. tolic relaxation, vascular tone, heart weight. In a further 0240 Patients with type 2 diabetes “T2DMs” exhibit aspect, compounds of the present invention result in amelio chronic high blood glucose levels. High fasting blood glucose ration of hyperinsulinemia and/or decreased glucose levels in in T2DMs is related to the overproduction of glucose by a diabetic animal models at doses that do not affect thyroid pathway in the liver known as the gluconeogenesis pathway. function, thyroid production of circulating iodinated thy Throughput in this pathway is controlled in part by enzymes ronines such as T3 and T4, and/or the ratio of T3 to T4. in the pathway such as PEPCK, fructose 1,6-bisphosphatase 0245. As discussed above, the previous use of T3 and T3 and glucose 6-phosphatase as well as by hormones such as mimetics to treat metabolic diseases have been limited by the insulin, which can influence the expression and activities of deleterious side-effects on the heart. Previous attempts to these enzymes. T3 is known to worsen diabetes. While the overcome this limitation have focused on selectively target reason T3 worsens diabetes is not known, T3's effect on ing the liver over the heart using T3 mimetics that selectively increasing the gene expression of PEPCK and glucose-6- bind TRB over TRC. Because the heart expresses mainly phosphatase may be the cause of increased glucose levels. T3 TRC, previous investigators have attempted to increase the is known to increase lipolysis of triglyceride pools in fat and therapeutic index of T3 mimetics by increasing the selec to increase circulating levels of free fatty acids. (K. S. Park, et tively of the compounds for TRB which is expressed in the al., Metabolism (1999) Oct.: 48(10): 1318-21) T3's effect on liver. Previous attempts have not focused on T3 mimetics that free fatty acid levels may also be responsible for the negative selectively distribute to the liver over the heart or at least have effect on diabetes because high free fatty acid levels enhance not been Successful. Thus, rather than selecting for a particu flux through the gluconeogenesis pathway. lar tissue or organ, previous work has been directed to dis 0241 Compounds of this invention, while they mimic T3, covering T3 mimetics that act selectively at the receptor level result in preferential activation of liver T3 genes, are not after the drug is non-selectively distributed to both heart and expected to increase lipolysis in peripheral tissues which is liver tissue. It was therefore unexpected when the present expected to avoid the T3-induced higher circulating levels of Inventors discovered that the phosphonic acid compounds of free fatty acids and their effects on increasing gluconeogen the present invention selectively distributed to the liver over esis flux and decreasing insulin sensitivity. Increased hepatic the heart. The selective distribution to the liver over the heart insulin sensitivity will decrease PEPCK and glucose 6-phos was also found with prodrugs, that although were processed phatase gene expression thus reducing gluconeogenesis. TR in the liver, were excreted from the liver into the blood stream activation in the liver should also decrease liver fat content, as active phosphonic acid compounds. Thus the compounds which in turn is expected to improve diabetes and steatohepa of the present invention are able to selectively target the liver titis (e.g., NASH), thus providing another use for the com and thereby increase the therapeutic index and compared to pounds of the present invention. A decrease in liver fat content T3 and T3 mimetics containing a carboxylic acid. The com is associated with increased hepatic insulin sensitivity (Shul pounds of the present invention can therefore be dosed at man, 2000) and accordingly should improve glycemic control levels that are effective in treating metabolic and other disor in type 2 diabetics through decreased glucose production and ders where the liver is the drug target without significantly enhanced glucose uptake. The overall effect on the patient negatively affecting heart function. will be better glycemic control, thus providing another use for 0246 Because of the selectivity of the phosphonic acid the compounds of the present invention. containing compounds of the present invention for the liver 0242 TH also stimulates GLUT4 transporter expression over the heart, it is not necessary for the compound to have in skeletal muscle which produces concomitant increases in greater selectivity for TRB over TRC, although this may be basal glucose uptake. Studies in obese, insulin-resistant desired. In fact, Surprisingly some of the compounds of the Zucker rats showed that TH therapy induces GLUT4 expres present invention selectively bind TRC. over TRB and are US 2009/011 8236 A1 May 7, 2009 highly effective for the uses disclosed herein without having Compounds of the present invention were tested using the the negative side-effects normally associated with TRC. selec methods described in Examples B, D, and I. tive compounds. Thus, included as an embodiment of the (0250 Other methods are also available to assess the thera present invention are compounds of Formula I, II and III that peutic index including effects on muscle wasting and bone selectively bind TRB over TRC. by at least 5 fold, 10 fold, 20 density. Compounds of the present invention were tested fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, using the methods described in Examples C and G. 100 fold, 200 fold, 300 fold, 400 fold or at least 500 fold, and 0251. The therapeutic index is determined by administer compounds of Formula I, I and III that selectively bind TRO. ing to animals a wide range of doses and determining the over TRB by at least 5 fold, 10 fold, 20 fold, 30 fold, 40 fold, minimal dose capable of inducing a response in the liver 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, 100 fold, 200 fold, relative to the dose capable of inducing a response in the 300 fold, 400 fold or at least 500 fold. heart. 0247 Changes in the therapeutic index are readily deter (0252) Phosphonic acids are often poorly transported into mined using assays and methods well described in the litera cultured cells. Accordingly, cell reporter assays, while often ture. Genes in extrahepatic tissues are monitored using meth useful for confirming agonist activity, may not provide a ods well understood by those skilled in the art. Assays include suitable indication of potency. Thus, evidence of agonist using cDNA microarray analysis of tissues isolated from activity is often more readily obtained in vivo for compounds treated animals. The sensitivity of the heart to T3 makes of the present invention. In vivo assays include but are not analysis of T3-responsive genes in the heart as well as the limited to treating animals with phosphonic acids of the functional consequences of these changes on cardiac proper invention or a phosphonic acid prodrug and monitoring the ties one further strategy for evaluating the therapeutic index expression of T3-responsive genes in the liver or the func of the compounds of the present invention. Cardiac genes tional consequences of changes of T3-responsive genes. measured include mGPDH, myosin heavy and light chain. (0253). In one aspect, compounds useful in the novel meth One method of measuring the effects of T3 mimetics on the ods bind to thyroid receptors and produce changes in the heart is by the use of assays that measure T3 mediated myosin expression of two or more hepatic genes. Animals used for heavy chain gene transcription in the heart Compounds of the testing compounds useful in the methods include normal rats present invention were tested using the methods described in and mice, animals made hypothyroid using methods well Examples B, D, and I. described in the literature, including thyroid hormone recep 0248. In one embodiment the compounds of the present tor knockout mice (e.g., TRO, such as those used in Grover invention have a therapeutic index, defined as the difference et al., 2003), or animals exhibiting high cholesterol (e.g., high between the dose at which a significant effect is observed for cholesterol fed rat or hamster), obesity and/or diabetes (e.g., a use disclosed herein, e.g., lowering cholesterol, and the dose fa/fa rat, Zucker diabetic fatty rat, ob/ob mice, db/db mice, at which a significant effect on a property or function, as high fat fed rodent). (Liureau et al. Biochem Pharmacol. disclosed herein (e.g., heart rate), is observed, is at least 50 35(10): 1691-6 (1986); Trost et al., Endocrinology 141 (9): fold, 100 fold, 200 fold,300 fold, 400 fold,500 fold, 600 fold, 3057-64 (2000); and Grover, PNAS 2003). The drug or pro 700 fold, 800 fold, 900 fold, 1000 fold, 2000 fold, 3000 fold, drug is administered by a variety of routes including by bolus 4000 fold, 5000 fold, 6000 fold, 7000 fold, 8000 fold, 9000 injection, oral, and continuous infusion (Examples B, D and fold or at least 10000 fold. Examples of said use disclosed I). Animals are treated for 1-28 days and the liver, heart and herein includes but is not limited to reducing lipid levels, blood are isolated. Changes in gene transcription relative to increasing the ratio of HDL to LDL or apoAI to LDL, reduc vehicle treated animals and T3-treated animals are deter ing weight or preventing weight gain, maintaining or improv mined using northern blot analysis, RNAase protection or ing glycemic control, lowering blood glucose levels, increas reverse-transcription and subsequent PCR. While methods ing mitochondrial biogenesis, increasing expression of PGC are available for monitoring changes in thousands of hepatic 1, AMP activated protein kinase or nuclear respiratory factor, genes, only a small number need to be monitored to demon inhibiting hepatic gluconeogenesis or for the treatment or strate the biological effect of compounds in this invention. prevention of a disease or disorder selected from the group Typically, genes such as spot-14. FAS, mGPDH, CPT-1, and consisting of atherosclerosis, hypercholesterolemia, obesity, LDL receptor are monitored. Changes of >1.5 fold in two or NASH, NAFLD, insulin resistance, diabetes, metabolic syn more genes is considered proof that the compound modulates drome X, impaired glucose tolerance, hyperlipidemia, coro T3-responsive genes in vivo. Alternative methods for mea nary heart disease, thyroid disease, thyroid cancer, depres suring changes in gene transcription include monitoring the sion, glaucoma, cardiac arrhythmias, heart failure, and activity or expression level of the protein encoded by the osteoporosis. Examples wherein the property or function is a gene. For instance, in cases where the genes encode enzyme cardiac property/function include but is not limited to cardiac activities (e.g., FAS, mGPDH), direct measurements of hypertrophy (heart weight to body weight ratio), heart rate, enzyme activity in appropriately extracted liver tissue can be and various hemodynamic parameters, including systolic and made using standard enzymological techniques. In cases diastolic arterial pressure, end systolic left ventricular pres where the genes encode receptor functions (e.g., the LDL sure and maximal speeds of contraction and relaxation. receptor) ligand binding studies or antibody-based assays 0249. A variety of methods are described that provide a (e.g., Westerns) can be performed to quantify the number of means for evaluating the functional consequences of T3-car receptors expressed. Depending on the gene, TRagonists will diac action, including measurement of cardiac hypertrophy either increase or decrease enzyme activity or increase or (heart weight to body weight ratio), heart rate, and various decrease receptor binding or number. hemodynamic parameters, including systolic and diastolic 0254 The functional consequences of changing the arterial pressure, end-systolic left ventricular pressure and expression levels of hepatic genes responsive to T3 is many maximal speeds of contraction and relaxation using methods fold and readily demonstrated using assays well described in described by Trost et al., (Endocrinol, 141:3057-64 (2000)). the literature. Administering phosphonic acid containing US 2009/011 8236 A1 May 7, 2009

compounds that bind to a TR to animals can result in changes In another embodiment said compound is a prodrug. In in lipids, including hepatic and/or plasma cholesterol levels; another embodiment said compound of Formula I, II, III, or changes in lipoprotein levels including LDL-cholesterol, VII or a prodrug thereof comprises a stereocenter. In another lipoproteina (Lp(a)); changes in hepatic glycogen levels; and embodiment said compound is administered as a racemic changes in energy expenditure as measured by changes in mixture. In another embodiment said compound is adminis oxygen consumption and in some cases animal weight. For tered as an enantiomerically enriched mixture. In another example, the effect on cholesterol is determined using cho embodiment said compound is administered as a diastero lesterol fed animals such as normal rats and hamsters, or meric mixture. In still another embodiment said compound is TRC knockout mice. Cholesterol is measured using stan administered as an individual stereoisomer. In one embodi dard tests. Compounds of the present invention were tested ment said methods of reducing cholesterol results in a lower using the methods described in Example D and I. Hepatic ing of total cholesterol. In one embodiment said methods of glycogen levels are determined from livers isolated from reducing cholesterol results in a reduction of high density treated animals. Compounds of the present invention were lipoprotein (HDL). In one embodiment said methods of tested using the methods described in Examples D and E. reducing cholesterol results in a reduction of low density Changes in energy expenditure are monitored by measuring lipoprotein (LDL). In one embodiment said methods of changes in oxygen consumption (MVo). A variety of meth reducing cholesterol results in a reduction of very low density ods are well described in the literature and include measure lipoprotein (VLDL). In another embodiment said LDL is ment in the whole animal using Oxymax chambers (U.S. Pat. reduced to a greater extent than said HDL. In another embodi No. 6,441,015). Livers from treated rats can also be evaluated ment said VLDL is reduced to a greater extent than said HDL. (Fernandez et al., Toxicol Lett. 69(2):205-10 (1993)) as well In another embodiment said VLDL is reduced to a greater as isolated mitochondria from liver (Carreras, et al., Am J extent than said LDL. Physiol Heart Circ Physiol. 281 (6):H2282-8 (2001)). Hepa 0259. In one embodiment of the methodofreducing lipids, tocytes from treated rats can also be evaluated (Ismail-Beigi F lipid is triglycerides. In one embodiment said lipid is liver et al., J Gen Physiol. 73(3):369-83 (1979)). Compounds of triglycerides. In another embodiment said lipid is in the form the present invention are tested using the methods described of a lipoprotein. In another embodiment said lipoprotein is in Examples C and G. Lp(a). In another embodiment said lipoprotein is apoAII. 0255 Phosphonic acid containing Ends that bind to a TR 0260 Also provided are methods of increasing the ratio of modulate expression of certain genes in the liver resulting in HDL to LDL, HDL to VLDL, LDL to VLDL, apoAI to LDL effects on lipids (e.g., cholesterol), glucose, lipoproteins, and or apoAI to VLDL in an animal, the method comprising the triglycerides. Such compounds can lower cholesterol levels step of administering to a patientanamount of a compound of which is useful in the treatment of patients with hypercholes Formula I, II, III or VIII a prodrug thereof, or a pharmaceu terolemia. Such compounds can lower levels of lipoproteins tically acceptable salt or co-crystal thereof. In one embodi Such as Lp(a) or LDL and are useful in preventing or treating ment said compound is an active form. In another embodi patients with atherosclerosis and heart disease. Such com ment said compound is a prodrug. In another embodiment pounds can raise levels of lipoproteins such as apoAI or HDL said compound of Formula I, II, II, or VIII or a prodrug and are useful in preventing or treating patients with athero thereof comprises a stereocenter. In another embodiment said Sclerosis and heart disease. Such compounds can cause a compound is administered as a racemic mixture. In another reduction in weight. Such compounds can lower glucose lev embodiment said compound is administered as an enantio els in patients with diabetes. merically enriched mixture. In another embodiment said 0256 Another aspect are compounds that in the presence compound is administered as a diasteromeric mixture. In still of liver cells or microsomes results in compounds of Formula another embodiment said compound is administered as an I, II and III wherein X is -P(O)(OH). individual stereoisomer. 0257 Also provided are methods of reducing plasma lipid 0261 Also provided are methods of treating hypercholes levels in an animal, the method comprising the step of admin terolemia in an animal, the method comprising the step of istering to a patient an amount of a compound of Formula I, II, administering to a patient an amount of a compound of For III, or VIII a prodrug thereof, or a pharmaceutically accept mula I, II, III, or VIII, a prodrug thereof, or a pharmaceutically able salt or co-crystal thereof. In one embodiment said com acceptable salt or co-crystal thereof. In one embodiment said pound is an active form. In another embodiment said com compound is an active form. In another embodiment said pound is a prodrug. In another embodiment said compound of compound is a prodrug. In another embodiment said com Formula I, II, I, or VIII or a prodrug thereof comprises a pound of Formula I, II, III, or VIII or a prodrug thereof Stereocenter enantiomerically enriched diastereomeric comprises a stereocenter. In another embodiment said com enriched, or a stereoisomer covered later. In another embodi pound is administered as a racemic mixture. In another ment said compound is administered as a racemic mixture. In embodiment said compound is administered as an enantio another embodiment said compound is administered as an merically enriched mixture. In another embodiment said enantiomerically enriched mixture. In another embodiment compound is a administered as a diasteromeric mixture. In said compound is a administered as a diasteromeric mixture. still another embodiment said compound is administered as In still another embodiment said compound is administered an individual stereoisomer. as an individual stereoisomer. 0262 Also provided are methods of preventing or treating 0258 Also provided are methods of reducing plasma lipid atherosclerosis in an animal, the method comprising the step levels in an animal wherein the lipid is cholesterol, the of administering to a patient an amount of a compound of method comprising the step of administering to a patient an Formula I, II, III, or VIII, a prodrug thereof, or a pharmaceu amount of a compound of Formula I, II, III, or VIII, a prodrug tically acceptable salt or co-crystal thereof. In one embodi thereof, or a pharmaceutically acceptable salt or co-crystal ment said compound is an active form. In another embodi thereof. In one embodiment said compound is an active form. ment said compound is a prodrug. In another embodiment US 2009/011 8236 A1 May 7, 2009 20 said compound of Formula I, II, III, or VIII or a prodrug embodiment said compound is administered as an enantio thereof comprises a stereocenter. In another embodiment said merically enriched mixture. In another embodiment said compound is administered as a racemic mixture. In another compound is a administered as a diasteromeric mixture. In embodiment said compound is administered as an enantio still another embodiment said compound is administered as merically enriched mixture. In another embodiment said an individual stereoisomer. compound is a administered as a diasteromeric mixture. In 0267 Also provided are methods of maintaining or still another embodiment said compound is administered as improving glycemic control in an animal being treated with a an individual stereoisomer. T3 mimetic, the method comprising the step of administering 0263. Also provided are methods of reducing fat content in to a patient an amount of a compound of Formula I, II, III, or the liver or of preventing or treating steatosis, NASH or VIII, a prodrug thereof, or a pharmaceutically acceptable salt NAFLD in an animal, the method comprising the step of or co-crystal thereof. In one embodiment said compound is an administering to a patient an amount of a compound of For active form. In another embodiment said compound is a pro mula I, II, III, or VIII, a prodrug thereof, or a pharmaceutically drug. In another embodiment said compound of Formula I, II, acceptable salt or co-crystal thereof. In one embodiment said III, or VIII or a prodrug thereof comprises a stereocenter. In compound is an active form. In another embodiment said another embodiment said compound is administered as a compound is a prodrug. In another embodiment said com racemic mixture. In another embodiment said compound is pound of Formula I, II, III, or VIII or a prodrug thereof administered as an enantiomerically enriched mixture. In comprises a stereocenter. In another embodiment said com another embodiment said compound is administered as a pound is administered as a racemic mixture. In another diasteromeric mixture. In still another embodiment said com embodiment said compound is administered as an enantio pound is administered as an individual stereoisomer. In one merically enriched mixture. In another embodiment said embodiment said glycemic control is maintained after said compound is a administered as a diasteromeric mixture. In animal is treated for at least 14 days with said compound. In still another embodiment said compound is administered as another embodiment said glycemic control is improved by 28 an individual stereoisomer. days in an animal treated with said compound. 0264. Also provided are methods of reducing weight or 0268 Also provided are methods of lowering blood glu preventing weight gain in an animal, the method comprising cose levels in an animal, the method comprising the step of the step of administering to a patient an amount of a com administering to a patient an amount of a compound of For pound of Formula I, II, III, or VIII, a prodrug thereof, or a mula I, II, III, or VIII, a prodrug thereof, or a pharmaceutically pharmaceutically acceptable salt or co-crystal thereof. In one acceptable salt or co-crystal thereof. In one embodiment said embodiment said compound is an active form. In another compound is an active form. In another embodiment said embodiment said compound is a prodrug. In another embodi compound is a prodrug. In another embodiment said com ment said compound of Formula I, II, III, or VIII or a prodrug pound of Formula I, II, III, or VIII or a prodrug thereof thereof comprises a stereocenter. In another embodiment said comprises a stereocenter. In another embodiment said com compound is administered as a racemic mixture. In another pound is administered as a racemic mixture. In another embodiment said compound is administered as an enantio embodiment said compound is administered as an enantio merically enriched mixture. In another embodiment said merically enriched mixture. In another embodiment said compound is a administered as a diasteromeric mixture. In compound is a administered as a diasteromeric mixture. In still another embodiment said compound is administered as still another embodiment said compound is administered as an individual stereoisomer. an individual stereoisomer. 0265 Also provided are methods of preventing or treating 0269. Also provided are methods of preventing or treating obesity in an animal, the method comprising the step of diabetes, insulin resistance, metabolic syndrome X or administering to a patient an amount of a compound of For impaired glucose tolerance in an animal, the method com mula I, II, III, or VIII, a prodrug thereof, or a pharmaceutically prising the step of administering to a patient an amount of a acceptable salt or co-crystal thereof. In one embodiment said compound of Formula I, II, III, or VII, a prodrug thereof, or a compound is an active form. In another embodiment said pharmaceutically acceptable salt or co-crystal thereof. In one compound is a prodrug. In another embodiment said com embodiment said compound is an active form. In another pound of Formula I, II, III, or VIII or a prodrug thereof embodiment said compound is a prodrug. In another embodi comprises a stereocenter. In another embodiment said com ment said compound of Formula I, II, III, or VIII or a prodrug pound is administered as a racemic mixture. In another thereof comprises a stereocenter. In another embodiment said embodiment said compound is administered as an enantio compound is administered as a racemic mixture. In another merically enriched mixture. In another embodiment said embodiment said compound is administered as an enantio compound is a administered as a diasteromeric mixture. In merically enriched mixture. In another embodiment said still another embodiment said compound is administered as compound is a administered as a diasteromeric mixture. In an individual stereoisomer. still another embodiment said compound is administered as 0266. Also provided are methods of preventing or treating an individual stereoisomer. coronary heart disease in an animal, the method comprising 0270. Also provided are methods of preventing or treating the step of administering to a patient an amount of a com altered energy expenditure in an animal, the method compris pound of Formula I, II, III, or VIII, a prodrug thereof, or a ing the step of administering to a patient an amount of a pharmaceutically acceptable salt or co-crystal thereof. In one compound of Formula I, II, III, or VIII, a prodrug thereof, or embodiment said compound is an active form. In another a pharmaceutically acceptable salt or co-crystal thereof. In embodiment said compound is a prodrug. In another embodi one embodiment said compound is an active form. In another ment said compound of Formula I, II, III, or VIII or a prodrug embodiment said compound is a prodrug. In another embodi thereof comprises a stereocenter. In another embodiment said ment said compound of Formula I, II, III, or VIII or a prodrug compound is administered as a racemic mixture. In another thereof comprises a stereocenter. In another embodiment said US 2009/011 8236 A1 May 7, 2009

compound is administered as a racemic mixture. In another said compound is administered as an enantiomerically embodiment said compound is administered as an enantio enriched mixture. In another embodiment said compound is a merically enriched mixture. In another embodiment said administered as a diasteromeric mixture. In still another compound is a administered as a diasteromeric mixture. In embodiment said compound is administered as an individual still another embodiment said compound is administered as Stereoisomer. an individual stereoisomer. 0275 Also provided are methods of inhibiting hepatic 0271 Also provided are methods of preventing or treating gluconeogenesis in an animal, the method comprising the a liver disease responsive to modulation of T3-responsive step of administering to a patientanamount of a compound of genes in an animal, the method comprising the step of admin Formula I, II, III, or VIII, a prodrug thereof, or a pharmaceu istering to a patient an amount of a compound of Formula I, II, tically acceptable salt or co-crystal thereof. In one embodi III, or VIII, a prodrug thereof, or a pharmaceutically accept ment said compound is an active form. In another embodi able salt or co-crystal thereof. In one embodiment said com ment said compound is a prodrug. In another embodiment pound is an active form. In another embodiment said com said compound of Formula I, II, III, or VIII or a prodrug pound is a prodrug. In another embodiment said compound of thereof comprises a stereocenter. In another embodiment said Formula I, II, III, or VIII or a prodrug thereof comprises a compound is administered as a racemic mixture. In another Stereocenter. In another embodiment said compound is embodiment said compound is administered as an enantio administered as a racemic mixture. In another embodiment merically enriched mixture. In another embodiment said said compound is administered as an enantiomerically compound is a administered as a diasteromeric mixture. In enriched mixture. In another embodiment said compound is a still another embodiment said compound is administered as administered as a diasteromeric mixture. In still another an individual stereoisomer. embodiment said compound is administered as an individual 0276 Also provided are kits for reducing lipid levels, Stereoisomer. increasing the ratio of IDL to LDL or apoAI to LDL, reducing 0272. Also provided are methods of preventing or treating weight or preventing weight gain, maintaining or improving thyroid disease, thyroid cancer, depression, glaucoma, car glycemic control, lowering blood glucose levels, increasing diac arrhythmias, heart failure, or osteoporosis in an animal, mitochondrial biogenesis, increasing expression of PGC-1, the method comprising the step of administering to a patient AMP activated protein kinase or nuclear respiratory factor, an amount of a compound of Formula I, II, III, or VIII, or a inhibiting hepatic gluconeogenesis, or for the prevention or pharmaceutically acceptable salt or co-crystal thereof. In one treatment of a disease or disorder for which a compound of embodiment said compound is an active form. In another the present invention is effective in preventing or treating, the embodiment said compound is a prodrug. In another embodi kits comprising: ment said compound of Formula I, II, III, or VIII or a prodrug 0277 a) a pharmaceutical composition comprising a com thereof comprises a stereocenter. In another embodiment said pound of Formula I, II, III, or VIII or a prodrug thereof; and compound is administered as a racemic mixture. In another 0278 b) at least one container for containing said pharma embodiment said compound is administered as an enantio ceutical composition. merically enriched mixture. In another embodiment said 0279 Also provided are pharmaceutical compositions compound is a administered as a diasteromeric mixture. In comprising a compound of Formula I and a pharmaceutically still another embodiment said compound is administered as acceptable excipient, carrier or diluent. Also provided are an individual stereoisomer. pharmaceutical compositions comprising a first pharmaceu 0273 Also provided are methods of increasing mitochon tical compound selected from Formula I, Formula II or For drial biogenesis in an animal, the method comprising the step mula III or Formula VIII or a prodrug thereof and a second of administering to a patient an amount of a compound of pharmaceutical compound of the same Formula but wherein Formula I, II, III, or VIII, a prodrug thereof, or a pharmaceu said first and second pharmaceutical compounds are not the tically acceptable salt or co-crystal thereof. In one embodi same molecules. Also provided are pharmaceutical composi ment said compound is an active form. In another embodi tions comprising a first pharmaceutical compound selected ment said compound is a prodrug. In another embodiment from Formula I, Formula II or Formula III or Formula VIII or said compound of Formula I, II, III, or VIII or a prodrug a prodrug thereof and a second pharmaceutical compound thereof comprises a stereocenter. In another embodiment said selected from Formula I, Formula II, Formula III, or Formula compound is administered as a racemic mixture. In another VIII or a prodrug thereof, but wherein said first and said embodiment said compound is administered as an enantio second pharmaceutical compounds are not both from the merically enriched mixture. In another embodiment said same Formula. Also provided are pharmaceutical composi compound is a administered as a diasteromeric mixture. In tions comprising a first pharmaceutical compound selected still another embodiment said compound is administered as from Formula I, Formula II, Formula III, or Formula VIII or an individual stereoisomer. a prodrug thereof and a second pharmaceutical compound 0274 Also provided are methods of increasing expression that is not a compound selected from Formula I, Formula II, of PGC-1, AMP activated protein kinase or nuclear respira Formula III, or Formula VIII or a prodrug thereof. tory factor in an animal, the method comprising the step of 0280 Also provided are pharmaceutical compositions administering to a patient an amount of a compound of For comprising a first compound of present invention and a sec mula I, II, III, or VIII, a prodrug thereof, or a pharmaceutically ond compound useful for reducing lipid levels, increasing the acceptable salt or co-crystal thereof. In one embodiment said ratio of HDL to LDL or apoAI to LDL, reducing weight or compound is an active form. In another embodiment said preventing weight gain, maintaining or improving glycemic compound is a prodrug. In another embodiment said com control, lowering blood glucose levels, increasing mitochon pound of Formula I, II, II, or VIII or a prodrug thereof com drial biogenesis, increasing expression of PGC-1, AMP acti prises a stereocenter. In another embodiment said compound vated protein kinase or nuclear respiratory factor, inhibiting is administered as a racemic mixture. In another embodiment hepatic gluconeogenesis or for the treatment or prevention of US 2009/011 8236 A1 May 7, 2009 22 atherosclerosis, hypercholesterolemia, obesity, Steatosis, prevention of atherosclerosis, hypercholesterolemia, obesity, NASH, NAFLD, insulin resistance, diabetes, metabolic syn NASH, NAFLD, insulin resistance, diabetes, metabolic syn drome X, impaired glucose tolerance, hyperlipidemia, coro drome X, impaired glucose tolerance, hyperlipidemia, coro nary heart disease, thyroid disease, thyroid cancer, depres nary heart disease, thyroid disease, thyroid cancer, depres Sion, glaucoma, cardiac arrhythmias, heart failure, or Sion, glaucoma, cardiac arrhythmias, heart failure, or osteoporosis. In one embodiment, and composition compris osteoporosis the methods comprising the step of administer ing said first and second compound is a single unit dose. In ing to a patient atherapeutically effective amount of 1) a first another embodiment, said unit does is in the form of a tablet, pharmaceutical composition comprising a compound of For hard capsule or soft gel capsule. mula I, II, III, or VIII or a prodrug thereof, and 2) a second 0281 Also provided are pharmaceutical compositions of pharmaceutical composition, wherein said second pharma the present invention having an oral bioavailability of least ceutical composition is either another compound of Formula 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, I, II, III, or VIII or a prodrug thereof, or is not another com 70% 75% or at least 80%. pound of Formula I, II, III, or VIII or a prodrug thereof. 0282 Also provided are kits for the prevention or treat 0291. Also provided are methods for reducing lipid levels, ment of a disease or disorder for which a compound of the increasing the ratio of HDL to LDL or apoAI to LDL, reduc present invention is effective in preventing or treating, the kits ing weight or preventing weight gain, maintaining or improv comprising: ing glycemic control, lowering blood glucose levels, increas 0283 a) a first pharmaceutical composition comprising a ing mitochondrial biogenesis, increasing expression of PGC compound of I, II, III, or VIII or a prodrug thereof; 1, AMPactivated protein kinase or nuclear respiratory factor, 0284 b) a second pharmaceutical composition compris inhibiting hepatic gluconeogenesis or for the treatment or ing an additional compound useful for the treatment or pre prevention of atherosclerosis, hypercholesterolemia, obesity, vention of a disease or disorder for which a compound of the NASH, NAFLD, insulin resistance, diabetes, metabolic syn present invention is effective in preventing or treating; and drome X, impaired glucose tolerance, hyperlipidemia, coro 0285 c) at least one container for containing said first or nary heart disease, thyroid disease, thyroid cancer, depres second or both first and second pharmaceutical composition. Sion, glaucoma, cardiac arrhythmias, heart failure, or 0286 Also provided are kits for reducing lipid levels, osteoporosis the methods comprising the step of administer increasing the ratio of HDL to LDL or apoAI to LDL, reduc ing to a patient atherapeutically effective amount of 1) a first ing weight or preventing weight gain, maintaining or improv pharmaceutical composition comprising a compound of For ing glycemic control, lowering blood glucose levels, increas mula I, II, III, or VIII or a prodrug thereof and 2) an second ing mitochondrial biogenesis, increasing expression of PGC pharmaceutical composition that is effective alone for reduc 1, AMPactivated protein kinase or nuclear respiratory factor, ing lipid levels, increasing the ratio of HDL to LDL or apoAI inhibiting hepatic gluconeogenesis or for the treatment or to LDL, reducing weight or preventing weight gain, main prevention of a disease or disorder selected from the group taining or improving glycemic control, lowering blood glu consisting of atherosclerosis, hypercholesterolemia, obesity, cose levels, increasing mitochondrial biogenesis, increasing steatosis, NASH, NAFLD, insulin resistance, diabetes, meta expression of PGC-1, AMP activated protein kinase or bolic syndrome X, impaired glucose tolerance, hyperlipi nuclear respiratory factor, inhibiting hepatic gluconeogenesis demia, coronary heart disease, thyroid disease, thyroid can or for the treatment or prevention of atherosclerosis, hyperc cer, depression, glaucoma, cardiac arrhythmias, heart failure, holesterolemia, obesity, NASH, NAFLD, insulin resistance, and osteoporosis, the kits comprising: diabetes, metabolic syndrome X, impaired glucose tolerance, 0287 a) a first pharmaceutical composition comprising a hyperlipidemia, coronary heart disease, thyroid disease, thy compound of Formula I, II, III, or VIII or a prodrug thereof; roid cancer, depression, glaucoma, cardiac arrhythmias, heart 0288 b) a second pharmaceutical composition compris failure, or osteoporosis. ing an additional compound useful for reducing lipid levels, 0292 Also provided is the use of a compound of the increasing the ratio of HDL to LDL or apoAI to LDL, reduc present invention for the manufacture of a medicament for ing weight or preventing weight gain, maintaining or improv reducing lipid levels, increasing the ratio of HDL to LDL or ing glycemic control, lowering blood glucose levels, increas apoAI to LDL, reducing weight or preventing weight gain, ing mitochondrial biogenesis, increasing expression of PGC maintaining or improving glycemic control, lowering blood 1, AMPactivated protein kinase or nuclear respiratory factor, glucose levels, increasing mitochondrial biogenesis, increas inhibiting hepatic gluconeogenesis or for the treatment or ing expression of PGC-1, AMP activated protein kinase or prevention of atherosclerosis, hypercholesterolemia, obesity, nuclear respiratory factor, inhibiting hepatic gluconeogenesis steatosis, NASH, NAFLD, insulin resistance, diabetes, meta or for the treatment or prevention of atherosclerosis, hyperc bolic syndrome X, impaired glucose tolerance, hyperlipi holesterolemia, obesity, NASH, NAFLD, insulin resistance, demia, coronary heart disease, thyroid disease, thyroid can diabetes, metabolic syndrome X, impaired glucose tolerance, cer, depression, glaucoma, cardiac arrhythmias, heart failure, hyperlipidemia, coronary heart disease, thyroid disease, thy or osteoporosis; and roid cancer, depression, glaucoma, cardiac arrhythmias, heart 0289 c) at least one container for containing said first or failure, or osteoporosis. second or both first and second pharmaceutical composition. 0293 Also provided are compounds that selectively dis 0290 Also provided are methods for reducing lipid levels, tribute to the liver. In one embodiment, the compounds have increasing the ratio of HDL to LDL or apoAI to LDL, reduc at least 10 fold, 25 fold, 50 fold, 75 fold, 100 fold, 200 fold, ing weight or preventing weight gain, maintaining or improv 300 fold, 400 fold, 500 fold, 600 fold, 700 fold, 800 fold, 900 ing glycemic control, lowering blood glucose levels, increas fold, 1000 fold, 2000 fold, 3000 fold, 4000 fold, 5000 fold ing mitochondrial biogenesis, increasing expression of PGC 6000 fold, 7000 fold, 8000 fold, 9000 fold, 10,000 fold, 1, AMPactivated protein kinase or nuclear respiratory factor, 20,000 fold, 30,000 fold, 40,000 fold or 50,000 fold greater inhibiting hepatic gluconeogenesis or for the treatment or selectivity. In one embodiment the selectivity for the liver is US 2009/011 8236 A1 May 7, 2009

compared to the heart. In another embodiment the selectivity roid receptors in the liver. The present invention relates to for the liver is compared to the pituitary. In another embodi compounds of Formula I, II, III, and VIII, including stereoi ment the selectivity for the liver is compared to the kidney. Somers and mixtures of Stereoisomers thereof, pharmaceuti 0294 Also provided are T3 mimetics comprising a phos cally acceptable salts thereof, co-crystals thereof, and pro phonic acid or prodrug thereofthat have improved liver selec drugs (including stereoisomers and mixtures of stereoisomers tivity as compared to a corresponding compound where the thereof) thereof, and pharmaceutically acceptable salts and phosphonic acid is replaced with a carboxylic acid, but co-crystals of the prodrugs. wherein the corresponding compound is otherwise identical. 0299 The compounds of the present invention may be In one embodiment, the phosphonic acid (or prodrug thereof) either crystalline, amorphous or a mixture thereof. Composi compound has at least 10 fold, 25 fold, 50 fold, 75 fold, 100 tions comprising a crystalline form a compound of the present fold, 200 fold, 300 fold, 400 fold,500 fold, 600 fold, 700 fold, invention may contain only one crystalline form of said com 800 fold,900 fold, 1000 fold, 2000 fold, 3000 fold, 4000 fold, pound or more than one crystalline form. For example, the 5000 fold 6000 fold, 7000 fold, 8000 fold, 9000 fold, 10,000 composition may contain two or more different polymorphs. fold, 20,000 fold, 30,000 fold, 40,000 fold or 50,000 fold The polymorphs may be two different polymorphs of the free greater selectivity for the liver as compared to the correspond form, two or more polymorphs of different co-crystal forms, ing carboxylic acid compound. In one embodiment the liver two or more polymorphs of different salt forms, a combina selectivity is relative to the heart. In another embodiment the tion of one or more polymorphs of one or more co-crystal liver selectivity is relative to the kidney. In another embodi forms and one or more polymorphs of the free form, a com ment the liver selectivity is relative to the pituitary. bination of one or more polymorphs of one or more salt forms 0295 Also provided are T3 mimetics comprising a phos and one or more polymorphs of the free form, or a combina phonic acid or producing thereof and that have a decreased Ki tion of one or more polymorphs of one or more co-crystal as compared to a corresponding compound where the phos forms and one or more polymorphs of one or more salt forms. phoric acid is replaced with a carboxylic acid, but wherein the 0300 Pharmaceutically acceptable base addition salt of corresponding compound is otherwise identical. In one the compounds herein are included in the present invention. embodiment, the phosphonic acid compound has at least 2 Pharmaceutically acceptable base addition salt refers to those fold, 5 fold, 7 fold, 10 fold, 25 fold, or 50 fold lower Ki than salts which retain the biological effectiveness and properties the corresponding carboxylic acid derivative compound of the free acids, which are not biologically or otherwise (wherein Ki is measured relative to T3). In another embodi undesirable. These salts are prepared from addition of an ment, the Ki of the phosphonic acid compound is s 150 inorganic base or an organic base to the free acid. Salts nMs 100 nM, is 90 nM, is 80 nM, is 70 nM, sG0 nM, s50 derived from inorganic bases include, but are not limited to: nM. s.40 nM, s30 nM, relative to T3. For purposes of clarity, Sodium, potassium, lithium, ammonium, calcium, magne it is noted that binding affinity increases as the numerical sium, Zinc, aluminum salt and the like. Preferred inorganic value of Ki decreases, i.e., there is an inverse relationship salts are the ammonium, Sodium, potassium, calcium, and between Ki and binding affinity. In another embodiment the magnesium salts. Salts derived from organic bases include, phosphonic acid compound has the same Ki as the corre but are not limited to, salts of primary, secondary, and tertiary sponding carboxylic acid derivative. In another embodiment amines, Substituted amines including naturally occurring the phosphonic acid compound has a greater Ki than the Substituted amines, cyclic amines and basic ion exchange corresponding carboxylic acid derivative. resins, such as isopropylamine, trimethylamine, diethy 0296 Also provided are compounds of the present inven lamine, triethylamine, tripropylamine, ethanolamine, 2-dim tion that bind at least one thyroid hormone receptor with an Ki ethylaminoethanol, 2-diethylaminoethanol, trimethamine, ofs 100 nM, is 90 nM, is 80 nM, is 70 nM, S 60 nM, is 50 nM, dicyclohexylamine, lysine, arginine, histidine, caffeine, s40 nM, s30 nM, s20 nM, is 10 nM, is 50 nM, is 1 nM, or procaine, hydrabamine, choline, betaine, ethylenediamine, s0.5 nM relative to T3. In one embodiment said thyroid glucosamine, methylglucamine, theobromine, purines, pip hormone receptor is TRC. In one embodiment said thyroid erazine, piperidine, N-ethylpiperidine, polyamine resins and hormone receptor is TRB. Also provided are compounds that the like. bind at least one thyroid hormone receptor with an Ki of 0301 Pharmaceutically acceptable acid addition salt of 2100 nM, 290 nM, 280 nM, 270 nM, 260 nM, 250 nM, the compounds herein having a base functional group (e.g., a 240 nM, 2-30 nM, 220 nM, 210 nM, 250 nM, 21 nM, or prodrug whereby the phosphonic acid is protected with a 20.5 nM relative to T3, but in each cases 150 nM. In one group comprising a base functional group) are also included embodiment said thyroid hormone receptor is TRC. In one in the present invention. Pharmaceutically acceptable acid embodiment said thyroid hormone receptor is TRB. In one addition salt refers to those salts which retain the biological embodiment said thyroid hormone receptor is TRC.1. In one effectiveness and properties of the free base, which are not embodiment said thyroidhormone receptor is TRB1. In one biologically or otherwise undesirable. These salts are pre embodiment said thyroid hormone receptor is TRC2. In one pared from addition of an inorganic acid oran organic acid to embodiment said thyroid hormone receptor is TRB2. the free base. Salts derived from inorganic acids include, but 0297 Novel methods described herein describe the use of are not limited to: acistrate, hydrobromide, hydrochloride, phosphonic acid-containing compounds that bind to TRS. In Sulfate, bisulfate, nitrate, acetate, oxalate, besylate, palmitate, one aspect, novel compounds described below include com Stearate, laurate, borate, benzoate, lactate, phosphate, tosy pounds of Formula I, II, III or VIII. The compounds of the late, citrate, maleate, fumarate. Succinate, tartrate, naphthy present invention can be used in the methods described late, mesylate, glucoheptonate, lactobionate, laurylsulpho herein. nate, bromide, fumarate, pamoate, glucouronate, Novel Compounds of the Invention hydroiodide, iodide, sulfate, xinofoate and chloride salts 0298. The novel compounds of the invention are phospho 0302) The compounds of the present invention may be nic acid containing compounds that bind to and activate thy pure or substantially pure or have a purity of at least 75%, US 2009/011 8236 A1 May 7, 2009 24

80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, from the group consisting of halogen, Substituted or unsub 98%, 99% or purity at least 99.5%. The compounds may also stituted C-C alkyl, and Substituted or unsubstituted C-Cs be part of the pharmaceutically acceptable composition. The cycloalkyl; R is selected selected from the group consisting compounds may also be part of a biological material or of hydrogen, halogen, amino, hydroxyl. —O—C-C alkyl, sample. Thus, included in the present invention are cells and —SH and S C-C alkyl; and R is selected from the tissues comprising a compound of the present invention. The group consisting of hydroxyl, optionally substituted —OC cells or tissues can be in vivo, ex vivo or in vitro. Examples C alkyl, and —OC(O)R; then X is not —P(O)(OH). include liver or liver cells (e.g., hepatocytes), blood, gastric 0308 Inanother aspect the invention relates to a method of fluid (simulated or actual), intestinal fluid (simulated or improving liver versus heart selectivity or for increasing the actual) and urine. therapeutic index of a thyromimetic compound of FormulaY: 0303. In one aspect the invention relates to a phosphonic acid-containing-thyromimetic compound of Formula X: (Ar)-G-(Ar)-T-E 0309 wherein: 0310 Ar" and Art are aryl groups; 0304 wherein: 0311 G is an atom or group of atoms that links Ar" and Art 0305 Ar" and Art are aryl groups: are aryl groups; through a single C. S, O, or Natom; (0306 G is an atom or group of atoms that links Ar" and A 0312 T is an atom or group of atoms linking Art to E are aryl groups; through a single C. S, O, or Natom; through 1-4 contiguous atoms or is absent; (0307 T is an atom or group of atoms linking Ar to X E is a functional group or moiety with a pKas7.4, is carboxy through 1-4 contiguous atoms or is absent; lic acid (COOH) or esters thereof, sulfonic acid, tetrazole, X is a —P(O)(OH) or prodrug thereof. In one embodiment hydroxamic acid, 6-azauracil, thiazolidinedione, acylsul the compound has a Kis 150 nM. Another embodiment fonamide, or other carboxylic acid Surrogates known in the included a pharmaceutical composition comprising the com art or a prodrug thereof, or an atom or group of atoms con poundanda at least one excipient. In another embodiment the taining an O or N that binds the thyroid hormone binding pharmaceutical composition has a bioavailability of at least pocket of a TRC. or TRB, but wherein E is nota—P(O)(OH), 15%. In another embodiment the compound is crystalline. In or ester thereof; comprising the step of replacing E with a another embodiment the pharmaceutical composition is a unit —P(O)(OH), or prodrug thereof. In one embodiment the dose. In one embodiment, when the compound of Formula X compound has a Kis 150 nM. Another embodiment included is a compound of Formula I wherein G is —O , T is a pharmaceutical composition comprising the compound and —CH2—, R' and Rare each bromo, R is iso-propyl, R is a at least one excipient. In another embodiment the pharma hydrogen, and R is -OH, then X is not P(O)(OH), or P(O) ceutical composition has a bioavailability of at least 15%. In (OCHCH). In another embodiment, when the compound another embodiment the compound is crystalline. In another of Formula X is a compound of Formula I wherein G is embodiment the pharmaceutical composition is a unit dose. —O , T is —CH2). , R' and R are independently halo In one embodiment, when the compound of Formula X is a gen, alkyl of 1 to 3 carbons, and cycloalkyl of 3 to 5 carbons, compound of Formula I wherein G is —O—, T is —CH2—, R is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 7 carbons, R' R" and Rare each bromo, R is iso-propyl, R is hydrogen, is hydrogen, and R is —OH, then X is not - P(O)(OH), or and Ris-OH, then X is not P(O)(OH), or P(O)(OCHCH.) —P(O)(O-lower alkyl). In another embodiment, when the 2. In another embodiment, when the compound of Formula X compound of Formula X is a compound of Formula I wherein is a compound of Formula I wherein G is - O Tis—(CH) G is - O - R is NHC(O)R, NHS(=O), R, NHC of, R' and R are independently halogen, alkyl of 1 to 3 (S)NH(R'), or -NHC(O)NH(R), T is —(CH), , carbons, and cycloalkyl of 3 to 5 carbons, R is alkyl of 1 to 4 —CH=CH-, -O(CH) , or—NH(CH2). , then X carbons or cycloalkyl of 3 to 7 carbons, R is hydrogen, and is not -P(O)(OH), or -P(O)(OH)NH2. In another embodi R is -OH, then X is not -P(O)(OH) or -P(O)(O-lower ment, when the compound of Formula X is a compound of alkyl). In another embodiment, when the compound of For Formula III wherein Gis —O , T is NH-CH , R' and mula X is a compound of Formula I wherein G is —O , R Rare each chloro, R is iso-propyl, R is hydrogen, R7 is is NHC(O)R, NHS(=O), R, NHC(S)NH(R'), or fluoro, and R is -OH, then X is not P(O)(OH), P(O)(OH) - NHC(O)NH(R'), T is —(CH), , -CH=CH-, (OCH) or P(O)(OCH). In another embodiment, when the —O(CH) , or —NH(CH2). , then X is not —P(O) compound of Formula X is a compound of Formula III (OH), or—P(O)(OH)NH2. In another embodiment, when the wherein G is selected from the group consisting of —O—, compound of Formula X is a compound of Formula III S , —S(=O)— —S(=O) , —CH2—, —C(O)—and wherein G is —O , T is NH-CH , R' and Rare each NR' : T is -A-B where A is selected from the group chloro, R is iso-propyl, R' is hydrogen, R is fluoro, and R' consisting of NR , —O , —CH2—and-S and B is is -OH, then X is not P(O)(OH), P(O)(OH)(OCH) or selected from the group consisting of a bond and Substituted P(O)(OCH). In another embodiment, when the compound or unsubstituted C-C alkyl; R is selected from the group of Formula X is a compound of Formula III wherein G is consisting of halogen, trifluoromethyl, Substituted or unsub selected from the group consisting of —O— —S—, stituted C-C alkyl, substituted or unsubstituted aryl, substi S(=O) , S(=O) , CH2—, C(O) and tuted or unsubstituted heteroaryl, aryloxy, substituted amide, —NR : T is -A-B where A is selected from the group Sulfone, Sulfonamide and C-C cycloalkyl, wherein said consisting of NR' , -O-, -CH2—and-S and B is aryl, heteroaryl or cycloalkyl ring(s) are attached or fused to selected from the group consisting of a bond and Substituted the aromatic; R is selected from the group consisting of or unsubstituted C-C alkyl; R is selected from the group hydrogen, halogen, Substituted or unsubstituted C-C alkyl, consisting of halogen, trifluoromethyl, Substituted or unsub substituted or unsubstituted aryl, and substituted or unsubsti stituted C-C alkyl, substituted or unsubstituted aryl, substi tuted heteroaryl; R' and Rare each independently selected tuted or unsubstituted heteroaryl, aryloxy, substituted amide, US 2009/011 8236 A1 May 7, 2009

Sulfone, Sulfonamide and C-C cycloalkyl, wherein said thenX is not P(O)(OH), P(O)(OH)(OCH) or P(O)(OCH). aryl, heteroaryl or cycloalkyl ring(s) are attached or fused to In another embodiment, when the compound of the aromatic; R is selected from the group consisting of 0319 Formula X is a compound of Formula III wherein G hydrogen, halogen, Substituted or unsubstituted C-C alkyl, is selected from the group consisting of —O— —S , substituted or unsubstituted aryl, and substituted or unsubsti S(=O) , S(=O) , CH2—, C(O) and tuted heteroaryl; R' and Rare each independently selected NR' : T is -A-B where A is selected from the group from the group consisting of halogen, Substituted or unsub consisting of NR ,-O-, -CH-and-S and B is stituted C-C alkyl, and Substituted or unsubstituted C-Cs selected from the group consisting of a bond and Substituted cycloalkyl; R is selected selected from the group consisting or unsubstituted C-C alkyl; R is selected from the group of hydrogen, halogen, amino, hydroxyl. —O—C-C alkyl, consisting of halogen, trifluoromethyl, Substituted or unsub —SH and S C-C alkyl; and R is selected from the stituted C-C alkyl, substituted or unsubstituted aryl, substi group consisting of hydroxyl, optionally Substituted —OC tuted or unsubstituted heteroaryl, aryloxy, substituted amide, C alkyl, and —OC(O)R; then X is not —P(O)(OH). Sulfone, Sulfonamide and C-C cycloalkyl, wherein said 0313. In another aspect the invention relates to a method of aryl, heteroaryl or cycloalkyl ring(s) are attached or fused to designing a thyromimetic compound with improved liver the aromatic; R is selected from the group consisting of Versus heart selectivity or improved therapeutic index com hydrogen, halogen, Substituted or unsubstituted C-C alkyl, substituted or unsubstituted aryl, and substituted or unsubsti prising the steps of: tuted heteroaryl; R' and Rare each independently selected 0314 obtaining a formula for a thyromimetic of Formula from the group consisting of halogen, Substituted or unsub Y: stituted C-C alkyl, and Substituted or unsubstituted C-Cs (Ar)-G-(Ar)-T-E cycloalkyl; R is selected selected from the group consisting of hydrogen, halogen, amino, hydroxyl. —O-C-C alkyl, 0315 wherein: —SH and —S C-C alkyl; and R is selected from the 0316) Ar' and Arare aryl groups; group consisting of hydroxyl, optionally Substituted —OC 0317 Gisanatom or group of atoms that links Ar' and Ar C alkyl, and —OC(O)R; then X is not —P(O)(OH). are aryl groups; through a single C. S, O, or Natom; 0320 In one aspect, the present invention relates to com 0318 T is an atom or group of atoms lining Ar° to E pounds of Formula I: through 1-4 contiguous atoms or is absent; E is a functional group or moiety with a pKas7.4, is carboxy lic acid (COOH) or esters thereof, sulfonic acid, tetrazole, R3 R2 hydroxamic acid, 6-azauracil, thiazolidinedione, acylsul fonamide, or other carboxylic acid Surrogates known in the art or a prodrug thereof, or an atom or group of atoms con R5 G T-X taining an O or N that binds the thyroid hormone binding pocket of a TROO.or TRB, but wherein E is nota—P(O)(OH) R4 R1 or ester thereof; comprising the step of replacing E with a —P(O)(OH) or prodrug thereof; and synthesizing a com pound of Formula X wherein X is phosphonic acid or prodrug wherein: thereof. In one embodiment the compound has a Kis 150 nM. 0321 G is selected from the group consisting of —O—, Another embodiment included a pharmaceutical composition comprising the compound and a at least one excipient. In CHF , —C(O) , —CH(OH)— —NH , and —N(C- another embodiment the pharmaceutical composition has a Calkyl)-; bioavailability of at least 15%. In another embodiment the 0322 T is selected from the group consisting of (CR) compound is crystalline. In another embodiment the pharma ceutical composition is a unit dose. In one embodiment, when the compound of Formula X is a compound of Formula I wherein G is —O , T is —CH2—, R' and R are each bromo, R is iso-propyl, Rishydrogen, and Ris-OH, then X is not P(O)(OH), or P(O)(OCHCH). In another embodi ment, when the compound of Formula X is a compound of 0323 k is an integer from 0-4: Formula I wherein G is —O , T is —(CH) , RandR are independently halogen, alkyl of 1 to 3 carbons, and 0324 m is an integer from 0-3: cycloalkyl of 3 to 5 carbons, R is alkyl of 1 to 4 carbons or 0325 n is an integer from 0-2: cycloalkyl of 3 to 7 carbons, R is hydrogen, and Ris-OH, 0326 p is an integer from 0-1; then X is not —P(O)(OH) or —P(O)(O-lower alkyl). In 0327 Each R" is independently selected from the group another embodiment, when the compound of Formula X is a consisting of hydrogen, optionally Substituted—C-C alkyl, compound of Formula I wherein G is —O , R is NHC halogen, —OH, optionally Substituted —O—C-C alkyl, (O)R, NHS(=O), R, NHC(S)NH(R'), or NHC —OCF, optionally substituted—S C-C alkyl, NRR, (O)NH(R'), T is —(CH), , -CH=CH-, -O(CH), optionally Substituted —C-C alkenyl, and optionally Sub 2—, or NH(CH) , then X is not —P(O)(OH), or stituted—C-C alkynyl; with the proviso that when one Ris —P(O)(OH)NH2. In another embodiment, when the com attached through O, S, or N, then the other R' attached to the pound of Formula X is a compound of Formula III wherein G same C is a hydrogen, or attached via carbon atom. Each R' is —O , T is NH-CH , R' and Rare each chloro, R is independently selected from the group consisting of hydro is iso-propyl, R is hydrogen, R is fluoro, and R is -OH, gen, optionally Substituted—C-C alkyl; US 2009/011 8236 A1 May 7, 2009 26

0328. Each R is independently selected from the group - C(R) OC(O)R’, C(R) O C(O)OR, C(R) consisting of hydrogen and optionally substituted —C-C, OC(O)SR, -alkyl-S C(O)R’, -alkyl-S-S-alkylhydroxy, alkyl, optionally substituted —C(O)—C-C alkyl, and and -alkyl-S S S-alkylhydroxy: C(O)H: 0338 when Y and Y are - NR' , then R'' attached to 0329) R' and Rare each independently selected from the —NR'—is independently selected from the group consisting group consisting of halogen, optionally Substituted —C- of H, -C(R). COORC(R)-COOR,-(C(R), Calkyl, optionally Substituted—S C-C alkyl, optionally C(O)SR, Substituted—C-C alkenyl, optionally Substituted—C-C, and -cycloalkylene-COOR': alkynyl, -CF, —OCF, optionally substituted-O-C-C, 0339 when Y is - O - and Y is NR, then R'' attached to alkyl, and cyano; —O—is independently selected from the group consisting of 0330 R and Rare each independently selected from the —H, alkyl, optionally substituted aryl, optionally substituted group consisting of hydrogen, halogen, —CF, —OCF, heterocycloalkyl, optionally substituted CH-heterocy cyano, optionally Substituted—C-C alkyl, optionally Sub cloaky1 wherein the cyclic moiety contains a carbonate or stituted —C-C alkenyl, optionally substituted —C-C, thiocarbonate, optionally substituted -alkylaryl, —C(R)OC alkynyl, optionally Substituted —(CR), aryl, optionally (O)NR', NR C(O) R', C(R). OC(O)R’, C(r) Substituted —(CR), cycloalkyl, optionally substituted O C(O)CR, C(R)OC(O)SR, -alkyl-S C(O)R’, —(CR"), heterocycloalkyl, -OR', SR', -S(=O)R, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhy S(=O).R., S(=O)NR'Rs, C(O)NR'Rs, C(O) droxy; and R'' attached to NR' is independently OR, C(O)R, N(R)C(O)R, N(R)C(O)NR'Rs, selected from the group consisting of -H, -IC(R), N(R)S(=O).R., N(R)S(=O)NR'Rs, and NR/Rs: COOR, C(R)-COOR, C(R), C(O)SR', and -cy 0331 Each R" is selected from the group consisting of cloalkylene-COOR: optionally Substituted—C-C alkyl, optionally Substituted 0340 or when Y and Y are independently selected from —C-C alkenyl, optionally substituted —C-C alkynyl. —O— and NR' , then together R'' and R'' are -alkyl optionally substituted. —CR), aryl, optionally substituted, S S-alkyl- to form a cyclic group, or together R'' and R' —(CR), cycloalkyl, optionally substituted (CR), hetero are the group: cycloalkyl, and –C(O)NR'Rs: 0332 Each R is selected from the group consisting of optionally substituted—C-C alkyl, optionally substituted V —C-C alkenyl, optionally substituted —C-C alynyl, H optionally substituted —(CR), aryl, optionally Substituted, Z —(CR), cycloalkyl, and optionally Substituted —(CR) heterocycloalkyl; H 0333 R and Rs are each independently selected from the W group consisting of hydrogen, optionally substituted —C- W Calkyl, optionally Substituted—C-C alkenyl, optionally Substituted —C-C alkynyl, optionally Substituted wherein: —(CR),aryl, optionally substituted —(CR), cycloalkyl, (0341 V, W, and W are independently selected from the and optionally substituted —(CR), heterocycloalkyl, or R group consisting of hydrogen, optionally Substituted alkyl, and R may together form an optionally substituted hetero optionally substituted aralkyl, heterocycloalkyl, aryl, Substi cyclic ring, which may contain a second heterogroup selected tuted aryl, heteroaryl, substituted heteroaryl, optionally sub from the group of O. NR, and S, wherein said optionally stituted 1-alkenyl, and optionally substituted 1-alkynyl: substituted heterocyclic ring may be substituted with 0-4 0342 or together V and Z are connected via an additional Substituents selected from the group consisting of optionally 3-5 atoms to form a cyclic group containing 5-7 atoms, substituted —C-C alkyl, -OR''. Oxo, cyano, —CFs, wherein 0-1 atoms are heteroatoms and the remaining atoms optionally substituted phenyl, and —C(O)OR"; are carbon, Substituted with hydroxy, acyloxy, alkylthiocar 0334). Each R" is selected from the group consisting of bonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy optionally Substituted—C-C alkyl, optionally Substituted attached to a carbon atom that is three atoms from both Y —C-C alkenyl, optionally Substituted —C-C alkynyl, groups attached to the phosphorus; or optionally substituted —(CR),aryl, optionally substituted 0343 or together V and Z are connected via an additional (CR), cycloalkyl, and optionally substituted—(CR), het 3-5 atoms to form a cyclic group, wherein 0-1 atoms are erocycloalkyl, heteroatoms and the remaining atoms are carbon, that is fused 0335) R is selected from the group consisting of -OH, to an aryl group at the beta and gamma position to the Y optionally substituted —OC-C alkyl, —OC(O)R. —OC attached to the phosphorus: (O)OR, F, NHC(O)R, NHS(—O)R, NHS(—O) 0344 or together V and Ware connected via an additional R, NHC(=S)NH(R'), and NHC(O)NH(R'); 3 carbonatoms to forman optionally Substituted cyclic group 0336 X is P(O)YR''Y'R'': containing 6 carbon atoms and Substituted with one substitu 0337 Y and Y are each independently selected from the ent selected from the group consisting of hydroxy, acyloxy, group consisting of —O—, and —NR'—, when Y and Y are alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycar —O , R'' attached to —O is independently selected from bonyloxy, attached to one of said carbon atoms that is three the group consisting of —H, alkyl, optionally substituted atoms from a Y attached to the phosphorus: aryl, optionally Substituted heterocycloalkyl, optionally Sub 0345 or together Z and Ware connected via an additional stituted CH-heterocycloaky1 wherein the cyclic moiety con 3-5 atoms to form a cyclic group, wherein 0-1 atoms are tains a carbonate or thiocarbonate, optionally substituted heteroatoms and the remaining atoms are carbon, and V must -alkylaryl, -C(R),OC(O)NR, NR C(O) R', be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; US 2009/011 8236 A1 May 7, 2009 27

0346 or together W and W are connected via an addi —(CR),C(O)— —(CR)C(O)(CR), —(CR),C tional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are (O)(CR) , and –C(O)NH(CR)(CR)pr; heteroatoms and the remaining atoms are carbon, and V must 0362 k is an integer from 0-4: be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; 0363 m is an integer from 0-3: 0347 Z is selected from the group consisting of —CHR 0364 n is an integer from 0-2: *OH, CHROC(O)R’, CHROC(S)R’, CHROC(S) 0365 p is an integer from 0-1; OR, CHROC(O)SR, CHROCOR, OR, SR, 0366 Each R" is independently selected from the group —CHRN, -CHaryl, -CH(aryl)OH, -CH(CH=CR) consisting of hydrogen, optionally Substituted—C-C alkyl, OH, -CH(C=CR)OH, -R, NR, OCOR', halogen, —OH, optionally Substituted —O—C-C alkyl, OCOR', SCOR, SCOR, NHCOR, —OCF, optionally substituted—S C-C alkyl, NRR, NHCO.R, CHNHaryl, -(CH), OR, and -(CH.) optionally Substituted —C-C alkenyl, and optionally Sub SR; stituted—C-C alkynyl; with the proviso that when one Ris 0348 q is an integer 2 or 3: attached through O, S, or N, then the other R' attached to the 0349 Each R is selected from the group consisting of R' same C is a hydrogen, or attached via carbon atom. Each R' and —H; is independently selected from the group consisting of hydro 0350 Each R" is selected from the group consisting of gen, optionally Substituted—C-C alkyl; alkyl, aryl, heterocycloalkyl, and aralkyl; 0367. Each R is independently selected from the group 0351 Each R is independently selected from the group consisting of hydrogen and optionally substituted —C-C, consisting of —H, and alkyl, or together R and R' form a alkyl, optionally substituted —C(O)—C-C alkyl, and cyclic alkyl group; C(O)H: 0352 Each R" is selected from the group consisting of 0368 R' and Rare each independently selected from the —H. lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and group consisting of halogen, optionally substituted—C-C, lower acyl. alkyl, optionally Substituted —S C-C alkyl, optionally 0353 Rather than specifically excluding a specific com Substituted—C-C alkenyl, optionally substituted —C-C, pound from the present invention, provisos may used for alkynyl. —CF —OCF, optionally Substituted-O—C-C, exclusionary purposes. Examples of independent provisos of alkyl, and cyano; the present invention include the following: 0369 RandR are each independently selected from the 0354) a) when G is -O-, T is —CH2—, R' and Rare group consisting of hydrogen, halogen, —CF, —OCF, each bromo, R is isopropyl, R' is hydrogen, and R is -OH, cyano, optionally substituted—C-C alkyl, optionally sub then X is not -P(O)(OH), or -P(O)(OCHCH): stituted —C-C alkenyl, optionally substituted —C- 0355 b) V, Z, W, Ware not all H; Calkynyl, optionally substituted—(CR), aryl, optionally 0356 c) when Z is R, then at least one of V, W, and W. Substituted —(CR), cycloalkyl, optionally Substituted is not —H, alkyl, aralkyl, or heterocycloalkyl, —(CR"), heterocycloalkyl, -OR', SR', -S(=O)R, 0357 d) when G is - O -, T is -(CH) , R' and R. - S(=O),R, S(=O)NR'Rs, C(O)NR'Rs, -(O)OR", are independently halogen, alkyl of 1 to 3 carbons, and C(O)R, N(R)C(O)R, N(R)C(O)NR'Rs, N(R)S cycloalkyl of 3 to 5 carbons, R is alkyl of 1 to 4 carbons or (=O),R, N(R)S(=O)NR'Rs, and NR'Rs: cycloalkyl of 3 to 7 carbons, R is hydrogen, and R is OH, 0370. Each R" is selected from the group consisting of then X is not —P(O)(OH) or - P(O)(O lower alkyl); and optionally Substituted—C-C alkyl, optionally Substituted 0358 e) when G is - O - R is NHC(O)R, NHS —C-C alkenyl, optionally Substituted —C-C alkynyl, (=O) R, NHC(S)NH(R'), or NHC(O)NH(R'), T is optionally substituted. —(CR'2),aryl, optionally substituted, —(CH), , —CH=CH-. —O(CH) , or —NH —(CR), cycloalkyl, optionally substituted —(CR), het (CH) , then X is not—P(O)(OH) or —P(O)(OH)NH2. erocycloalkyl, and –C(O)NR'R'': 0359. In one aspect, the present invention relates to com 0371. Each R is selected from the group consisting of pounds of Formula I: optionally Substituted—C-C alkyl, optionally Substituted —C-C alkenyl, optionally Substituted —C-C alkynyl, optionally substituted —(CR), aryl, optionally substituted, R3 R2 —(CR)cycloalkyl, and optionally Substituted —(CR) heterocycloalkyl: 0372 R and Rare each independently selected from the R5 G T-X group consisting of hydrogen, optionally substituted —C- Calkyl, optionally substituted—C-C alkenyl, optionally Substituted —C-Calkynyl, optionally Substituted R4 RI —(CR),aryl, optionally substituted —(CR), cycloalkyl, and optionally substituted CR”), heterocycloalkyl, or R wherein: and R may together form an optionally substituted hetero 0360 G is selected from the group consisting of —O , cyclic ring, which may contain a second heterogroup selected S s S(=O) s S(=O), s CH s CF, s from the group of O, NR, and S, wherein said optionally CHF , —C(O) , —CH(OH) , NH , and—N(C- substituted heterocyclic ring may be substituted with 0-4 Calkyl)-; Substituents selected from the group consisting of optionally 0361 T is selected from the group consisting of (CR) substituted —C-C alkyl, -OR''. Oxo, cyano, —CF, , CR”—CR (CR), , —(CR), CR”—CR', optionally substituted phenyl, and C(O)OR"; —(CR) CR”—R' (CR), —O(CR)(CR), , 0373) Each R" is selected from the group consisting of —S(CR)(CR), N(R)(CR)(CR), N(R)C(O) optionally Substituted—C-C alkyl, optionally Substituted (CR), , —(CR"),CH(NRR)-, -C(O)(CR), , —C-C alkenyl, optionally substituted —C-Calkynyl, US 2009/011 8236 A1 May 7, 2009 28 optionally substituted —(CR),aryl, optionally substituted 0382 or together V and Z are connected via an additional —(CR), cycloalkyl, and optionally substituted —(CR) 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heterocycloalkyl; heteroatoms and the remaining atoms are carbon, that is fused 0374 R is selected from the group consisting of —OH, to an aryl group at the beta and gamma position to the Y optionally substituted —OC-C alkyl, —OC(O)R. —OC attached to the phosphorus: (O)OR, F, NHC(O)R, NHS(—O)R, NHS(—O) 0383 or together V and Ware connected via an additional R, NHC(=S)NH(R'), and NHC(O)NH(R'); 3 carbonatoms to forman optionally Substituted cyclic group 0375 X is P(O)YR''Y'R'': containing 6 carbon atoms and Substituted with one substitu 0376 Y and Y are each independently selected from the ent selected from the group consisting of hydroxy, acyloxy, group consisting of —O—, and —NR'—, when Y and Y are alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycar —O , R'' attached to —O is independently selected from bonyloxy, attached to one of said carbon atoms that is three the group consisting of —H, alkyl, optionally substituted atoms from a Y attached to the phosphorus: aryl, optionally Substituted heterocycloalkyl, optionally Sub 0384 or together Z and Ware connected via an additional stituted CH-heterocycloaky1 wherein the cyclic moiety con 3-5 atoms to form a cyclic group, wherein 0-1 atoms are tains a carbonate or thiocarbonate, optionally substituted heteroatoms and the remaining atoms are carbon, and V must -alkylaryl, -C(R),OC(O)NR, NR C(O) R', be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; —C(R). OC(O)R’, C(R),O C(O)CR, C(R)OC 0385 or together W and W are connected via an addi (O)SR', -alkyl-S C(O)R’, -alkyl-S-S-alkylhydroxy, nd tional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are alkyl-S—S S-alkylhydroxy: heteroatoms and the remaining atoms are carbon, and V must 0377 when Y and Y are - NR' , then R'' attached to be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; —NR—is independently selected from the group consisting 0386 Z is selected from the group consisting of —CHR of-H, -C(R), COOR, —C(R)-COOR. -IC(R) *OH, CHROC(O)R’, CHROC(S)R’, CHROC(S) al, C(O)SR, and -cycloalkylene-COOR: OR, CHROC(O)SR, CROCOR, OR, SR, 0378 when Yis-O- and Y is NR', then R'' attached to —CHRN, -CHaryl, -CH(aryl)OH, -CH(CH=CR) —O—is independently selected from the group consisting of OH, -CH(C=CR)OH, R, NR, OCOR', —H, alkyl, optionally substituted aryl, optionally substituted OCOR', SCOR, SCOR, NHCOR, heterocycloalkyl, optionally substituted CH-heterocy NHCO.R. CH-NHaryl, -(CH2), OR, and -(CH2) cloakyl wherein the cyclic moiety contains a carbonate or SR; thiocarbonate, optionally substituted -alkylaryl, —C(R)OC (0387 q is an integer 2 or 3: (O)NR, NR C(O) R', C(R), OC(O)R’, 0388. Each R is selected from the group consisting of R' —C(R) O C(O)OR, C(R),OC(O)SR, -alkyl-S-C and —H; (O)R’, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alky 0389. Each R" is selected from the group consisting of Ihydroxy; and R'' attached to NR' is independently alkyl, aryl, heterocycloalkyl, and aralkyl; selected from the group consisting of -H, -IC(R), 0390 Each R is independently selected from the group COOR, C(R)-COOR,-(C(R), C(O)SR', and -cy consisting of —H, and alkyl, or together R and R' form a cloalkylene-COOR: cyclic alkyl group; 0379 or when Y and Y are independently selected from 0391) Each R" is selected from the group consisting of —O— and NR' , then together R'' and R'' are -alkyl —H. lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and S S-alkyl- to form a cyclic group, or together R'' and R' lower acyl: are the group: 0392 with the provisos that: 0393 a) when G is O. , T is —CH2—, R' and Rare each bromo, R is iso-propyl, R is hydrogen, and R is -H, V H then X is not P(O)(OH), or P(O)(OCHCH): 0394 b) V, Z, W, Ware not all-H; and Z 0395 c) when Z is R, then at least one of V, W, and W. H is not—H, alkyl, aralkyl, or heterocycloalkyl. W 0396. In another aspect, the invention comprises a com W pound of Formula I: wherein: R3 R2 0380 V, W, and W are independently selected from the group consisting of hydrogen, optionally Substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, Substi R5 G T-X tuted aryl, heteroaryl, substituted heteroaryl, optionally sub stituted 1-alkenyl, and optionally substituted 1-alkynyl: R4 R1 0381 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 wherein: are carbon, Substituted with hydroxy, acyloxy, alkylthiocar 0397 G is selected from the group consisting of —O—, bonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy S s S(=O) s S( O) s CH s CF, s attached to a carbon atom that is three atoms from both Y CHF , —C(O) , —CH(OH)— —NH , and —N(C- groups attached to the phosphorus; or Calkyl)-; US 2009/011 8236 A1 May 7, 2009 29

0398 T is selected from the group consisting of (CR) with 0-4 Substituents selected from the group consisting of –CR'—CR (CR), , —(CR), CR=CR , optionally substituted C-C alkyl, OR, OXO, cyano, —(CR")—CR'—CR' (CR)-, -(CR, —(CR) —CFs, optionally substituted phenyl, and C(O)CR"; (CR), , S(CR)(CR), , N(R)(CR)(CR), , 0411) Each R" is selected from the group consisting of N(R)C(O)(CR) , (CR), CH(NRR) , C(O) optionally Substituted—C-C alkyl, optionally Substituted (CR), , —(CR),C(O), —(CR)C(O)(CR), —C-C alkenyl, optionally substituted —C-C alkynyl. (CR"),C(O)(CR",)—, and –C(O)NH(CR',)(CR".) ; optionally substituted —(CR),aryl, optionally substituted 0399 k is an integer from 0-4: —(CR), cycloalkyl, and optionally substituted —(CR) 0400 m is an integer from 0-3: heterocycloalkyl: 0401 n is an integer from 0-2: 0412 R is selected from the group consisting of -OH, 0402 p is an integer from 0-1; optionally substituted —OC-C alkyl, —OC(O)R. —OC 0403. Each R" is independently selected from the group (O)OR, F, NHC(O)R, NHS(—OR, NHS(—O) consisting of hydrogen, optionally Substituted—C-C alkyl, R, NHC(=S)NH(R'), and NHC(O)NH(R'); halogen, —OH, optionally substituted —O-C-C alkyl, 0413 X is P(O)YR''Y'R'': —OCF, optionally substituted S C-C alkyl, NRR, 0414 Y and Y are each independently selected from the optionally substituted —C-C alkenyl, and optionally Sub group consisting of O—, and —NR'—, when Y and Y are stituted—C-C alkynyl; with the proviso that when one R is —O , R'' attached to —O is independently selected from attached to C through an O, S, or Natom, then the other R' the group consisting of —H, alkyl, optionally substituted attached to the same C is a hydrogen, or attached via a carbon aryl, optionally Substituted heterocycloalkyl, optionally Sub atom; stituted CH-heterocycloaky1 wherein the cyclic moiety con 04.04 Each R" is independently selected from the group tains a carbonate or thiocarbonate, optionally consisting of hydrogen, optionally substituted—C-C alkyl; substituted -alkylaryl, -C(R)OC(O)NR, NR C 04.05 Each R is independently selected from the group (O) R', —C(R), OC(O)R’, C(R), O C(O)OR, consisting of hydrogen and optionally substituted —C-C, - C(R)OC(O)SR, -alkyl-S C(O)R’, -alkyl-S-S-alkyl alkyl, optionally substituted —C(O)—C-C alkyl, and hydroxy, and -alkyl-S-S S-alkylhydroxy: C(O)H: 0415 when Y and Y are NR' , then R'' attached to 0406) R' and Rare each independently selected from the —NR'—is independently selected from the group consisting group consisting of halogen, optionally Substituted —C- of -H, -C(R). COOR, C(R)-COOR. -IC(R) Calkyl, optionally substituted—S-C-C alkyl, optionally C(O)SR', and -cycloalkylene-COOR': Substituted—C-C alkenyl, optionally Substituted—C-C, 0416 when Y is - O - and Y is NR, then R'' attached to alkynyl, -CF, —OCF, optionally substituted-O-C-C, —O—is independently selected from the group consisting of alkyl, and cyano; —H, alkyl, optionally substituted aryl, optionally substituted 0407 R and Rare each independently selected from the heterocycloalkyl, optionally substituted CH-heterocy group consisting of hydrogen, halogen, —CF, —OCF, cloaky1 wherein the cyclic moiety contains a carbonate or cyano, optionally Substituted—C-C alkyl, optionally Sub thiocarbonate, optionally substituted-alkylaryl, —C(R)OC stituted —C-C alkenyl, optionally substituted —C-C, (O)NR, NR C(O) R', C(R), OC(O)R’, alkynyl, optionally Substituted —(CR), aryl, optionally - C(R), O C(O)OR, C(R)OC(O)SR, -alkyl-S-C Substituted —(CR), cycloalkyl, optionally Substituted (O)R’, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alky —(CR), heterocycloalkyl, -OR. -SR, -S(=O)R, Ihydroxy; and R'' attached to NR' is independently –SG-O).R., -S(-O)NR'R. C(O)NR'R'', C(O) selected from the group consisting of -H, -IC(R), OR, C(O)R, N(R)C(O)R, N(R)C(O)NR'Rs, COOR, C(R)-COOR,-(C(R), C(O)SR', and -cy N(R)S(=O).R., N(R)S(=O)NR'Rs, and NR/Rs: cloalkylene-COOR': (0408. Each R" is selected from the group consisting of 0417 or when Y and Y are independently selected from optionally Substituted—C-C alkyl, optionally Substituted —O— and NR' , then together R'' and R'' are -alkyl —C-C alkenyl, optionally Substituted —C-C alkynyl, S S-alkyl- to form a cyclic group, or together R'' and R' optionally substituted —(CR),aryl, optionally substituted are the group: —(CR), cycloalkyl, optionally substituted —(CR), het erocycloalkyl, and –C(O)NR'Rs: V 04.09 Each R is selected from the group consisting of H optionally Substituted—C-C alkyl, optionally Substituted —C-C alkenyl, optionally substituted —C-C alkynyl. Z optionally substituted —(CR),aryl, optionally substituted H —(CR), cycloalkyl, and optionally substituted —(CR) heterocycloalkyl; W 0410 R and Rare each independently selected from the W group consisting of hydrogen, optionally substituted C-C2 alkyl, optionally substituted —C-C alkenyl, optionally wherein: Substituted —C-C alkynyl, optionally substituted 0418 V, W, and W are independently selected from the —(CR),aryl, optionally substituted —(CR), cycloalkyl, group consisting of hydrogen, optionally Substituted alkyl, and optionally substituted —(CR), heterocycloalkyl, or R optionally substituted aralkyl, heterocycloalkyl, aryl, Substi and R may together form an optionally substituted hetero tuted aryl, heteroaryl, substituted heteroaryl, optionally sub cyclic ring, which may contain a second heterogroup selected stituted 1-alkenyl, and optionally substituted 1-alkynyl: from the group consisting of O, NR, and S, wherein said 0419 or together V and Z are connected via an additional optionally substituted heterocyclic ring may be substituted 3-5 atoms to form a cyclic group containing 5-7 atoms, US 2009/011 8236 A1 May 7, 2009 30 wherein 0-1 atoms are heteroatoms and the remaining atoms wherein: are carbon, Substituted with hydroxy, acyloxy, alkylthiocar 0433 G is selected from the group consisting of —O—, bonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy S— —S(=O)— —S(=O) , —CH2—, —CF , attached to a carbon atom that is three atoms from both Y CHF , —C(O) , —CH(OH)— —NH , and —N(C- groups attached to the phosphorus; or Calkyl)-; 0420 or together V and Z are connected via an additional 0434 T is selected from the group consisting of (CR) 3-5 atoms to form a cyclic group, wherein 0-1 atoms are , —CR'—CR' (CR), (CR), CR”—CR, heteroatoms and the remaining atoms are carbon, that is fused (CR) CR-CR (CR) , O(CR)(CR), , to an aryl group at the beta and gamma position to the Y S(CR)(CR), , – N(R)(CR)(CR), , N(R)C(O) attached to the phosphorus; (CR), , —(CR)CH(NRR)-, -C(O)(CR), , 0421 or together V and Ware connected via an additional —(CR),C(O), —(CR)C(O)(CR), , —(CR)C(O) 3 carbonatoms to forman optionally Substituted cyclic group containing 6 carbon atoms and Substituted with one substitu 0435 k is an integer from 0-4: ent selected from the group consisting of hydroxy, acyloxy, 0436 m is an integer from 0-3: alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycar 0437 n is an integer from 0-2: 0438 p is an integer from 0-1; bonyloxy, attached to one of said carbon atoms that is three 0439 Each R" is independently selected from the group atoms from a Y attached to the phosphorus: consisting of hydrogen, optionally Substituted—C-C alkyl, 0422 or together Z and Ware connected via an additional halogen, —OH, optionally substituted —OC-C alkyl, 3-5 atoms to form a cyclic group, wherein 0-1 atoms are OCF, optionally substituted S C-C alkyl, NRR, heteroatoms and the remaining atoms are carbon, and V must optionally substituted —C-C alkenyl, and optionally sub be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; stituted—C-C alkynyl; with the proviso that when one R is 0423 or together W and W are connected via an addi attached through O, S, or N, then the other R' attached to the tional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are same C is a hydrogen, or attached via carbon atom. heteroatoms and the remaining atoms are carbon, and V must I0440 Each R" is independently selected from the group be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; consisting of hydrogen and optionally substituted —C-C, 0424 Z is selected from the group consisting of —CHR alkyl: *OH, CHROC(O)R’, CHROC(S)R’, CHROC(S) 0441. Each R is independently selected from the group OR, CHROC(O)SR, CHROCOR, OR, SR, consisting of hydrogen, optionally Substituted—C-C alkyl, —CHRN —CHaryl, -CH(aryl)OH, -CH(CH=CR) optionally substituted—C(O) C-C alkyl, and —C(O)H: OH, -CH(C=CR)OH, R, NR, OCOR', 0442 R and Rare each independently selected from the –OCOR', SCOR, SCOR, NHCOR, group consisting of halogen, optionally substituted —C- NHCO.R. CH-NHaryl, -(CH2), OR, and -(CH2) Calkyl, optionally substituted—S C-C alkyl, optionally SR; Substituted—C-C alkenyl, optionally Substituted —C-C, 0425 q is an integer 2 or 3: alkynyl. —CF —OCF, optionally Substituted-O—C-C, 0426 Each R is selected from the group consisting of R' alkyl, and cyano; and —H; 10443) RandR are each independently selected from the 0427 Each R" is selected from the group consisting of group consisting of hydrogen, halogen, —CF, —OCF, alkyl, aryl, heterocycloalkyl, and aralkyl; cyano, optionally Substituted—C-C alkyl, optionally Sub 0428 Each R is independently selected from the group stituted —C-C alkenyl, optionally substituted —C-C, consisting of —H, and alkyl, or together R and R form a alkynyl, optionally Substituted —(CR), aryl, optionally cyclic alkyl group; substituted —(CR).cycloalkyl, optionally substituted 0429 Each R is selected from the group consisting of (CR).heterocycloalkyl, -OR', SR, -S(=O)R, —H. lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and S(=O).R., S(=O)NR'Rs, C(O)NR'Rs, C(O) lower acyl: OR, C(O)R, N(R)C(O)R, N(R)C(O)NR'Rs, 0430 with the proviso that when G is —O—, T is N(R)S(=O).R., N(R)S(=O)NR'Rs, and NRRS: —CH2—, R' and Rare each bromo, R is iso-propyl, R is 0444. Each R" is selected from the group consisting of hydrogen, and R is -OH, then X is not P(O)(OH), or P(O) optionally Substituted—C-C alkyl, optionally Substituted (OCH2CH): —C-C alkenyl, optionally Substituted —C-C alkynyl, 0431 and pharmaceutically acceptable salts and prodrugs optionally substituted, -(CR),aryl, optionally substituted thereof and pharmaceutically acceptable salts of said pro —(CR), cycloalkyl, optionally substituted —(CR), het drugs. erocycloalkyl, and –C(O)NR'Rs: 0432. In a second aspect the present invention relates to 0445. Each R is optionally substituted —C-C alkyl, compounds of Formula I, Stereoisomers, pharmaceutically optionally substituted —C-C alkenyl, optionally substi acceptable salts and prodrugs thereof and pharmaceutically tuted—C-Calkynyl, optionally substituted —(CR).aryl, acceptable salts of the prodrugs as represented by Formula I: optionally Substituted —(CR), cycloalkyl, and optionally substituted —(CR), heterocycloalkyl: R3 R2 I0446. RandR are each independently selected from the group consisting of hydrogen, optionally substituted —C- Calkyl, optionally Substituted—C-C alkenyl, optionally Substituted —C-C alkynyl, optionally substituted —(CR),aryl, optionally substituted —(CR), cycloalkyl, and optionally substituted —CR), heterocycloalkyl, or R and R may together form an optionally substituted hetero cyclic ring, which may contain a second heterogroup selected US 2009/011 8236 A1 May 7, 2009

from the group of O. NR, and S, wherein said optionally tuted aryl, heteroaryl, substituted heteroaryl, optionally sub substituted heterocyclic ring may be substituted with OW stituted 1-alkenyl, and optionally substituted 1-alkynyl: Substituents selected from the group consisting of optionally 0455 or together V and Z are connected via an additional substituted —C-C alkyl, -OR''. Oxo, cyano, —CF, 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally substituted phenyl, and C(O)OR': wherein 0-1 atoms are heteroatoms and the remaining atoms 0447. Each R" is selected from the group consisting of are carbon, Substituted with hydroxy, acyloxy, alkylthiocar optionally substituted—C-C alkyl, optionally substituted bonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy —C-C alkenyl, optionally Substituted —C-Calkynyl, attached to a carbon atom that is three atoms from both Y optionally substituted —(CR),aryl, optionally substituted groups attached to the phosphorus; or —CR).cycloalkyl, and optionally substituted—CR), het 0456 or together V and Z are connected via an additional erocycloalkyl, 3-5 atoms to form a cyclic group, wherein 0-1 atoms are 0448 R is selected from the group consisting of —OH, heteroatoms and the remaining atoms are carbon, that is fused optionally substituted —OC-C alkyl, —OC(O)R. —OC to an aryl group at the beta and gamma position to the Y (O)OR, F, NHC(O)R, NHS(—O)R, NHS(—O) attached to the phosphorus: R, NHC(=S)NH(R'), and NHC(O)NH(R'); 0457 or together V and Ware connected via an additional 0449 X is P(O)YR''Y'R'': 3 carbonatoms to forman optionally Substituted cyclic group 0450 Y and Y are each independently selected from the containing 6 carbon atoms and Substituted with one substitu group consisting of —O—, and —NR'—, when Y and Y are ent selected from the group consisting of hydroxy, acyloxy, —O , R'' attached to —O is independently selected from alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycar the group consisting of —H, alkyl, optionally substituted bonyloxy, attached to one of said carbon atoms that is three aryl, optionally Substituted heterocycloalkyl, optionally Sub atoms from a Y attached to the phosphorus: stituted CH-heterocycloaky1 wherein the cyclic moiety con 0458 or together Z and Ware connected via an additional tains a carbonate or thiocarbonate, optionally substituted 3-5 atoms to form a cyclic group, wherein 0-1 atoms are -alkylaryl, -C(R),OC(O)NR, NR C(O) R', heteroatoms and the remaining atoms are carbon, and V must —C(R) OC(O)R’, C(R) O C(O)OR, C(R) be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; OC(O)SR', -alkyl-S C(O)R’, -alkyl-S-S-alkylhydroxy, 0459 or together W and W are connected via an addi and -alkyl-S S S-alkylhydroxy: tional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are 0451 when Y and Y are NR' , then R'' attached to heteroatoms and the remaining atoms are carbon, and V must —NR' is independently selected from the group consisting be aryl, Substituted aryl, heteroaryl, or substituted heteroaryl; of -H, -IC(R). COOR, C(R)-COOR. -IC(R) 0460 Z is selected from the group consisting of —CHR al, C(O)SR, and -cycloalkylene-COOR: *OH, CHROC(O)R’, CHROC(S)R’, CHROC(S) 0452 when Yis-O- and Y is NR', then R'' attached to OR, CHROC(O)SR, CHROCOR, OR, SR, —O—is independently selected from the group consisting of - CHRN, -CHaryl, -CH(aryl)OH, -CH(CH=CR) —H, alkyl, optionally substituted aryl, optionally substituted OH, -CH(C=CR)OH, -R, NR, OCOR', heterocycloalkyl, optionally substituted CH-heterocy OCOR', SCOR, SCOR, NHCOR, cloakyl wherein the cyclic moiety contains a carbonate or NHCO.R, CHNHaryl, -(CH), OR, and -(CH.) thiocarbonate, optionally SR; substituted -alkylaryl, -C(R)OC(O)NR, NR C 0461) q is an integer 2 or 3: (O) R', C(R). OC(O)R’, C(R) O C(O)OR, 0462 Each R is selected from the group consisting of R' —C(R)OC(O)SR, -alkyl-S C(O)R’, -alkyl-S-S-alkyl and —H; hydroxy, and -alkyl-S-S S-alkylhydroxy; and R' 0463 Each R" is selected from the group consisting of attached to —NR' is independently selected from the alkyl, aryl, heterocycloalkyl, and aralkyl; group consisting of H, IC(R), COOR, C(R) 0464. Each R is independently selected from the group COOR. -IC(R), C(O)SR, and -cycloalkylene consisting of —H, and alkyl, or together R and R form a COOR; cyclic alkyl group; 0453 or when Y and Y are independently selected from 0465. Each R is selected from the group consisting of —O— and NR' , then together R'' and R'' are -alkyl —H. lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and S S-alkyl- to form a cyclic group, or together R'' and R' lower acyl: are the group: 0466 with the provisos that: 10467 a) when G is —O , T is —(CH) , R' and R' 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 is hydrogen, and R is —OH, then X is not—P(O)(OH) or —P(O)(O-lower alkyl); 0468 b) when G is -O-, R is NHC(O)R, NHS (=O), R, NHC(S)NH(R'), or NHC(O)NH(R'), T is —(CH) , —CH=CH-, -O(CH) , or —NH (CH) , then X is not—P(O)(OH), or—P(O)(OH)NH; 0469 c) V, Z, W, Ware not all-H; and wherein: 0470 d) when Zis-R, then at least one of V, W, and W. 0454) V, W, and W are independently selected from the is not—H, alkyl, aralkyl, or heterocycloalkyl. group consisting of hydrogen, optionally Substituted alkyl, 0471. In a further aspect, the present invention relates to optionally substituted aralkyl, heterocycloalkyl, aryl, Substi compounds of Formula I, Stereoisomers, pharmaceutically US 2009/011 8236 A1 May 7, 2009 32 acceptable salts and prodrugs thereof and pharmaceutically —(CR), cycloalkyl, optionally substituted—(CR)hetero acceptable salts of the prodrugs as represented by Formula I: cycloalkyl, and –C(O)NR'Rs: 0484. Each R is optionally substituted —C-Calkyl, optionally Substituted —C-C alkenyl, optionally Substi R3 R2 tuted —C-C alkynyl, optionally Substituted —(CR) aryl, optionally Substituted —(CR), cycloalkyl, and R5 G T-X optionally substituted —(CR), heterocycloalkyl: 0485 RandR are each independently selected from the group consisting of hydrogen, optionally substituted —C- R4 RI Calkyl, optionally Substituted—C-C alkenyl, optionally Substituted —C-C alkynyl, optionally Substituted wherein: —(CR),aryl, optionally substituted —(CR), cycloalkyl, 0472. G is selected from the group consisting of —O , and optionally substituted —(CR), heterocycloalkyl, or R and R may together form an optionally substituted hetero CHF , —C(O) , —CH(OH) , NH , and—N(C- cyclic ring, which may contain a second heterogroup selected Calkyl)-; from the group of O, NR, and S, wherein said optionally 0473. T is selected from the group consisting of (CR) substituted heterocyclic ring may be substituted with 0-4 , —CR'=CR' (CR), , (CR), Substituents selected from the group consisting of optionally CRC–CR (CR) CR(CR)(CR) O(CR) substituted —C-C alkyl, -OR''. Oxo, cyano, —CFs, (CR), , S(CR)(CR), , – N(R)(CR)(CR) optionally substituted phenyl, and C(O)OR"; , – N(R)C(O)(CR), , —(CR"),CH(NR'R' , 0486) Each R" is selected from the group consisting of —C(O)(CR), , —(CR),C(O)— —(CR)C(O) optionally substituted—C-C alkyl, optionally substituted (CR), , (CR),C(O)(CR)—, and C(O)NH(CR) —C-C alkenyl, optionally Substituted —C-C alkynyl, (CR'2) ; optionally substituted —(CR),aryl, optionally substituted 0474 k is an integer from 0-4: —(CR), cycloalkyl, and optionally substituted —(CR). 0475 m is an integer from 0-3: heterocycloalkyl; 0476 n is an integer from 0-2: 0487 R is selected from the group consisting of -OH, 0477 p is an integer from 0-1: optionally substituted —OC-C alkyl, —OC(O)R. —OC 0478 Each R" is independently selected from the group consisting of hydrogen, optionally Substituted—C-C alkyl, (O)OR, F, NHC(O)R, NHS(—OR, NHS(—O) halogen, —OH, optionally Substituted —O—C-C alkyl, R, NHC(=S)NH(R'), and NHC(O)NH(R'); —OCF, optionally substituted—S C-C alkyl, NRR, 0488 X is P(O)YR''Y'R'': optionally substituted —C-C alkenyl, and optionally Sub 0489 Y and Y are each independently selected from the stituted—C-C alkynyl; with the proviso that when one Ris group consisting of O—, and —NR'—, when Y and Y are attached through O, S, or N, then the other R' attached to the —O , R'' attached to —O is independently selected from same C is a hydrogen, or attached via carbon atom. the group consisting of —H, alkyl, optionally substituted 0479. Each R is independently selected from the group aryl, optionally Substituted heterocycloalkyl, optionally Sub consisting of hydrogen and optionally substituted —C-C, stituted CH-heterocycloaky1 wherein the cyclic moiety con alkyl: tains a carbonate or thiocarbonate, optionally substituted 0480 Each R is independently selected from the group -alkylaryl, -C(R 96 OC(O)NR, NR C(O) R', consisting of hydrogen, optionally Substituted—C-C alkyl, - C(R). OC(O)R’, C(R), O C(O)OR, C(R)OC optionally substituted—C(O)—C-C alkyl, and —C(O)H: (O)SR', -alkyl-S C(O)R’, -alkyl-S-S-alkylhydroxy, and 0481) R' and Rare each independently selected from the -alkyl-S-S-S-alkylhydroxy: group consisting of halogen, optionally Substituted—C-C, 0490 when Y and Y are - NR' , then R'' attached to alkyl, optionally Substituted —S C-C alkyl, optionally —NR'—is independently selected from the group consisting Substituted—C-C alkenyl, optionally Substituted—C-C, alkynyl. —CF —OCF, optionally Substituted-O—C-C, of-H, -C(R), COOR, —C(R)-COOR. -IC(R) alkyl, and cyano; al, C(O)SR, and -cycloalkylene-COOR: 0482 R and Rare each independently selected from the 0491 when Y is - O - and Y is NR, then R'' attached to group consisting of hydrogen, halogen, —CF, —OCF, —O—is independently selected from the group consisting of cyano, optionally substituted—C-C alkyl, optionally sub —H, alkyl, optionally substituted aryl, optionally substituted stituted —C-C alkenyl optionally substituted —C-C2 heterocycloalkyl, optionally substituted CH-heterocy alkynyl, optionally substituted —(CR), aryl, optionally cloaky1 wherein the cyclic moiety contains a carbonate or Substituted —(CR), cycloalkyl, optionally Substituted thiocarbonate, optionally (CR), heterocycloalkyl, -OR', SR, -S(=O)R, substituted -alkylaryl, -C(R)OC(O)NR, NR C S(=O).R., S(=O)NR'Rs, C(O)NR'Rs, C(O) (O) R', —C(R), OC(O)R’, C(R), O C(O)OR, OR", C(O)R, N(O)C(O)R, N(R)C(O)NR'Rs, - C(R)OC(O)SR, -alkyl-S C(O)R’, -alkyl-S-S-alkyl N(R)S(=O),R, N(R)S(=O)NR'Rs, and NRRs: hydroxy, and -alkyl-S-S-S-alkylhydroxy; and R' 0483 Each R" is selected from the group consisting of attached to —NR' is independently selected from the optionally Substituted—C-C alkyl, optionally Substituted group consisting of H. —C(R), COOR, C(R) —C-C alkenyl, optionally Substituted —C-C alkynyl, COOR, C(R), C(O)SR, and -cycloalkylene optionally substituted, -(CR), aryl, optionally substituted COOR; US 2009/011 8236 A1 May 7, 2009

0492 or when Y and Y are independently selected from 0504. Each R" is selected from the group consisting of —O— and NR' , then together R'' and R'' are -alkyl —H. lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and S S-alkyl- to form a cyclic group, or together R'' and R' lower acyl: are the group: (0505 with the provisos that: (0506 a) V, Z, W, Ware not all-H; and (0507 b) when Zis-R, then at least one of V, W, and W. V H is not—H, alkyl, aralkyl, or heterocycloalkyl. 0508. In another aspect, the invention comprises a com Z pound of Formula I: H, W R3 R2 W wherein: R5 G T-X 0493 V, W, and W are independently selected from the group consisting of hydrogen, optionally Substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, Substi R4 R1 tuted aryl, heteroaryl, substituted heteroaryl, optionally sub stituted 1-alkenyl, and optionally substituted 1-alkynyl: wherein: 0494 or together V and Z are connected via an additional 0509 G is selected from the group consisting of —O—, 3-5 atoms to form a cyclic group containing 5-7 atoms, S s S(=O) s S(=O), s CH s CF, s wherein 0-1 atoms are heteroatoms and the remaining atoms CHF , —C(O) , —CH(OH)— —NH , and —N(C- are carbon, Substituted with hydroxy, acyloxy, alkylthiocar Calkyl)-; bonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy 0510 T is selected from the group consisting of (CR) attached to a carbon atom that is three atoms from both Y , —CR'—CR (CR), , -(CR), CR=CR, groups attached to the phosphorus; or —(CR")—CR'—CR' (CR)-, -O(CR)(CR), , 0495 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 gamma position to the Y attached to the phosphorus; 0511 k is an integer from 0-4: 0496 or together V and Ware connected via an additional 0512 m is an integer from 0-3: 3 carbonatoms to forman optionally Substituted cyclic group 0513 n is an integer from 0-2: containing 6 carbon atoms and Substituted with one substitu 0514 p is an integer from 0-1; ent selected from the group consisting of hydroxy, acyloxy, 0515 Each R" is independently selected from the group alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycar consisting of hydrogen, optionally Substituted—C-C alkyl, bonyloxy, attached to one of said carbon atoms that is three halogen, —OH, optionally substituted —O-C-C alkyl, atoms from a Y attached to the phosphorus: OCF, optionally substituted S C-C alkyl, NRR, 0497 or together Z and Ware connected via an additional optionally Substituted —C-C alkenyl, and optionally Sub 3-5 atoms to form a cyclic group, wherein 0-1 atoms are stituted—C-C alkynyl; with the proviso that when one Ris heteroatoms and the remaining atoms are carbon, and V must attached to C through an O, S, or N atom, then the other R' be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; attached to the same C is a hydrogen, or attached via a carbon 0498 or together W and W are connected via an addi atom; tional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are (0516) Each R" is independently selected from the group heteroatoms and the remaining atoms are carbon, and V must consisting of hydrogen and optionally substituted —C-C, be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; alkyl: 0517 Each R is independently selected from the group 0499 Z is selected from the group consisting of —CHR consisting of hydrogen, optionally Substituted—C-C alkyl, *OH, CHROC(O)R’, CHROC(S)R’, CHROC(S) optionally substituted—C(O)—C-C alkyl, and —C(O)H: OR, CHROC(O)SR, CHROCOR, OR, SR, 0518) R' and Rare each independently selected from the —CHRN, -CHaryl, -CH(aryl)OH, -CH(CH=CR) group consisting of halogen, optionally substituted —C- OH, -CH(C=CR)OH, -R, NR, OCOR', Calkyl, optionally substituted—S C-C alkyl, optionally OCOR', SCOR, SCOR, NHCOR, Substituted—C-C alkenyl, optionally Substituted —C-C, NHCO.R. CH-NHaryl, -(CH2), OR, and -(CH2) alkynyl, -CF, —OCF, optionally substituted-O-C-C, SR; alkyl, and cyano; 0500 q is an integer 2 or 3: 0519 Rand Rare each independently selected from the 0501) Each R is selected from the group consisting of R' group consisting of hydrogen, halogen, —CF, —OCF, and —H; cyano, optionally Substituted—C-C alkyl, optionally Sub 0502. Each R" is selected from the group consisting of stituted —C-C alkenyl, optionally substituted —C-C, alkyl, aryl, heterocycloalkyl, and aralkyl; alkynyl, optionally substituted—(CR).aryl, optionally Sub 0503. Each R is independently selected from the group stituted —(CR), cycloalkyl, optionally substituted (CR) consisting of —H, and alkyl, or together R and R' form a heterocycloalkyl, -OR', SR, S(–O)R, S(=O) cyclic alkyl group; R, S(=O).RRS, C(O)NR'Rs, C(O)OR, C(O) US 2009/011 8236 A1 May 7, 2009 34

R, N(R)C(O)R, N(R)C(O)NR'Rs, N(R)S(—O) group consisting of H, IC(R), COOR, C(R) R, N(R)S(=O)NR'Rs, and NR/Rs: COOR, C(R), C(O)SR, and -cycloalkylene 0520 Each R" is selected from the group consisting of COOR; optionally substituted—C-C alkyl, optionally substituted 0529) or when Y and Y are independently selected from —C-C alkenyl, optionally Substituted —C-C alkynyl, —O— and NR' , then together R'' and R'' are -alkyl optionally substituted —(CR),aryl, optionally substituted S S-alkyl- to form a cyclic group, or together R'' and R' —(CR), cycloalkyl, optionally substituted —(CR'2), het are the group: erocycloalkyl, and –C(O)NR'R'': 0521. Each R is optionally substituted —C-C alkyl, optionally Substituted —C-C alkenyl, optionally Substi V tuted —C-C, alkynyl, optionally substituted —(CR) H aryl, optionally substituted —(CR), cycloalkyl, and Z optionally substituted —(CR), heterocycloalkyl: 0522 R and Rs are each independently selected from the H, group consisting of hydrogen, optionally substituted —C- W Calkyl, optionally substituted—C-C alkenyl, optionally W Substituted —C-C alkynyl, optionally Substituted —(CR),aryl, optionally substituted —(CR), cycloalkyl, wherein: and optionally substituted —(CR), heterocycloalkyl, or R 0530 V, W, and W are independently selected from the and R may together form an optionally substituted hetero group consisting of hydrogen, optionally Substituted alkyl, cyclic ring, which may contain a second heterogroup selected optionally substituted aralkyl, heterocycloalkyl, aryl, Substi from the group of O. NR, and S, wherein said optionally tuted aryl, heteroaryl, substituted heteroaryl, optionally sub substituted heterocyclic ring may be substituted with 0-4 stituted 1-alkenyl, and optionally substituted 1-alkynyl: Substituents selected from the group consisting of optionally 0531 or together V and Z are connected via an additional substituted —C-C alkyl, -OR''. Oxo, cyano, —CFs, 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally substituted phenyl, and —C(O)OR"; wherein 0-1 atoms are heteroatoms and the remaining atoms 0523. Each R" is selected from the group consisting of are carbon, Substituted with hydroxy, acyloxy, alkylthiocar optionally substituted—C-C alkyl, optionally substituted bonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy —C-C alkenyl, optionally substituted —C-C alkynyl, attached to a carbon atom that is three atoms from both Y optionally substituted —(CR),aryl, optionally substituted groups attached to the phosphorus; or —(CR), cycloalkyl, and optionally substituted —(CR) 0532 or together V and Z are connected via an additional heterocycloalkyl; 3-5 atoms to form a cyclic group, wherein 0-1 atoms are 0524 R is selected from the group consisting of —OH, heteroatoms and the remaining atoms are carbon, that is fused optionally substituted —OC-C alkyl, —OC(O)R. —OC to an aryl group at the beta and gamma position to the Y (O)OR, F, NHC(O)R, NHS(—O)R, NHS(—O) attached to the phosphorus: R, NHC(=S)NH(R'), and NHC(O)NH(R): 0533 or together V and Ware connected via an additional 0525 X is P(O)YR''Y'R'': 3 carbonatoms to forman optionally Substituted cyclic group 0526 Y and Y are each independently selected from the containing 6 carbon atoms and Substituted with one substitu group consisting of —O—, and —NR'—, when Y and Y are ent selected from the group consisting of hydroxy, acyloxy, —O , R'' attached to —O is independently selected from alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycar the group consisting of —H, alkyl, optionally substituted aryl, optionally Substituted heterocycloalkyl, optionally Sub bonyloxy, attached to one of said carbon atoms that is three stituted CH-heterocycloaky1 wherein the cyclic moiety con atoms from a Y attached to the phosphorus: tains a carbonate or thiocarbonate, optionally substituted 0534 or together Z and Ware connected via an additional -alkylaryl, 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V must —C(R)OC(O)NR, NR C(O) R', C(R). OC be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; (O)R’, C(R), O C(O)CR, C(R).OC(O)SR, -alkyl-S C(O)R’, -alkyl-S-S-alkylhydroxy, and -alkyl 0535 or together W and W are connected via an addi S–S S-alkylhydroxy: tional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are 0527 when Y and Y are - NR' , then R'' attached to heteroatoms and the remaining atoms are carbon, and V must —NR—is independently selected from the group consisting be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; of-H, -C(R), COOR, —C(R)-COOR. -IC(R) 0536 Z is selected from the group consisting of —CHR C(O)SR', and -cycloalkylene-COOR'; *OH, CHROC(O)R’, CHROC(S)R’, CHROC(S) 0528 when Yis-O- and Y is NR', then R'' attached to OR, CHROC(O)SR, CHROCOR, OR, SR, —O—is independently selected from the group consisting of - CHRN, -CHaryl, -CH(aryl)OH, -CH(CH=CR) —H, alkyl, optionally substituted aryl, optionally substituted OH, -CH(C=CR)OH, -R, NR, OCOR', heterocycloalkyl, optionally substituted CH-heterocy OCOR', SCOR, SCOR, NHCOR, cloakyl wherein the cyclic moiety contains a carbonate or NHCO.R. CH-NHaryl, -(CH2), OR, and -(CH2) thiocarbonate, optionally SR; substituted -alkylaryl, -C(R).OC(O)NR, NR C 0537 q is an integer 2 or 3: (O) R', C(R). OC(O)R’, C(R) O C(O)OR, 0538 Each R is selected from the group consisting of R' —C(R)OC(O)SR, -alkyl-S C(O)R’, -alkyl-S-S-alkyl and —H; hydroxy, and -alkyl-S-S-S-alkylhydroxy; and R' 0539. Each R" is selected from the group consisting of attached to —NR' is independently selected from the alkyl, aryl, heterocycloalkyl, and aralkyl; US 2009/011 8236 A1 May 7, 2009

0540 Each R is independently selected from the group optionally substituted —C-C alkyl with the proviso that consisting of —H, and alkyl, or together R and R' form a when one R is attached to C through an O, S, or Natom, then cyclic alkyl group; the other R' attached to the same C is a hydrogen, or attached 0541. Each R is selected from the group consisting of via a carbonatom. In a further aspect, each R" is halogen with —H. lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and the proviso that when one R is attached to C through an O, S, lower acyl: or N atom, then the other R' attached to the same C is a 0542 with the provisos that: hydrogen, or attached via a carbon atom. In another aspect, (0543 a) when G is —O , T is —(CH) , R' and R' each R" is —OH with the proviso that when one R is attached are independently halogen, alkyl of 1 to 3 carbons, and to C through an O, S, or Natom, then the other Rattached to cycloalkyl of 3 to 5 carbons, R is alkyl of 1 to 4 carbons or the same C is a hydrogen, or attached via a carbon atom. In a cycloalkyl of 3 to 7 carbons, R is hydrogen, and Ris-OH, further aspect, each R" is optionally substituted—O-C-C, then X is not —P(O)(OH) or —P(O)(O-lower alkyl); alkyl with the proviso that when one R is attached to C (0544 b) when G is -O-, R is NHC(O)R, NHS through an O, S, or Natom, then the other Rattached to the (=O), R, NHC(S)NH(R'), or NHC(O)NH(R'), T is same C is a hydrogen, or attached via a carbon atom. In —(CH) , —CH=CH-, -O(CH) , or —NH another aspect, each R" is —OCF with the proviso that when (CH) , then X is not—P(O)(OH), or—P(O)(OH)NH2: one R is attached to C through an O, S, or Natom, then the 0545 and pharmaceutically acceptable salts and prodrugs other Rattached to the same C is a hydrogen, or attached via thereof and pharmaceutically acceptable salts of said pro a carbon atom. In a further aspect, each R" is optionally drugs. substituted—S C-C alkyl with the proviso that when one 0546. In one aspect, G is —O—. In another aspect, G is R" is attached to C through an O, S, or Natom, then the other —CH2—. In yet another aspect, G is selected from the group R attached to the same C is a hydrogen, or attached via a consisting of —O— and —CH2—. In another aspect, G is carbon atom. In another aspect, each R" is NR'R' with the —S-. In a further aspect, G is —S(=O)—. In another proviso that when one R is attached to C through an O, S, or aspect, G is —S(=O) . In a further aspect, G is —CH2—. Natom, then the other Rattached to the same C is a hydro In another aspect, G is —CF-. In a further aspect, G is gen, or attached via a carbonatom. Inafurther aspect, each R' —CHF . In another aspect, G is —C(O)—. In another is optionally Substituted —C-C alkenyl with the proviso aspect, G is —CH(OH)—. In a further aspect, G is —NH-. that when one R is attached to C through an O, S, or Natom, 0547. In another aspect, G is —N(C-C alkyl)-. In yet then the other R attached to the same C is a hydrogen, or another aspect, G is selected from the group consisting of attached via a carbon atom. In another aspect, each R is —O— —S— and —CH2—. optionally substituted—C-C alkynyl with the proviso that (0548. In one aspect, T is T is —CH2—. In another aspect, when one R is attached to C through an O, S, or Natom, then T is —(CH2) -. In another aspect, T is selected from the the other Rattached to the same C is a hydrogen, or attached group consisting of —(CH), , —CH=CH-, —O(CH2) via a carbon atom. , and —NH(CH) . In yet another aspect, T is (0552. In one aspect, R is hydrogen. In an additional selected from the group consisting of (CR'2), —O(CR) aspect, R is optionally substituted—C-C alkyl. (CR") , N(CR')(CR") , S(CR')(CR") , 0553. In one aspect, R is hydrogen. In another aspect, R —NR(CO)—, and CH-CH(NRR)-. In another aspect, is optionally substituted—C-C alkyl. In a further aspect, R T is —CH-CH(NH)—. In another aspect, T is N(H)C is optionally substituted—C(O)—C-C alkyl. In yet another (O)—. In a further aspect, T is —OCH2—. In another aspect, aspect, R is —C(O)H. T is —CH2CH2—. In yet another aspect, T is —CHCH (0554. In one aspect, RandR are each bromo. In another (NH)—. In another aspect, T is N(H)C(O)—. aspect, R' and Rare independently selected from the group 0549. In a further aspect, T is —(CR) . In another consisting of hydrogen, halogen, alkyl of 1 to 3 carbons, and aspect, T is CRCR (CR), . In a further aspect, T is cycloalkyl of 3 to 5 carbons. In another aspect, R' and Rare —(CR), CR”—CR -. In another aspect, T is independently halogen, alkyl of 1 to 3 carbons, and cycloalkyl —(CR")—CR'—CR' (CR)-. In a further aspect, T is of 3 to 5 carbons. In a further aspect, R' and Rare the same —O(CR)(CR), . In another aspect, T is S(CR) and are selected from the group consisting of halogen, —C- (CR), . In a further aspect, T is N(CR)(CR), . In Calkyl, -CFs, and cyano. In an additional aspect, RandR another aspect, T is N(R)C(O)(CR), . In a further are different and are selected from the group consisting of aspect, T is —(CR),CH(NRR)-. In another aspect, T is halogen, —C1-C4 alkyl, -CFs, and cyano. In one aspect, R' —C(O)(CR), . In a further aspect, T is —(CR),C and R are each independently selected from the group con (O)—. In another aspect, T is —(CR)C(O)(CR), . In a sisting of halogen, —C-C alkyl, -CF, and cyano. In further aspect, T is —(CR),C(O)(CR)—. In yet another another aspect, R' and R are each independently selected aspect, T is —C(O)NH(CR',)(CR".) . from the group consisting of iodo, bromo, chloro, methyl, and 0550. In one aspect k is 0. In a further aspect, k is 1. In an cyano. In another aspect, R' and R are each iodo. In one additional aspect, k is 2. In a further aspect, k is 3. In yet aspect, R' and Rare each methyl. In a further aspect, R' and another aspect, k is 4. In one aspect m is 0. In a further aspect, Rare each chloro. In another aspect, R' and R are each m is 1. In an additional aspect, m is 2. In a further aspect, m is independently selected from the group consisting of iodo, 3. In one aspect n is 0. In a further aspect, n is 1. In an bromo, chloro, and methyl. additional aspect, n is 2. In one aspect, p is 0. In another (0555. In an additional aspect, R' and Rare each halogen. aspect, p is 1. In another aspect, R' and Rare each optionally substituted 0551. In one aspect, each R" is hydrogen with the proviso —C-C alkyl. In a further aspect, R' and Rare each option that when one R is attached to C through an O, S, or Natom, ally substituted—S C-C alkyl. In another aspect, R' and then the other R attached to the same C is a hydrogen, or Rare each optionally substituted—C-C alkenyl. In a fur attached via a carbon atom. In another aspect, each R is ther aspect, R' and Rare each optionally substituted—C- US 2009/011 8236 A1 May 7, 2009 36

C alkynyl. In another aspect, RandR are each —CFs. In a cyclic ring, which may contain a second heterogroup which is further aspect, R' and Rare each—OCF. In another aspect, NR. In another aspect, R and R may together form an RandR are each optionally substituted-O-C-C alkyl. In optionally Substituted heterocyclic ring, which may contain a a further aspect, R' and Rare each cyano. In yet another second heterogroup which is S. In one aspect, RandR may aspect, R and Rare each hydrogen. In another aspect, R together form an unsubstituted heterocyclic ring, which may and R are each halogen. In a further aspect, R and R are contain a second heterogroup. In another aspect, the option each —CFs. In another aspect, R and ally substituted heterocyclic ring may be substituted with 1 0556 Rare each–OCF. In a further aspect, Rand R' Substituent selected from the group consisting of optionally are each cyano. In another aspect, RandR are each option substituted —C-C alkyl, -OR''. Oxo, cyano, —CFs, ally substituted—C-C alkyl. In a further aspect, RandR optionally substituted phenyl, and —C(O)OR". In further are each optionally substituted —C-C alkenyl. In another aspect, R and R are each optionally substituted —C-C2 aspect, the optionally Substituted heterocyclic ring may be alkynyl. In a further aspect, R and R are each optionally substituted with 2 substituents selected from the group con substituted —(CR), aryl. In another aspect, R and Rare sisting of optionally substituted—C-C alkyl, -OR". Oxo, each optionally substituted —(CR).cycloalkyl. In a further cyano. —CF, optionally Substituted phenyl, and —C(O) aspect, R and R are each optionally substituted —(CR) OR". In another aspect, the optionally substituted heterocy heterocycloalkyl. In another aspect, R and R are each clic ring may be substituted with 3 substituents selected from —OR". In another aspect, R and R are each - SR". In a the group consisting of optionally Substituted—C-C alkyl, further aspect, R and R are each - S(=O)R. In another —OR''. Oxo, cyano, -CFs, optionally substituted phenyl, aspect, Rand Rare each - S(=O).R. In a further aspect, and C(O)OR". In a further aspect, the optionally substi R and R are each - S(=O)NR'R's. In another aspect, R tuted heterocyclic ring may be substituted with 4 substituents and Rare each–C(O)NR. Inafurther aspect, RandR are selected from the group consisting of optionally Substituted each —C(O)OR". In another aspect, R and R are each —C-C alkyl, -OR. Oxo, cyano, —CF, optionally substi —C(O)R. In a further aspect, RandR are each - N(R)C tuted phenyl, and C(O)OR". (O)R. In another aspect, R and R are each - N(R)C(O) (0562. In a further aspect, R" is optionally substituted NR/R3. In a further aspect, RandR are each - N(R)S(=O) —C-C2 alkyl. In another aspect, R" is optionally substituted R. In another aspect, R and R are each - N(R)S(=O) —C-C2 alkenyl. In a further aspect, R" is optionally substi NR/R3. In a further aspect, R' and Rare each - NR/R3. tuted —Ca-Cia alkynyl. In another aspect, R" is optionally 0557. In one aspect, R is selected from the group consist substituted—(CR), aryl. Inafurther aspect, R" is optionally ing of hydrogen, halogen, —C-C alkyl, cyano and CF. In substituted —(CR), cycloalkyl. In another aspect, R" is another aspect, R is not hydrogen. In a further aspect, R is optionally substituted —(CR), heterocycloalkyl. In one selected from the group consisting of hydrogen and halogen. aspect, R is —OH. In another aspect, R is selected from the In another aspect, R is selected from the group consisting of group consisting of OH, OC(O)R, OC(O)OR", F, hydrogen and iodo. In a further aspect, R is hydrogen. and—NHC(O)R. In a further aspect, R is selected from the 0558. In another aspect, each R" is optionally substituted group consisting of —OH and —OC(O)R. In an additional —C-C2 alkyl. In a further aspect, each R" is optionally aspect, R is optionally substituted —OC-C alkyl. In substituted —C-C2 alkenyl. In another aspect, each R is another aspect, R is —OC(O)R. In a further aspect, R is optionally substituted—C-C alkynyl. In a further aspect, —OC(O)OR". In another aspect, R is —F. In another aspect, each R" is optionally substituted —(CR),aryl. In another Ris-NHC(O)R. In a further aspect, R is NHS(=O)R. aspect, each R" is optionally substituted —(CR),cy In another aspect, R is NHS(=O).R. In a further aspect, cloalkyl. In a further aspect, each R" is optionally substituted R is NHC(=S)NH(R'). In another aspect, R is NHC —(CR), heterocycloalkyl. In another aspect, each R" is (O)NH(Oh). C(O)NR'R8. 10563. In one aspect, R is selected from the group consist 0559. In an additional aspect, R is optionally substituted ing of halogen, optionally substituted—C-C alkyl, -CF, —C-C alkyl. In another aspect, R is optionally substituted cyano, C(O)NR'R'', optionally substituted (CR),aryl, —C-C alkenyl. In a further aspect, R is optionally Substi —SO.NR'R'', and -SO.R. In another aspect, R is iso tuted —C-C alkynyl. In another aspect, R is optionally propyl. In a further aspect, R is alkyl of 1 to 4 carbons or substituted—CR), aryl. In a further aspect, R is optionally cycloalkyl of 3 to 7 carbons. In yet another aspect, R is substituted —(CR), cycloalkyl. In another aspect, R is selected from the group consisting of halogen, optionally optionally substituted —(CR), heterocycloalkyl. Substituted—C-C alkyl, optionally Substituted —CH2aryl, 0560. In one aspect, Rand R are each hydrogen. In an optionally substituted —CH(OH)aryl, —C(O)-amido, additional aspect, R and R are each optionally substituted —S(=O)-amido, wherein the amido group is selected from —C-C, alkyl. In another aspect, Rand Rare each option the group consisting of phenethylamino, piperidinyl, 4-me ally substituted—Ca-Cia alkenyl. In an additional aspect, R thylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and and R are each optionally substituted—C-C alkynyl. In a indolinyl, and—SOR" wherein R is selected from the group further aspect, R and R are each optionally substituted consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, and —(CR),aryl. In an additional aspect, R and R are each 4-pyridyl. In another aspect, R is iodo. In yet another aspect, optionally substituted —(CR), cycloalkyl. In another R is selected from the group consisting of iodo, bromo, aspect, R and R are each optionally substituted —(CR) optionally substituted —C-C alkyl, optionally Substituted heterocycloalkyl. —CHaryl, optionally substituted —CH(OH)aryl, —(O)- 0561. In an additional aspect, RandR may togetherform amido. —S(=O)-amido, wherein the amido group is an optionally Substituted heterocyclic ring, which may con selected from the group consisting of phenethylamino, pip tain a second heterogroup which is O. In another aspect, R eridinyl, 4-methypiperizinyl, morpholinyl, cyclohexylamino, and R may together form an optionally substituted hetero anilinyl, and indolinyl, and —SOR wherein R is selected US 2009/011 8236 A1 May 7, 2009 37 from the group consisting of phenyl, 4-chlorophenyl, 4-fluo OCHCH, -P(O) N(H)C(CH),C(O)OCHCH), rophenyl, and 4-pyridyl. In one aspect, R is —CH(OH)(4- -P(O) N(H)CH(CH)C(O)OCH2CH3.4-methylene fluorophenyl). dioxyphenyl, -P(O) N(H)C(CH),C(O)OCHCH-3, 0564) In one aspect, X is - P(O)YR''Y'R''. 4-methylenedioxyphenyl, and —P(O)—OCH(3-chlo 0565. In one aspect, X is selected from the group consist rophenyl)CHCHO . ing of POH, -P(O) OCR OC(O)RI. -P(O)— 0567. In another aspect, X is - P(O)YR''Y'R'' OCROC(O)ORI, -P(O) N(H)CRC(O)ORI, 0568 wherein Y and Y are each independently selected - P(O) N(H)CRC(O)OR OR'', and P(O) from O-and-NR—; together R'' andR'' are the group: OCH(V)CHCHO I, wherein V is selected from the group consisting of optionally Substituted aryl, aryl, heteroaryl, and V optionally Substituted heteroaryl. In another aspect, is H selected from the group consisting of POH, -P(O) OCR OC(O)RT -P(O)— Z OCROC(O)ORT, -P(O) OCHCHSC(O)Nels, H, - P(O) N(H)CRC(O)ORT - P(O) N(H)CRC(O) ORT OR'' and P(O) OCH(V)CHCHO I, W wherein V is selected from the group consisting of optionally W substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl. In another aspect, X is selected from the group wherein consisting of —POH, -P(O)—OCR OC(O)R’, 0569) V, W, and W are independently selected from the -P(O) OCR OC(O)ORT, -P(O) Oalk-SC(O)R’, group consisting of hydrogen, optionally Substituted alkyl, - P(O) N(H)CRC(O)ORT - P(O) N(H)CRC(O) optionally substituted aralkyl, heterocycloalkyl, aryl, Substi OR OR'' tuted aryl, heteroaryl, substituted heteroaryl, optionally sub and -P(O) OCH(V)CHCHO I, wherein V is selected stituted 1-alkenyl, and optionally substituted 1-alkynyl: from the group consisting of optionally Substituted aryl, aryl, 0570 or together V and Z are connected via an additional heteroaryl, and optionally substituted heteroaryl. In one 3-5 atoms to form a cyclic group containing 5-7 atoms, aspect, X is selected from the group consisting of —POH, wherein 0-1 atoms are heteroatoms and the remaining atoms -P(O) OCHOC(O)-t-butyl, -P(O) OCHOC(O) are carbon, Substituted with hydroxy, acyloxy, alkylthiocar O-i-propyl-, -P(O) N(H)CH(CH)C(O)OCHCHI, bonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy -P(O) N(H)C(CH),C(O)OCHCH, -P(O) N(H) attached to a carbon atom that is three atoms from both Y CH(CH)C(O)OCH2CH3.4-methylenedioxyphenyl, groups attached to the phosphorus; or -P(O) N(H)C(CH),C(O)OCHCH3.4-methylene 0571 or together V and Z are connected via an additional dioxyphenyl, - P(O)—O CHCHS C(O)CH, and 3-5 atoms to form a cyclic group, wherein 0-1 atoms are -P(O) OCH(3-chlorophenyl)CHCH-O-). In a further heteroatoms and the remaining atoms are carbon, that is fused aspect, X is selected from the group consisting of —POH, to an aryl group at the beta and gamma position to the Y -P(O) OCHOC(O)-t-butyl-, -P(O) OCHOC(O) attached to the phosphorus: O-i-propyl-, -P(O) N(CH(CH)C(O)OCHCH 0572 or together V and Ware connected via an additional -P(O) N(H)C(CH),C(O)OCHCH, -P(O) N(H) 3 carbonatoms to forman optionally Substituted cyclic group CH(CH)C(O)OCH2CH3.4-methylenedioxy-phenyl, containing 6 carbon atoms and Substituted with one substitu -P(O) N(H)C(CH),C(O)OCHCH3.4-methylene ent selected from the group consisting of hydroxy, acyloxy, dioxyphenyl, and -P(O) OCH(3-chlorophenyl) alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycar CHCHO . In another aspect, X is —POH. In yet bonyloxy, attached to one of said carbon atoms that is three another aspect, X is selected from the group consisting of atoms from a Y attached to the phosphorus: -P(O) OCHOC(O)-t-butyl and -P(O) OCHOC 0573 or together Z and Ware connected via an additional (O)-i-propyl. 3-5 atoms to form a cyclic group, wherein 0-1 atoms are 0566 In one aspect, X is selected from the group consist heteroatoms and the remaining atoms are carbon, and V must ing of —P(O) OCHOC(O)O-ethyl and —P(O)— be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; OCHOC(O)O-i-propyl. In another aspect, X is selected 0574 or together W and W are connected via an addi from the group consisting of —P(O) N(F)CH(CH)C(O) tional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are OCHCH and -P(O) N(H)C(CH),C(O)OCHCH). heteroatoms and the remaining atoms are carbon, and V must In a further aspect, X is - P(O)—OCHCHSC(O)Ne. In be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; another aspect, X is selected from the group consisting of 0575 Z is selected from the group consisting -P(O) N(H)CH(CH)C(O)CCHCH3.4-methylene of CHROH, CHROC(O)R’, CHROC(S)R’, dioxyphenyl and -P(O) N(H)C(CH),C(O)OCHCH CHROC(S)OR, CHROC(O)SR, CHROCOR', 3,4-methylenedioxyphenyl). In a further aspect, X is —OR, SR, —CHRN, -CHaryl, -CH(aryl)OH, selected from the group consisting of—POH, -P(O)— CH(CH=CR)OH, -CH(C=CR)OH, R, NR, OCROC(O)R’ - P(O) OCR OC(O)CRT - P(O) –OCOR', OCOR', SCOR, SCOR, NHCOR, N(H)CRC(O)ORT, -P(O) N(H)CRC(O)ORT NHCO.R. CH-NHaryl, -(CH2), OR, and -(CH2) OR'' and -P(O) OCH(V)CHCHO I, wherein V is selected from the group consisting of optionally Substituted 0576 q is an integer 2 or 3: aryl, aryl, heteroaryl, and optionally Substituted heteroaryl. In (0577 with the provisos that: another aspect, X is selected from the group consisting of (0578 a) V, Z, W, Ware not all-H; and —POH, -P(O) OCHOC(O)-t-butyl, -P(O)— (0579 b) when Zis-R, then at least one of V, W, and W. OCHOC(O)O-i-propyl, -P(O) N(H)CH(CH)C(O) is not—H, alkyl, aralkyl, or heterocycloalkyl; US 2009/011 8236 A1 May 7, 2009

0580 Each R is selected from the group consisting of R' selected from the group consisting of—POH, -P(O)— and —H; OCROC(O)R’ - P(O) OCR OC(O)CR - P(O) 0581. Each R" is selected from the group consisting of N(H). RC(O)CRT - P(O) N(H)CRC(O)ORT alkyl, aryl, heterocycloalkyl, and aralkyl, and OR'' and -P(O) OCH(V)CHCHO I, wherein V is 0582 Each R is selected from the group consisting of selected from the group consisting of optionally Substituted —H. lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and aryl, aryl, heteroaryl, and optionally Substituted heteroaryl. lower acyl. 0588. In an additional aspect, G is selected from the group 0583. In one aspect, V is optionally substituted aryl. In consisting of —O— and —CH2—, T is —CH2CH(NH)—; another aspect, V is selected from the group consisting of R" and R are each independently selected from the group 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 3-fluo consisting of iodo, bromo, chloro, methyl, and cyano; R is rophenyl, pyrid-4-yl, pyrid-3-yl and 3,5-dichlorophenyl. hydrogen; R is selected from the group consisting of —OH 0584. In one aspect, the relative stereochemistry between and—OC(O)R: R is selected from the group consisting of the V-group Substituent and T on the dioxaphosphonane ring halogen, optionally Substituted —C-C alkyl, optionally is cis. In another aspect, the cis dioxaphosphonane ring has R substituted —CHaryl, optionally substituted —CH(OH) stereochemistry at the carbon where V is attached. In another aryl, -C(O)-amido wherein the amido group is selected from aspect, the cis dioxaphosphonane ring has S Stereochemistry the group consisting of phenethylamino, piperidinyl, 4-met at the carbon where V is attached. hypiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and 0585. In one aspect R'' is not hydrogen. indolinyl. —S(=O)-amido wherein the amido group is 0586. In a further aspect when G is —O , T is —CH2—, selected from the group consisting of phenethylamino, pip R" and Rare each bromo, R is iso-propyl, and R is —OH, eridinyl, 4-methypiperizinyl, morpholinyl, cyclohexylamino, then R is not hydrogen. In another aspect, when G is —O , anilinyl, and indolinyl, and —SOR wherein R is selected T is —(CH) R' and Rare independently selected from from the group consisting of phenyl, 4-chlorophenyl, 4-fluo the group consisting of halogen, alkyl of 1 to 3 carbons, and rophenyl, and 4-pyridyl, and X is selected from the group cycloalkyl of 3 to 5 carbons, R is alkyl of 1 to 4 carbons or consisting of —POH, -P(O)—OCROC(O)R’, cycloalkyl of 3 to 7 carbons, and R is -OH, then R is not -P(O)I. OCR OC(O)ORT -P(O) N(H)CRC(O) hydrogen; and wherein when G is —O , R is selected from ORT - P(O) N(H)CRC(O)ORTIOR and P(O) the group consisting of OCR (aryl)CHCHO-). NHC(O)R, NHS(=O) R, NHC(=S)NH(R'), and 0589. In another aspect, when G is —O , T is —CH2—, —NHC(O)NH(R'), T is selected from the group consisting of R" and Rare bromo, R is iso-propyl, R is -OH, and X is —(CH), , —CH=CH-, -O(CH) , and —NH selected from the group consisting of —POH, -P(O)— (CH2)2 , then R is not hydrogen. In a further aspect for the OCROC(O)R’ - P(O) OCR OC(O)CRT - P(O) compounds of Formula I, G is selected from the group con N(H)CRC(O)ORT - P(O) N(H)CRC(O)ORT sisting of —O— and —CH2—, T is selected from the group OR consisting of —(CR), —O(CR)(CR")O , N(R) and -P(O) OCR (aryl)CHCHO I, then R is not (CR)(CR) , S(CR)(CR) , NR(CO) , and hydrogen. —CH-CH(NRR) : R* and R are each independently 0590. In one aspect for the compounds of Formula I, G is selected from the group consisting of halogen, —C-C alkyl, -O-; T is CH-CH(NH)–: R' and Rare each iodo; R' —CFs, and cyano; R is selected from the group consisting of is selected from the group consisting of hydrogen and iodo; hydrogen, halogen, —C-C alkyl, cyano and CF; R is Ris-OH; and R is iodo; and X is selected from the group selected from the group consisting of —OH, - OC(O)R. consisting of —POH, -P(O) —OCROC(O)R’. –OC(O)CR,-F and NHC(O)R: R is selected from the - P(O) OCR OC(O)ORT -P(O) N(H)CRC(O) group consisting of halogen, optionally Substituted—C-C, ORT, -P(O) N(H)CRC(O)ORTIOR alkyl, -CFs, cyano, C(O)NR'R'', optionally substituted and -P(O) OCR (aryl)CHCH-O-). —(CR), aryl, -SONR'Rs, and -SOR: and X is 0591. In another aspect G is - O -; T is —CHCH selected from the group consisting of—POH, -P(O)— (NH.) : R* and R are each iodo; R is selected from the OCROC(O)RT, -P(O) OCR OC(O)ORT -P(O) group consisting of hydrogen and iodo; R is —OH: R is Oalk-SC(O)R’, - P(O) N(H)CRC(O)CRT, iodo; and X is selected from the group consisting of -P(O)I. N(H)CRC(O)ORT OR'' and -P(O)- —POH, -P(O) OCHOC(O)-t-butyl-, -P(O) OCH(V)CHCHO I, wherein V is selected from the group OCHOC(O)O-i-propyl, -P(O) N(H)CH(CH)C consisting of optionally Substituted aryl, aryl, heteroaryl, and (O)OCHCH, -P(O) N(H)C(CH),C(O)OCHCH), optionally substituted heteroaryl. -P(O) N(H)CH(CH)C(O)OCH2CH3.4-methylene 0587. In another aspect, G is selected from the group con dioxyphenyl, -P(O) N(H)C(CH),C(O)OCHCH-3, sisting of —O— and —CH2—, T is selected from the group 4-methylenedioxyphenyl, consisting of (CR), O(CR'2)(CR), N(CR) and —P(O)—OCH(3-chlorophenyl)CHCHO—. (CR) , S(CR)(CR) , NR(CO) , and 0592. In a further aspect for compounds of Formula I, G is —CH-CH(NRR) : R* and R are each independently selected from the group consisting of O—and —CH2—, T selected from the group consisting of halogen, —C-C alkyl, is N(H)C(O) ; RandR are each independently selected —CF, and cyano; R is selected from the group consisting of from the group consisting of iodo, bromo, chloro, methyl, and hydrogen, halogen, —C-C alkyl, cyano and CF; R' is cyano; R is selected from the group consisting of hydrogen, selected from the group consisting of —OH, - OC(O)R. iodo, 4-chlorophenyl, and cyclohexyl; R is selected from the —OC(O)OR",—F and NHC(O)R’; R is selected from the group consisting of -OH and —OC(O)R: R is selected group consisting of halogen, optionally Substituted—C-C, from the group consisting of hydrogen, iodo, bromo, option alkyl, -CF, cyano, —C(O)NR'R'', optionally substituted ally Substituted —C-C alkyl, optionally Substituted —(CR"), aryl, -SONR'R'', and -SOR: and X is —CHaryl, optionally substituted —CH(OH)aryl, —C(O)- US 2009/011 8236 A1 May 7, 2009 39 amido wherein the amido group is selected from the group OCHCH, -P(O) N(H)C(CH),C(O)OCHCH), consisting of phenethylamino, piperidinyl, 4-methypiperiZ -P(O) N(H)CH(CH)C(O)OCH2CH3.4-methylene inyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, dioxyphenyl, -P(O) N(H)C(CH),C(O)OCHCH-3, —S(=O)-amido wherein the amido group is selected from 4-methylenedioxyphenyl, and —P(O)—OCH(3-chlo the group consisting of phenethylamino, piperidinyl, 4-met rophenyl)CHCHO . hypiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and 0598. In a further aspect, G is selected from the group indolinyl, and —SOR wherein R is selected from the group consisting of O— and —CH2—, T is —CH2—, RandR consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, and are each independently selected from the group consisting of 4-pyridyl; and X is selected from the group consisting of iodo, bromo, chloro, methyl, and cyano; R is selected from —POH, - P(O) OCR OC(O)RT, -P(O)— the group consisting of hydrogen, iodo, 4-chlorophenyl, and OCROC(O)ORI, -P(O) N(H)CRC(O)ORI, cyclohexyl; R is selected from the group consisting of OH - P(O) N(H)CRC(O)ORTIOR and—OC(O)R: R is selected from the group consisting of and -P(O) OCR (aryl)CHCHO . hydrogen, iodo, bromo, optionally substituted lower alkyl, 0593. An additional aspect is when G is —O : T is optionally substituted —CHaryl, optionally substituted -N(H)C(O)–: R' and Rare methyl; R is hydrogen; R is —CH(OH)aryl, —C(O)-amido wherein the amido group is —OH: R is —CH(OH)(4-fluorophenyl); and X is selected selected from the group consisting of phenethylamino, pip from the group consisting of POH, -P(O) OCR OC eridinyl, 4-methypiperizinyl, morpholinyl, cyclohexylamino, (O)R’ - P(O) OCROC(O)ORT - P(O) N(H) anilinyl, and indolinyl. —S(=O)-amido wherein the amido CRC(O)ORT - P(O) N(H)CRC(O)ORTIOR and group is selected from the group consisting of phenethy -P(O) OCR (aryl)CHCHO ). lamino, piperidinyl, 4-methypiperizinyl, morpholinyl, cyclo 0594. In an additional aspect, G is —O—: T is —N(H)C hexylamino, anilinyl, and indolinyl, and —SOR wherein R (O) ; R' and R are each methyl; R is hydrogen; R is is selected from the group consisting of phenyl, 4-chlorophe —OH: R is —CH(OH)(4-fluorophenyl); and X is selected nyl, 4-fluorophenyl, and 4-pyridyl; and X is selected from the from the group consisting of POH, -P(O)—OCHOC group consisting of POH, -P(O)—OCROC(O)R’, (O)-t-butyl, —P(O)—OCHOC (O)O-i-propyl -P(O) OCR OC(O)ORT, -P(O) N(H)CRC(O) ORT - P(O) N(H)CRC(O)ORTIOR and P(O) OCR (aryl)CHCHO-). 0599. In additional aspects, when G is —O—, T is (H)C(CH),C(O)OCH2CHasa-methylenedioxyphenyl). —CH2—, R' and Rare each bromo, R is iso-propyl, R is and —P(O)—OCH(3-chlorophenyl)CHCHO . —OH; and X is selected from the group consisting of 0595. In a further aspect G is selected from the group —POH, - P(O) OCR OC(O)RT, -P(O)— consisting of —O— and —CH2—, T is —OCH2 : R and OCROC(O)ORT, - P(O) N(H)CRC(O)ORT, Rare each independently selected from the group consisting - P(O) N(H)CRC(O)ORTIOR of iodo, bromo, chloro, methyl, and cyano; R is selected from and -P(O) OCR (aryl)CHCHO I, then R is not the group consisting of hydrogen, iodo, 4-chlorophenyl, and hydrogen. cyclohexyl; R is selected from the group consisting of OH 0600. In another aspect, Gis —O : T is —CH2 : R and and—OC(O)R: R is selected from the group consisting of Rare each chloro; R is hydrogen; R is OH: R is i-pro hydrogen, iodo, bromo, optionally Substituted lower alkyl, pyl; and X is selected from the group consisting of POH, optionally substituted —CHaryl, optionally substituted - P(O) OCR OC(O)RT-P(O) OCROC(O)ORT —CH(OH)aryl, —C(O)-amido wherein the amido group is , -P(O) N(H)CRC(O)ORT -P(O) N(H)CRC selected from the group consisting of phenethylamino, pip (O)ORTIOR and -P(O) OCR (aryl)CHCHO ). eridinyl, 4-methypiperizinyl, morpholinyl, cyclohexylamino, (0601 Inanother aspect, Gis—O ; Tis—CH2—, R' and anilinyl, and indolinyl. —S(=O)-amido wherein the amido Rare each chloro; R is hydrogen; R is —OH: R is i-pro group is selected from the group consisting of phenethy pyl; and X is selected from the group consisting of POH, lamino, piperidinyl, 4-methypiperizinyl, morpholinyl, cyclo -P(O) OCHOC(O)-t-butyl, -P(O) OCHOC(O) hexylamino, anilinyl, and indolinyl, and —SOR wherein R O-i-propyl, -P(O) N(H)CH(CH)C(O)OCHCH), is selected from the group consisting of phenyl, 4-chlorophe -P(O) N(H)C(CH),C(O)OCHCH, -P(O) N(H) nyl, 4-fluorophenyl, and 4-pyridyl; and X is selected from the CH(CH)C(O)CCHCH3.4-methylenedioxyphenyl), group consisting of POH, -P(O)—OCR OC(O)R’, -P(O) N(H)C(CH),C(O)OCHCH-3,4-methylene -P(O)I. OCR OC(O)ORI, P(O) N(H)CRC(O) dioxyphenyl, ORT - P(O) N(H)CRC(O)ORTIOR and P(O) and —P(O)—OCH(3-chlorophenyl)CHCHO—. OCR (aryl)CHCHO-). 0602. In additional aspects for compounds of Formula I.G 0596) In another aspect G is —CH. : T is —OCH. : R' is selected from the group consisting of O—and —CH2—, and Rare each methyl; R is hydrogen; R is —OH: R is Tis—CHCH. : RandR are each independently selected iso-propyl; and X is selected from the group consisting of from the group consisting of iodo, bromo, chloro, methyl, and —POH, - P(O) OCR OC(O)RT, -P(O)— cyano; R is selected from the group consisting of hydrogen, OCROC(O)ORT, - P(O) N(H)CRC(O)CRT, iodo, 4-chlorophenyl, and cyclohexyl; R is selected from the - P(O) N(H)CRC(O)ORTIOR and P(O) OCR group consisting of OH and —OC(O)R: R is selected (aryl)CHCHO . from the group consisting of hydrogen, iodo, bromo, option 0597. In another aspect, G is —CH : T is —OCH : ally substituted lower alkyl, optionally substituted R" and Rare each methyl; R is hydrogen; R is OH: R is —CHaryl, optionally substituted —CH(OH)aryl, —C(O)- iso-propyl; and X is selected from the group consisting of amido wherein the amido group is selected from the group —POH, -P(O) OCHOC(O)-t-butyl, -P(O)— consisting of phenethylamino, piperidinyl, 4-methypiperiZ OCHOC(O)O-i-propyl, -P(O) N(H)CH(CH)C(O) inyl, morpholinyl, cyclohexylamino, anilinyl, and indolinyl, US 2009/011 8236 A1 May 7, 2009 40

—S(=O)-amido wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-met hypiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and V indolinyl, and - SOR wherein R is selected from the group H consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, and Z 4-pyridyl; and X is selected from the group consisting of —POH, - P(O) OCR OC(O)RT, -P(O)— H OCROC(O)ORT, - P(O) N(H)CRC(O)CRT, W -P(O)I. N(H)CRC(O)ORTIOR W and -P(O) OCR (aryl)CHCHO . 0603. In a further aspect, G is —O : T is —CHCH : wherein: R" and Rare each chloro; R is hydrogen; R is OH: R is 0609 V, W, and W are independently selected from the iso-propyl; and X is selected from the group consisting of group consisting of hydrogen, optionally Substituted alkyl, —POH, -P(O)I. OCR OC(O)R), -P(O)— optionally substituted aralkyl, heterocycloalkyl, aryl, Substi OCROC(O)ORT, - P(O) N(H)CRC(O)CRT, tuted aryl, heteroaryl, substituted heteroaryl, optionally sub -P(O)I. N(H)CRC(O)ORTIOR stituted 1-alkenyl, and optionally substituted 1-alkynyl: and -P(O) OCR (aryl)CHCHO . 0610 or together V and Z are connected via an additional 0604. In another aspect, G is —O : T is —CH2CH2—, 3-5 atoms to form a cyclic group containing 5-7 atoms, R" and Rare each chloro; R is hydrogen; R is OH: R is wherein 0-1 atoms are heteroatoms and the remaining atoms iso-propyl; and X is selected from the group consisting of are carbon, Substituted with hydroxy, acyloxy, alkoxycarbo nyloxy, oraryloxycarbonyloxy attached to a carbon atom that is three atoms from both Ygroups attached to the phosphorus: O -P(O) N(H)CH(CH)C(O)OCH2CH3.4-methylene 0611 or together V and Z are connected via an additional dioxyphenyl), -P(O) N(H)C(CH),C(O)OCHCH-3, 3-5 atoms to form a cyclic group, wherein 0-1 atoms are 4-methylenedioxyphenyl, and —P(O)—OCH(3-chlo heteroatoms and the remaining atoms are carbon, that is fused rophenyl)CHCHO . to an aryl group at the beta and gamma position to the Y 0605. In an additional aspect, G is —CH2—, T is attached to the phosphorus: —OCH. : R* and Rare each methyl; R is hydrogen; R is 0612 or together V and Ware connected via an additional —OH: R is iso-propyl; and X is PO.H. In a further 3 carbonatoms to forman optionally Substituted cyclic group aspect, G is —CH. : T is —OCH. : R and Rare each containing 6 carbon atoms and Substituted with one substitu methyl; R is hydrogen; R is OH: R is iso-propyl; and X ent selected from the group consisting of hydroxy, acyloxy, is selected from the group consisting of P(O)—OCHOC alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycar (O)-t-butyl and —P(O)—OCHOC(O)-i-propyl. In bonyloxy, attached to one of said carbon atoms that is three another aspect, Gis —CH2 : T is —OCH. : RandR are atoms from a Y attached to the phosphorus: each methyl; R is hydrogen; R is —OH: R is iso-propyl; 0613 or together Z and Ware connected via an additional and X is selected from the group consisting of —P(O)— 3-5 atoms to form a cyclic group, wherein 0-1 atoms are OCHOC(O)O-ethyl), and -P(O) OCHOC(O)O-i-pro heteroatoms and the remaining atoms are carbon, and V must pyl. In an additional aspect, Gis —CH2—, T is —OCH -: be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R" and Rare each methyl; R is hydrogen; R is OH: R is 0614 or together W and W are connected via an addi iso-propyl; and X is selected from the group consisting of tional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are -P(O) N(H)CH(CH)C(O)OCHCH and -P(O) N (H)C(CH),C(O)CCHCH. In additional aspects, G is heteroatoms and the remaining atoms are carbon, and V must —CH2 : T is —OCH ; R' and Rare methyl: Rishydro be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; gen; R is OH: R is iso-propyl; and X is - P(O)— 0615 Z is selected from the group consisting of —CHR OCHCHSC(O)Nels, or X is -P(O) N(H)C(CH)C(O) *OH, CHROC(O)R’, CHROC(S)R’, CHROC(S) OCH2CH3.4-methylenedioxyphenyl, or X is —P(O)— OR, CHROC(O)SR, CHROCOR, OR, SR, N(H)C(CH),C(O)OCH2CH3.4-methylenedioxyphenyl. —CHRN, -CHaryl, -CH(aryl)OH, -CH(CH=CR) 0606 Inanother aspect, Gis - O Tis-(CH2). , R' OH, -CH(C=CR)OH, R, NR, OCOR', and R are independently selected from the group consisting –OCOR', SCOR, -SCOR, NHCOR, of hydrogen, halogen, alkyl of 1 to 3 carbons, and cycloalkyl NHCO.R. CH-NHaryl, -(CH2), OR, and -(CH2) of 3 to 5 carbons, R is alkyl of 1 to 4 carbons or cycloalkyl of SR; 3 to 7 carbons, and R is —OH, then R is not hydrogen; and 0616 q is an integer 2 or 3: wherein when G is —O , R is selected from the group 0617 with the provisos that: consisting of NHC(O)R, -NHS(=O) R, -NHC(S)NH 0618 a) V, Z, W, Ware not all-H; and (Th), and -NHC(O)NH(R'), T is selected from the group 0619 b) when Zis-R, then at least one of V, W, and W. consisting of —(CH) , —CH=CH-. —O(CH) , is not—H, alkyl, aralkyl, or heterocycloalkyl; and —NH(CH2)2 , then R is not hydrogen. 0620. Each R is selected from the group consisting of R' 0607. In an additional aspect, G is —CH2—, T is and —H; —OCH. : R* and Rare each methyl; R is hydrogen; R is 0621. Each R" is selected from the group consisting of OH: R is iso-propyl; and X is - P(O)YR''Y'R'': alkyl, aryl, heterocycloalkyl, and aralkyl; 0608 wherein Y and Y are each independently selected 0622. Each R is independently selected from the group from —O— and —NR' ; together R'' and R'' are the consisting of —H, and alkyl, or together R and R' form a group: cyclic alkyl group; US 2009/011 8236 A1 May 7, 2009

0623. Each R is selected from the group consisting of I0634) Each R" is selected from the group consisting of —H. lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and optionally substituted —C-C alkyl, optionally substituted lower acyl. In a further aspect V is aryl. In an additional aspect —C-C alkenyl, optionally Substituted —C-C alkynyl, Z is hydrogen, W is hydrogen, and W' is hydrogen. In an optionally substituted —(CH2)phenyl, optionally Substi additional aspect, V is 3-chlorophenyl, 4-chlorophenyl, tuted —(CH).monocyclic-heteroaryl, optionally substituted 3-bromophenyl, 3-fluorophenyl, pyrid-4-yl, pyrid-3-yl or —(CH2), C-C-cycloalkyl, optionally substituted 3,5-dichlorophenyl. In a further aspect the relative stere —(CH), Ca-Cs-heterocycloalkyl, and C(O)NR'R'': ochemistry between the substituents on the dioxaphospho nane ring is cis. 0635. Each R is selected from the group consisting of 0624. In another aspect, each R" is independently selected optionally substituted —C-C alkyl, optionally Substituted from the group consisting of hydrogen, optionally Substituted —C-C alkenyl, optionally Substituted —C-C alkynyl, —C-C alkyl, halogen, —OH, optionally substituted optionally substituted —(CH).phenyl, optionally substi —O—C-C alkyl, —OCF, optionally substituted tuted —(CH2).monocyclic-heteroaryl, optionally substituted —S C-C alkyl, - NRR, optionally substituted —C. —(CH2), C-C-Cycloalkyl, optionally substituted alkenyl, and optionally substituted—C alkynyl; —(CH), —C-C-heterocycloalkyl: 0625) Each R is independently selected from the group 10636 RandR are each independently selected from the consisting of hydrogen, optionally substituted—C-C alkyl; group consisting of hydrogen, optionally Substituted—C-C, 0626. Each R is independently selected from the group alkyl, optionally Substituted—C-C alkenyl, optionally Sub consisting of hydrogen, optionally Substituted—C-C alkyl, stituted —C-C alkynyl, optionally substituted —(CH) and optionally substituted—C(O)—C-C alkyl, —C(O)H: phenyl, optionally Substituted —CH2).monocyclic-het 0627. Each R" is selected from the group consisting of eroaryl, optionally substituted —(CH), C-C-cycloalkyl, optionally substituted —C-C alkyl, optionally Substituted optionally substituted —(CH), Ca-Cs-heterocycloalkyl, —C-C alkenyl, optionally Substituted —C-C alkynyl, or R and R may together form an optionally substituted optionally substituted —(CR), phenyl, optionally substi tuted —(CR), nonocyclic-heteroaryl, optionally substi heterocyclic ring, which may contain a second heterogroup tuted —(CR), Ca-Ca-cycloalkyl, optionally substituted selected from the group of O, NR', and S, wherein said —(CR), Ca-Cs-heterocycloalkyl, and C(O)NR'R': optionally substituted heterocyclic ring may be substituted 0628. Each R is selected from the group consisting of with 0-2 Substituents selected from the group consisting of optionally substituted —C-C alkyl, optionally substituted optionally substituted methyl, -OR''. Oxo, cyano, —CF, —C-C alkenyl, optionally Substituted —C-C alkynyl, optionally substituted phenyl, and C(O)OR"; optionally substituted —(CR), phenyl, optionally substi I0637. Each R" is optionally substituted C-C alkyl, tuted —(CR), monocyclic-heteroaryl, optionally substi optionally substituted —C-C alkenyl, optionally substi tuted —(CR), Ca-Ca-cycloalkyl, optionally substituted tuted —C-C alkynyl, optionally Substituted —(CH2)phe —(CR), Ca-Cs-heterocycloalkyl: nyl, optionally Substituted —CH2).monocyclic-heteroaryl, 0629 Rand Rare each independently selected from the optionally substituted —(CH), C-C-cycloalkyl, option group consisting of hydrogen, optionally Substituted—C-C, ally Substituted —(CH) Ca-Cs-heterocycloalkyl. alkyl, optionally Substituted—C-C alkenyl, optionally Sub 0638. Each of the individual species of compounds of stituted —C-C alkynyl, optionally substituted —(CR) Formula I which can be generated by making all of the above phenyl, optionally substituted —(CR), monocyclic-het permutations may be specifically set forth as for inclusion or eroaryl, optionally substituted —(CR), Ca-Ca may be specifically excluded from the present invention. cycloalkyl, optionally substituted —(CR)-Ca-Cs 0639. In another aspect, the invention relates to com heterocycloalkyl, or R and R may together form an pounds of Formula II, Stereoisomers, pharmaceutically optionally substituted heterocyclic ring, which may contain a acceptable salts and prodrugs thereof and pharmaceutically second heterogroup selected from the group of O, NR', and S. acceptable salts of the prodrugs as represented by Formula II: wherein said optionally Substituted heterocyclic ring may be substituted with 0-2 substituents selected from the group consisting of optionally substituted —C-C, alkyl, -OR. R3 R2 B D-X oXo, cyano. —CF, optionally Substituted phenyl, and C(O)OR; sy 0630. Each R" is optionally substituted C-C alkyl, R5 G A optionally Substituted —C-C alkenyl, optionally Substi tuted —C-C, alkynyl, optionally substituted —(CR) phenyl, optionally substituted —(CR), monocyclic-het R4 R1 eroaryl, optionally substituted —(CR), —Cs-Co cycloalkyl, optionally substituted —CR), Ca-Cs heterocycloalkyl. 0640 wherein: 0631. In a further aspect, each R" is independently (0641) A is selected from the group consisting of NR , selected from the group consisting of hydrogen, methyl, fluoro, chloro, OH, O CH, OCF, SCH, (0642 B is selected from the group consisting of CR . —NHCH, N(CH): and —N-; 0632. Each R" is independently selected from the group (0643 R' is selected from the group consisting of hydro consisting of hydrogen, and methyl; gen, —C(O)C-C alkyl, -C-C alkyl, and —C-C-aryl; 0633 Each R is independently selected from the group (0644) R' is selected from the group consisting of hydrogen consisting of hydrogen, methyl, —C(O)CH, —C(O)H; and optionally Substituted—C-C alkyl; US 2009/011 8236 A1 May 7, 2009 42

0645 G is selected from the group consisting of —O , (O)OR, F, NHC(O)R, NHS(—OR, NHS(—O) R, NHC(=S)NH(R'), and NHC(O)NH(R'); CHF , —C(O)— —CH(OH)— —NH , and—N(C- 0655 X is P(O)YR''Y'R'" ; Calkyl)-; 0656 Y and Y are each independently selected from the 0646 D is selected from the group consisting of a bond, group consisting of O—, and —NR'—, when Y and Y are —(CR)—, and —C(O)—; —O , R'' attached to —O is independently selected from 0647. Each R" is independently selected from the group the group consisting of —H, alkyl, optionally substituted consisting of hydrogen, optionally Substituted—C-C alkyl, aryl, optionally Substituted heterocycloalkyl, optionally Sub halogen, —OH, optionally substituted —O-C-C alkyl, stituted CH-heterocycloaky1 wherein the cyclic moiety con —OCF, optionally substituted S C-C alkyl, NRR, tains a carbonate or thiocarbonate, optionally substituted optionally substituted —C-C alkenyl, and optionally sub -alkylaryl, -C(R),OC(O)NR, NR C(O) R', stituted—C-C alkynyl; with the proviso that when one R is - C(R). OC(O)R’, C(R), O C(O)OR, C(R) attached to C through an O, S, or Natom, then the other R' OC(O)SR', -alkyl-S C(O)R’, -alkyl-S-S-alkylhydroxy, attached to the same C is a hydrogen, or attached via a carbon and -alkyl-S S S-alkylhydroxy: atom; 0657 when Y and Y are - NR' , then R'' attached to 0648) R' and Rare each independently selected from the —NR'—is independently selected from the group consisting group consisting of halogen, optionally Substituted—C-C, alkyl, optionally Substituted —S C-C alkyl, optionally of H,-(C(R), COOR, C(R),COOR. -IC(R), Substituted—C-C alkenyl, optionally Substituted—C-C, C(O)SR', and -cycloalkylene-COOR'; alkynyl. —CF —OCF, optionally Substituted-O—C-C, 0658 when Y is - O - and Y is NR, then R'' attached to alkyl, and cyano; —O—is independently selected from the group consisting of (0649. RandR are each independently selected from the —H, alkyl, optionally substituted aryl, optionally substituted group consisting of hydrogen, halogen, —CF, —OCF, heterocycloalkyl, optionally substituted CH-heterocy cyano, optionally Substituted—C-C alkyl, optionally Sub cloaky1 wherein the cyclic moiety contains a carbonate or stituted —C-C alkenyl, optionally Substituted —C-C2 thiocarbonate, optionally substituted -alkylaryl, —C(R)OC alkynyl, optionally substituted —(CR), aryl, optionally (O)NR, NR C(O) R', C(R), OC(O)R’, Substituted —(CR), cycloalkyl, optionally Substituted - C(R) O C(O)OR, C(R)OC(O)SR, -alkyl-S-C —(CR), heterocycloalkyl, -OR', SR, -S(=O)R, (O)R’, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alky –S(=O),R, S(=O)NR'R'', C(O)NR'Rs, C(O) lhydroxy; and R'' attached to NR— is independently OR, C(O)R, N(R)C(O)R, N(R)C(O)NR'Rs, selected from the group consisting of -H, -IC(R), N(R)S(=O).R, N(R)S(=O)NR'Rs, and NR/Rs: COOR, C(x),COOR. -IC(R), C(O)SR, and -cy 0650. Each R" is selected from the group consisting of cloalkylene-COOR: optionally substituted—C-C alkyl, optionally substituted 0659 or when Y and Y are independently selected from —C-C alkenyl, optionally Substituted —C-C alkynyl, —O— and NR' , then together R'' and R'' are -alkyl optionally substituted —(CR),aryl, optionally substituted S S-alkyl- to form a cyclic group, or together R'' and R' —(CR), cycloalkyl, optionally substituted —(CR'2), het are the group: erocycloalkyl, and –C(O)NR'R'': 0651 Each R is selected from the group consisting of optionally Substituted—C-C alkyl, optionally Substituted —C-C alkenyl, optionally substituted —C-C alkynyl. optionally substituted —(CR),aryl, optionally substituted —(CR), cycloalkyl, and optionally substituted —(CR) heterocycloalkyl; 0652 R and Rare each independently selected from the W group consisting of hydrogen, optionally substituted —C- Calkyl, optionally Substituted—C-C alkenyl, optionally Substituted —C-Calkynyl, optionally Substituted 0660 wherein: —(CR),aryl, optionally substituted —(CR), cycloalkyl, 0661 V, W, and W are independently selected from the and optionally substituted —(CR), heterocycloalkyl, or R group consisting of hydrogen, optionally Substituted alkyl, and R may together form an optionally substituted hetero optionally substituted aralkyl, heterocycloalkyl, aryl, Substi cyclic ring, which may contain a second heterogroup selected tuted aryl, heteroaryl, substituted heteroaryl, optionally sub from the group consisting of O, NR, and S, wherein said stituted 1-alkenyl, and optionally substituted 1-alkynyl: optionally substituted heterocyclic ring may be substituted 0662 or together V and Z are connected via an additional with 0-4 Substituents selected from the group consisting of 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally substituted —C-C alkyl, -OR, OXO, cyano, wherein 0-1 atoms are heteroatoms and the remaining atoms —CFs, optionally substituted phenyl, and C(O)CR"; are carbon, Substituted with hydroxy, acyloxy, alkylthiocar 0653. Each R" is selected from the group consisting of bonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy optionally Substituted—C-C alkyl, optionally Substituted attached to a carbon atom that is three atoms from both Y —C-C alkenyl, optionally Substituted —C-C alkynyl, groups attached to the phosphorus; or optionally substituted —(CR),aryl, optionally substituted 0663 or together V and Z are connected via an additional —(CR), cycloalkyl, and optionally substituted —(CR'2). 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heterocycloalkyl; heteroatoms and the remaining atoms are carbon, that is fused 0654 R is selected from the group consisting of —OH, to an aryl group at the beta and gamma position to the Y optionally substituted —OC-C alkyl, —OC(O)R. —OC attached to the phosphorus: US 2009/011 8236 A1 May 7, 2009

0664 or together V and Ware connected via an additional then the other R' attached to the same C is a hydrogen, or 3 carbonatoms to forman optionally Substituted cyclic group attached via a carbon atom. In a further aspect, R' is option containing 6 carbon atoms and Substituted with one substitu ally substituted—C-C alkyl with the proviso that when one ent selected from the group consisting of hydroxy, acyloxy, R" is attached to C through an O, S, or Natom, then the other alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycar R'' attached to the same C is a hydrogen, or attached via a bonyloxy, attached to one of said carbon atoms that is three carbonatom. In another aspect, Rishalogen with the proviso atoms from a Y attached to the phosphorus: that when one R is attached to C through an O, S, or Natom, 0665 or together Z and Ware connected via an additional then the other R' attached to the same C is a hydrogen, or 3-5 atoms to form a cyclic group, wherein 0-1 atoms are attached via a carbon atom. In a further aspect, R is —OH heteroatoms and the remaining atoms are carbon, and V must with the proviso that when one R is attached to C through an be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; O, S, or Natom, then the other Rattached to the same C is a 0666 or together W and W are connected via an addi hydrogen, or attached via a carbonatom. In another aspect, R' tional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are is optionally substituted —O—C-C alkyl with the proviso heteroatoms and the remaining atoms are carbon, and V must that when one R is attached to C through an O, S, or Natom, be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; then the other R' attached to the same C is a hydrogen, or 0667 Z is selected from the group consisting of —CHR attached via a carbon atom. In another aspect, R is —OCF *OH, CHROC(O)R’, CHROC(S)R’, CHROC(S) with the proviso that when one R is attached to C through an OR, CHROC(O)SR, CHROCOR, OR, SR, O, S, or Natom, then the other Rattached to the same C is a —CHRN, -CHaryl, -CH(aryl)OH, -CH(CH=CR) hydrogen, or attached via a carbon atom. In a further aspect, OH, -CH(C=CR)OH, R, NR, OCOR', R" is optionally substituted —S C-C alkyl with the pro OCOR', SCOR, SCOR, NHCOR, viso that when one R is attached to C through an O, S, or N NHCO.R. CH-NHaryl, -(CH2), OR, and -(CH2) atom, then the other R' attached to the same C is a hydrogen, SR; or attached via a carbon atom. In another aspect, R is —NR 0668 q is an integer 2 or 3: R with the proviso that when one R is attached to Cthrough 0669 Each R is selected from the group consisting of R' an O, S, or Natom, then the other Rattached to the same C and —H; is a hydrogen, or attached via a carbonatom. In further aspect, 0670. Each R" is selected from the group consisting of R" is optionally substituted—C-C alkenyl with the proviso alkyl, aryl, heterocycloalkyl, and aralkyl; that when one R is attached to C through an O, S, or Natom, 0671 Each R is independently selected from the group then the other R' attached to the same C is a hydrogen, or consisting of —H, and alkyl, or together R and R' form a attached via a carbonatom. In another aspect, R is optionally cyclic alkyl group; substituted —C-C alkynyl with the proviso that when one 0672 Each R is selected from the group consisting of R" is attached to C through an O, S, or Natom, then the other —H. lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and R'' attached to the same C is a hydrogen, or attached via a lower acyl: carbon atom. 0673 with the provisos that: 10684. In one aspect, R' and R are the same and are 0674) a) V, Z, W, Ware not all-H; and selected from the group consisting of halogen, —C-C alkyl, 0675 b) when Z is R, then at least one of V, W, and W" —CF, and cyano. In another aspect, R' and Rare different is not —H, alkyl, aralkyl, or heterocycloalkyl. and are selected from the group consisting of halogen, —C- 0676 In another aspect, G is selected from the group con Calkyl, -CFs, and cyano. In an additional aspect, RandR sisting of O- and —CH2—. In one aspect, G is —O—. In are each halogen. In another aspect, R' and R are each another aspect, G is —S—. In another aspect, G is optionally substituted—C-C alkyl. In a further aspect, R' —S(=O)—. In a further aspect, G is —S(=O) -. In and Rare each optionally substituted—S C-C alkyl. In another aspect, G is —CH2—. In a further aspect, G is another aspect, R' and R are each optionally substituted —CF . In another aspect, G is —CHF . In a further —C-C alkenyl. In a further aspect, R' and R are each aspect, G is —C(O)—. In another aspect, G is —CH(OH)—. optionally substituted—C-C alkynyl. In another aspect, R' In another aspect, G is —NH-. In a further aspect, G is and Rare each—CF. In a further aspect, RandR are each —N(C-C alkyl)-. —OCF. In another aspect, R' and R are each optionally 0677. In a further aspect, D is selected from the group substituted-O C-C alkyl. In a further aspect, RandR are consisting of a bond and —CH2—. each cyano. 0678. In another aspect D is a bond. In a further aspect D 10685. In yet another aspect, RandR are each hydrogen. is —(CR)—. In another aspect D is —C(O)—. In another aspect, R and R are each halogen. In a further 0679. In yet another aspect A is selected from —NH , aspect, Rand Rare each —CF. In another aspect, Rand —NMe—, —O—, and —S-. In one aspect, A is —N—. In Rare each —OCF. In a further aspect, RandR are each another aspect, A is —O—. In a further aspect, A is —S—. cyano. In another aspect, Rand Rare each optionally sub 0680. In a further aspect, B is selected from —CH2—, stituted—C-Clalkyl. Inafurther aspect, RandR are each CMe , and - N -. In another aspect, B is CR -. In a optionally Substituted —C-C alkenyl. In another aspect, further aspect, B is —N—. Rand Rare each optionally substituted—C-C, alkynyl. 0681. In one aspect, R is hydrogen, —C(O)C-C alkyl. In In a further aspect, RandR are each optionally substituted another aspect, R is —C-C alkyl. In a further aspect, R" is —(CR").aryl. In another aspect, Rand Rare each option —C-C-aryl. ally substituted —(CR).cycloalkyl. In a further aspect, R 0682. In one aspect, R is hydrogen. In another aspect, 10 and R are each optionally substituted —(CR)heterocy is optionally Substituted—C-C alkyl. cloalkyl. In another aspect, R and R are each —OR". In 0683. In another aspect, R is hydrogen with the proviso another aspect, RandR are each - SR". In a further aspect, that when one R is attached to C through an O, S, or Natom, RandR are each–S(=O)R. In another aspect, Rand R' US 2009/011 8236 A1 May 7, 2009 44 are each - S(=O).R. Inafurther aspect, Rand Rare each heterocyclic ring may be substituted with 4 substituents —S(=O)NR'R's. In another aspect, R and R are each selected from the group consisting of optionally Substituted —C(O)NR'R''. Inafurther aspect, RandR are each–C(O) —C-C alkyl, -OR''. Oxo, cyano. —CFs, optionally substi OR". In another aspect, R and Rare each –C(O)R. In a tuted phenyl, and C(O)CR". further aspect, RandR are each-N(R)C(O)R. In another (0690. In a further aspect, R" is optionally substituted aspect, R and Rare each - N(R)C(O)NR'R's. In a further —C-C2 alkyl. In another aspect, R" is optionally substituted aspect, R and R are each - N(R)S(=O).R. In another —C-C, alkenyl. In a further aspect, R" is optionally substi aspect, RandR are each - N(R)S(=O)NR'R''. In a further tuted —Ca-Cia alkynyl. In another aspect, R" is optionally aspect, RandR are each - NRR. In an additional aspect, substituted—(CR),aryl. Inafurther aspect, R" is optionally R" is selected from the group consisting of hydrogen, halo substituted —(CR), cycloalkyl. In another aspect, R" is gen, —C-C alkyl, cyano and CF. In an additional aspect, optionally substituted —(CR), heterocycloalkyl. R is selected from the group consisting of halogen, option (0691. In another aspect, R is selected from the group ally substituted—C-C alkyl, -CF, cyano, —C(O)NR'R'', consisting of -OH, - OC(O)R, —OC(O)OR", –F, and optionally substituted —(CR),aryl, -SO2NR'R'', and NHC(O)R. In an additional aspect, R is optionally sub - SOR. stituted—OC-C alkyl. In another aspect, Ris—OC(O)R. 0686. In another aspect, each R" is optionally substituted Inafurther aspect, Ris—OC(O)OR. In another aspect, R is —C-C2 alkyl. In a further aspect, each R" is optionally —F. In another aspect, R is NHC(O)R. Inafurther aspect, substituted —C-C2 alkenyl. In another aspect, each R is R is NHS(=O)R. In another aspect, R is NHS(=O) optionally Substituted—C-C alkynyl. In a further aspect, R. In a further aspect, R is each R" is optionally substituted —(CR),aryl. In another NHC(=S)NH(R'). In another aspect, R is NHC(O)NH aspect, each R" is optionally substituted —(CR),cy (R"). cloalkyl. In a further aspect, each R" is optionally substituted 0692. In a further aspect, X is selected from the group —(CR), heterocycloalkyl. In another aspect, each R" is consisting of —POH, -P(O)—OCROC(O)R’, C(O)NR'R8. -P(O)I. OCR OC(O)ORT -P(O) N(H)CRC(O) 0687 In an additional aspect, R is optionally substituted ORT - P(O) N(H)CRC(O)ORT OR'', —C-C alkyl. In another aspect, R is optionally substituted and-P(O) OCH(V) CHCHO I, wherein V is selected —C-C alkenyl. In a further aspect, R is optionally Substi from the group consisting of optionally Substituted aryl, aryl, tuted —C-C alkynyl. In another aspect, R is optionally heteroaryl, and optionally substituted heteroaryl. substituted—(CR), aryl. Inafurther aspect, R is optionally 0693. In one aspect, G is selected from the group consist substituted —(CR)cycloalkyl. In another aspect, R is ing of —O— and —CH2—, D is selected from the group optionally substituted —(CR), heterocycloalkyl. consisting of a bond and —CH2—, A is selected from the 0688. In one aspect, Rand R are each hydrogen. In an group consisting of NH-, —NMe—, —O—, and —S—; additional aspect, R and R are each optionally substituted B is selected from the group consisting of —CH-, —C-C, alkyl. In another aspect, RandR are each option —CMe , and - N - R' and R are each independently ally substituted—Ca-Cia alkenyl. In an additional aspect, R selected from the group consisting of halogen, —C-C alkyl, and R are each optionally substituted—C-C alkynyl. In a —CFs, and cyano; R is selected from the group consisting of further aspect, R and R are each optionally substituted hydrogen, halogen, —C-C alkyl, cyano and CF; R is —(CR),aryl. In an additional aspect, R and R are each selected from the group consisting of —OH, - OC(O)R. optionally substituted —(CR), cycloalkyl. In another –OC(O)CR', F, and -NHC(O)R: R is selected from aspect, R and R are each optionally substituted —(CR) the group consisting of halogen, optionally Substituted—C- heterocycloalkyl. Calkyl, CFs, cyano, C(O)NR'R'', optionally substituted 0689. In an additional aspect, RandR may togetherform —(CR), aryl, -SO2NR/R3, and -SOR: and X is an optionally Substituted heterocyclic ring, which may con selected from the group consisting of—POH, -P(O)— tain a second heterogroup which is O. In another aspect, R OCROC(O)RT, -P(O) OCR OC(O)ORT, -P(O) and R may together form an optionally substituted hetero N(H)CRC(O)ORT -P(O) N(H)CRC(O)ORT cyclic ring, which may contain a second heterogroup which is OR'' and -P(O) OCH(V) CHCHO I, wherein V NR. In another aspect, R and R may together form an is selected from the group consisting of optionally Substituted optionally substituted heterocyclic ring, which may contain a aryl, aryl, heteroaryl, and optionally Substituted heteroaryl. In second heterogroup which is S. In one aspect, RandR may another aspect, G is selected from the group consisting of together form an unsubstituted heterocyclic ring, which may —O—and —CH; D is selected from the group consisting of contain a second heterogroup. In another aspect, the option a bond and —CH2—, A is selected from the group consisting ally substituted heterocyclic ring may be substituted with 1 of NH , —NMe , —O—, and—S : B is selected from Substituent selected from the group consisting of optionally the group consisting of —CH-, -CMe—and —N-; R' substituted —C-C alkyl, -OR''. Oxo, cyano, —CFs, and Rare each independently selected from the group con optionally substituted phenyl, and C(O)OR". In further sisting of iodo, bromo, chloro, methyl, and cyano; R is aspect, the optionally Substituted heterocyclic ring may be selected from the group consisting of hydrogen and halogen; substituted with 2 substituents selected from the group con R is selected from the group consisting of OH and —OC sisting of optionally substituted—C-C alkyl, -OR''. Oxo, (O)R’; and R is selected from the group consisting of halo cyano. —CF, optionally Substituted phenyl, and —C(O) gen, optionally Substituted —C-C alkyl, optionally Substi OR". In another aspect, the optionally substituted heterocy tuted —CHaryl, optionally substituted —CH(OH)aryl, clic ring may be substituted with 3 substituents selected from —C(O)-amido. —S(=O)-amido, wherein the amido group the group consisting of optionally Substituted—C-C alkyl, is selected from the group consisting of phenethylamino, —OR''. Oxo, cyano. —CFs, optionally substituted phenyl, piperidinyl, 4-methylpiperizinyl, morpholinyl, cyclohexy and —C(O)OR. In a further aspect, the optionally substituted lamino, anilinyl, and indolinyl, and —SOR wherein R is US 2009/011 8236 A1 May 7, 2009 selected from the group consisting of phenyl, 4-chlorophenyl, —S(CR)(CR"), , – N(R)(CR)(CR), , – N(R)C 4-fluorophenyl, and 4-pyridyl. In yet another aspect, G is (O)(CR), , —(CR),CH(NRR), C(O)(CR), —O—; D is a bond; A is selected from the group consisting of —(CR),C(O)— —(CR)C(O)(CR), —(CR),C —NH and—NMe—; B is selected from the group consist (O)(CR) , and –C(O)NH(CR 2)(CR'2) ; ing of CH-and-CMe : R* and R' are each bromo; R' 0701. k is an integer from 0-4: is selected from the group consisting of hydrogen and iodo; 0702 m is an integer from 0-3: Ris-OH; and R is isopropyl. 0703 n is an integer from 0-2: 0694. In another aspect, G is —O—; D is a bond; A is 0704 p is an integer from 0-1; selected from the group consisting of —NH- and —NMe—; B is selected from the group consisting of 0705. Each R" is independently selected from the group —CH and —CMe : R* and R are each bromo; R is consisting of hydrogen, optionally Substituted—C-C alkyl, selected from the group consisting of hydrogen and iodo; R halogen, —OH, optionally substituted —O-C-C alkyl, is —OH: R is isopropyl, and X is selected from the group OCF, optionally substituted S C-C alkyl, NRR, consisting of —POH, -P(O)—OCHOC(O)-t-butyl, optionally substituted —C-C alkenyl, and optionally sub -P(O) OCHOC(O)O-i-propyl, -P(O) N(H)CH stituted—C-C alkynyl; with the proviso that when one R is (CH)C(O)OCHCH, -P(O) N(H)C(CH),C(O) attached to C through an O, S, or N atom, then the other R' OCHCH, -P(O) N(H)CH(CH)C(O)OCHCH-3, attached to the same C is a hydrogen, or attached via a carbon 4-methylenedioxyphenyl, - P(O) N(H)C(CH),C(O) atom; OCH2CH3.4-methylenedioxyphenyl, and —P(O)— (0706) Each R is independently selected from the group OCH(3-chlorophenyl)CHCH-O-). consisting of hydrogen and optionally substituted —C-C, 0695. In a further aspect, G is —O—; D is a bond: A is alkyl: —O—; B is selected from the group consisting of —CH 0707. Each R is independently selected from the group and CMe : R* and Rare each bromo; R is selected from consisting of hydrogen and optionally substituted —C-C, the group consisting of hydrogen and iodo; R is —OH; and alkyl, optionally substituted —C(O)—C-C alkyl, and R is isopropyl. In another aspect, Gis —O ; D is a bond; A C(O)H: is —O—; B is selected from the group consisting of CH (0708) R' and Rare each independently selected from the and CMe ; R' and Rare each bromo; R is selected from group consisting of halogen, optionally substituted —C- the group consisting of hydrogen and iodo; R is —OH: R is Calkyl, optionally Substituted—S C-C alkyl, optionally isopropyl. X is selected from the group consisting of Substituted—C-C alkenyl, optionally Substituted —C-C, —POH, -P(O) OCHOC(O)-t-butyl-, -P(O)— alkynyl, -CF, —OCF, optionally substituted-O-C-C, OCHOC(O)O-i-propyl, -P(O) N(H)CH(CH)C(O) alkyl, and cyano; OCHCH, -P(O) N(O)C(CH),C(O)OCHCH), (0709 Rand Rare each independently selected from the -P(O) N(H)CH(CH)C(O)OCH2CH3.4-methylene group consisting of hydrogen, halogen, —CF, —OCF, dioxyphenyl), -P(O) N(H)C(CH),C(O)OCHCH-3, cyano, optionally Substituted—C-C alkyl, optionally Sub 4-methylenedioxyphenyl, and —P(O)—OCH(3-chlo stituted —C-C alkenyl, optionally substituted —C-C, rophenyl)CHCHO . alkynyl, optionally Substituted —(CR), aryl, optionally 0696. In an additional aspect, X is —POH. Substituted —(CR), cycloalkyl, optionally Substituted 0697 Each of the individual species of compounds of —(CR"), heterocycloalkyl, -O, - SR", S(=O)R. Formula II which can be generated by making all of the above S(=O).R., S(=O)NR'Rs, C(O)NR'Rs, C(O) permutations may be specifically set forth as for inclusion or OR, C(O)R, N(R)C(O)R, N(R)C(O)NR'Rs, may be specifically excluded from the present invention. N(R)S(=O).R., N(R)S(=O)NRs, and NR/Rs: 0698. In another aspect, the invention relates to com (0710. Each R" is selected from the group consisting of pounds of Formula III, stereoisomers, pharmaceutically optionally substituted—C-C alkyl, optionally substituted acceptable salts and prodrugs thereof and pharmaceutically —C-C alkenyl, optionally substituted —C-Calkynyl, acceptable salts of the prodrugs as represented by Formula optionally substituted —(CR),aryl, optionally substituted III: —(CR), cycloalkyl, optionally substituted —(CR), het erocycloalkyl, and –C(O)NR'R'': 0711 Each R is selected from the group consisting of optionally Substituted—C-C alkyl, optionally Substituted —C-C alkenyl, optionally substituted —C-C alkynyl. optionally substituted —(CR),aryl, optionally substituted —(CR).cycloalkyl, and optionally substituted —(CR) heterocycloalkyl; (0712 R and Rare each independently selected from the R4 RI R7 group consisting of hydrogen, optionally substituted —C- Calkyl, optionally Substituted—C-C alkenyl, optionally wherein: Substituted —C-C alkynyl, optionally Substituted 0699 G is selected from the group consisting of —O , —(CR),aryl, optionally substituted —(CR), cycloalkyl, S —S(=O)— —S(=O) , —CH2—, —CF , and optionally substituted —(CR).heterocycloalkyl, or R CHF , —C(O) , —CH(OH) , NH , and—N(C- and R may together form an optionally substituted hetero Calkyl)-; cyclic ring, which may contain a second heterogroup selected 0700 T is selected from the group consisting of (CR) from the group consisting of O, NR, and S, wherein said CR-CR (CR), (CR), CR-CR, optionally substituted heterocyclic ring may be substituted —(CR")—CR'—CR' (CR)— —O(CR)(CR), , with 0-4 Substituents selected from the group consisting of US 2009/011 8236 A1 May 7, 2009 46 optionally substituted —C-C alkyl, -OR''. Oxo, cyano, 0722 or together V and Z are connected via an additional —CF, optionally substituted phenyl, and —C(O)OR; 3-5 atoms to form a cyclic group containing 5-7 atoms, 0713. Each R" is selected from the group consisting of wherein 0-1 atoms are heteroatoms and the remaining atoms optionally substituted—C-C alkyl, optionally substituted are carbon, Substituted with hydroxy, acyloxy, alkylthiocar —C-C alkenyl, optionally Substituted —C-C alkynyl, bonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy optionally substituted CR2)aryl, optionally substituted attached to a carbon atom that is three atoms from both Y —(CR)cycloalkyl, and optionally substituted —(CR) groups attached to the phosphorus; or heterocycloalkyl; 0714 R is selected from the group consisting of —OH, 0723 or together V and Z are connected via an additional optionally substituted —OC-C alkyl, —OC(O)R. —OC 3-5 atoms to form a cyclic group, wherein 0-1 atoms are (O)OR, F, NHC(O)R, NHS(=O)R, NHS( O) heteroatoms and the remaining atoms are carbon, that is fused R, NHC(=S)NH(R'), and NHC(O)NH(R'); to an aryl group at the beta and gamma position to the Y 0715I R' is selected from the group consisting of hydro attached to the phosphorus: gen, halogen, amino, hydroxyl. —O-C-C alkyl, -SH and 0724 or together V and Ware connected via an additional —S C-C alkyl, 3 carbonatoms to forman optionally Substituted cyclic group 0716 X is P(O)YR''Y'R'': containing 6 carbon atoms and Substituted with one substitu 0717 Y and Y are each independently selected from the ent selected from the group consisting of hydroxy, acyloxy, group consisting of —O—, and —NR'—, when Y and Y are alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycar —O , R'' attached to —O—is independently selected from bonyloxy, attached to one of said carbon atoms that is three the group consisting of —H, alkyl, optionally substituted atoms from a Y attached to the phosphorus: aryl, optionally Substituted heterocycloalkyl, optionally Sub 0725 or together Z and Ware connected via an additional stituted CH-heterocycloaky1 wherein the cyclic moiety con 3-5 atoms to form a cyclic group, wherein 0-1 atoms are tains a carbonate or thiocarbonate, optionally substituted heteroatoms and the remaining atoms are carbon, and V must -alkylaryl, -C(R),OC(O)NR, NR C(O) R', be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; —C(R) OC(O)R’, C(R) O C(O)OR, C(R) OC(O)SR, -alkyl-S C(O)R’, -alkyl-S-S-alkylhydroxy, 0726 or together W and W are connected via an addi and -alkyl-S S S-alkylhydroxy: tional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are 0718 when Y and Y are NR' , then R'' attached to heteroatoms and the remaining atoms are carbon, and V must —NR'—is independently selected from the group consisting be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; of-H, -C(R), COOR, —C(R)-COOR. -IC(R) 0727 Z is selected from the group consisting of —CHR C(O)SR', and -cycloalkylene-COOR'; *OH, CHROC(O)R’, CHROC(S)R’, CHROC(S) 0719 when Yis-O- and Y is NR', then R'' attached to OR, CHROC(O)SR, CHROCOR, OR, SR, —O—is independently selected from the group consisting of - CHRN, -CHaryl, -CH(aryl)OH, -CH(CH=CR) —H, alkyl, optionally substituted aryl, optionally substituted OH, -CH(C=CR)OH, -R, NR, OCOR', heterocycloalkyl, optionally substituted CH-heterocy OCOR', SCOR, SCOR, NHCOR, cloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally NHCO.R. CH-NHaryl, -(CH2), OR, and -(CH2) substituted -alkylaryl, C(R)OC(O)NR, NR C(O)— SR; R, C(R). OC(O)R’, C(R-O C(O)OR, C(R) 0728 q is an integer 2 or 3: OC(O)SR', -alkyl-S C(O)R’, -alkyl-S-S-alkylhydroxy, 0729. Each R is selected from the group consisting of R' and -alkyl-S-S-S-alkylhydroxy; and R'' attached to and —H; —NR—is independently selected from the group consisting 0730 Each R" is selected from the group consisting of of -H, -C(R). COOR, C(R)-COOR. -IC(R) alkyl, aryl, heterocycloalkyl, and aralkyl; al, C(O)SR, and -cycloalkylene-COOR: 0731 Each R is independently selected from the group 0720 or when Y and Y are independently selected from —O— and NR' , then together R'' and R'' are -alkyl consisting of —H, and alkyl, or together R and R' form a S S-alkyl- to form a cyclic group, or together R'' and R' cyclic alkyl group; are the group: (0732. Each R" is selected from the group consisting of —H. lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl: V H (0733 with the provisos that: (0734) a) when Gis-O-, T is NH-CH , RandR Z are each chloro, R is iso-propyl, R' is hydrogen, R is fluoro, H and R is -H, then X is not P(O)(OH), P(O)(OH)(OCH) or W P(O)(OCH): W (0735 b) V, Z, W, Ware not all H; and (0736 c) when Z is R, then at least one of V, W, and W. wherein: is not—H, alkyl, aralkyl, or heterocycloalkyl. 0721 V, W, and W are independently selected from the 0737. In an additional aspect, the invention relates to com group consisting of hydrogen, optionally Substituted alkyl, pounds of Formula III, stereoisomers, pharmaceutically optionally substituted aralkyl, heterocycloalkyl, aryl, Substi acceptable salts and prodrugs thereof and pharmaceutically tuted aryl, heteroaryl, substituted heteroaryl, optionally sub acceptable salts of the prodrugs as represented by Formula stituted 1-alkenyl, and optionally substituted 1-alkynyl: III: US 2009/011 8236 A1 May 7, 2009 47

0750 Each R is optionally substituted —C-C alkyl, optionally substituted —C-C alkenyl, optionally substi R3 R2 T-X tuted —C-C alkynyl, optionally Substituted —(CR) aryl, optionally Substituted —(CR), cycloalkyl, and optionally substituted —(CR), heterocycloalkyl: R5 G \ / N (0751) R' and Rs are each independently selected from the group consisting of hydrogen, optionally Substituted R4 RI R7 C-C alkyl, optionally substituted—C-Calkenyl, option ally substituted —C-C alkynyl, optionally Substituted —(CR),aryl, optionally substituted —(CR'2).cycloalkyl, wherein: and optionally substituted (CR).heterocycloalkyl, or Rand 0738 G is selected from the group consisting of —O , R may together form an optionally substituted heterocyclic S s S(=O) s S(=O), s CH s CF, s CHF , —C(O) , —CH(OH) , NH , and—N(C- ring, which may contain a second heterogroup selected from Calkyl)-; the group of O, NR, and S, wherein said optionally substi 0739 T is selected from the group consisting of (CR) tuted heterocyclic ring may be substituted with 0-4 substitu , —CR=CR(CR), —(CR), CR=CR , ents selected from the group consisting of optionally Substi (CR) CR-CR (CR) , O(CR)(CR) , tuted—C-C alkyl, -OR''. Oxo, cyano, —CF, optionally –S(CR)(CR), , N(R(CR)(CR) , N(R)C(O) substituted phenyl, and C(O)OR"; (CR), , —(CR"),CH(NRR, —C(O)(CR), , (0752 Each R" is selected from the group consisting of —(CR"),C(O)— —(CR")C(O)(CR")— —(CR),C optionally Substituted—C-C alkyl, optionally Substituted (O)(CR",)—, and –C(O)NH(CR')(CR") ; —C-C alkenyl, optionally substituted —C-Calkynyl. 0740 k is an integer from 0-4: optionally substituted —(CR),aryl, optionally substituted 0741 m is an integer from 0-3: —(CR).cycloalkyl, and optionally substituted —(CR) 0742 n is an integer from 0-2: heterocycloalkyl: 0743 p is an integer from 0-1; (0753 R is selected from the group consisting of —OH, 0744. Each R" is independently selected from the group optionally substituted —OC-C alkyl, —OC(O)R. —OC consisting of hydrogen, optionally substituted—C-C alkyl, (O)OR, F, NHC(O)R, NHS(—OR, NHS(—O) halogen, —OH, optionally Substituted —O—C-C alkyl, R, NHC( S)NH(R'), and NHC(O)NH(R'); —OCF, optionally substituted S C-C alkyl, NRR, (0754) R' is selected from the group consisting of hydro optionally substituted —C-C alkenyl, and optionally Sub gen, halogen, amino, hydroxyl. —O—C-C alkyl, -SH and stituted—C-C alkynyl; with the proviso that when one R is —S-C-C alkyl: attached to C through an O, S, or Natom, then the other R' attached to the same C is a hydrogen, or attached via a carbon 0755. X is P(O)YR'Y'R'': atom; (0756 Y and Y are each independently selected from the 0745) Each R is independently selected from the group group consisting of O—, and —NR'—, when Y and Y are consisting of hydrogen and optionally substituted —C-C, —O—, R'' attached to —O—is independently selected from alkyl: the group consisting of —H, alkyl, optionally substituted aryl, optionally Substituted heterocycloalkyl, optionally Sub 0746. Each R is independently selected from the group stituted CH-heterocycloaky1 wherein the cyclic moiety con consisting of hydrogen, optionally Substituted—C-C alkyl, tains a carbonate or thiocarbonate, optionally substituted optionally substituted—C(O) C-C alkyl, and —C(O)H: -alkylaryl, -C(R),OC(O)NR - NR C(O) R', 0747 R and Rare each independently selected from the - C(R) OC(O)R’, C(R), C(O)OR, C(R)OC group consisting of halogen, optionally Substituted —C- (O)SR, -alkyl-S C(O)R’, -alkyl-S-S-alkylhydroxy, and Calkyl, optionally substituted—S C-C alkyl, optionally -alkyl-S-S-S-alkylhydroxy: Substituted—C-C alkenyl, optionally Substituted—C-C, alkynyl. —CF —OCF, optionally Substituted-O—C-C, (0757 when Y and Y are NR' , then R'' attached to alkyl, and cyano; —NR'—is independently selected from the group consisting 0748 Rand Rare each independently selected from the of-H, -C(R). COOR, C(R),COOR. -IC(R), group consisting of hydrogen, halogen, —CF, —OCF, C(O)SR', cyano, optionally Substituted—C-C alkyl, optionally Sub and -cycloalkylene-COOR': stituted —C-C alkenyl, optionally Substituted —C-C2 (0758 when Y is O—and Y is NR', then R'' attached to alkynyl, optionally substituted —(CR), aryl, optionally —O—is independently selected from the group consisting of Substituted —(CR), cycloalkyl, optionally Substituted —H, alkyl, optionally substituted aryl, optionally substituted (CR).heterocycloalkyl, -OR', SR, -S(=O)R, heterocycloalkyl, optionally substituted CH-heterocy —S(=O).R., -S(=O)NR'R –C(O)NR'R. —C(O) cloaky1 wherein the cyclic moiety contains a carbonate or OR, C(O)R, N(RC(O)R, N(RC(O)NR'R. thiocarbonate, optionally N(R)S(=O).R., N(R)S(=O)NR'Rs, and NRRS: substituted -alkylaryl, -C(R)OC(O)NR, NR C 0749. Each R" is selected from the group consisting of (O) R', C(R). OC(O)R’, C(R) O C(O)OR, optionally substituted—C-C alkyl, optionally substituted - C(R)OC(O)SR, -alkyl-S C(O)R’, -alkyl-S-S-alkyl —C-C alkenyl, optionally Substituted —C-C alkynyl, hydroxy, and -alkyl-S-S S-alkylhydroxy; and R' optionally substituted —(CR),aryl, optionally substituted attached to —NR—is independently selected from the group —(CR), cycloalkyl, optionally substituted—(CR)hetero consisting of -H, -IC(R), COOR, —C(R)-COOR, cycloalkyl, and –C(O)NR'R'': |C(R), C(O)SR, and -cycloalkylene-COOR: US 2009/011 8236 A1 May 7, 2009 48

(0759 or when Y and Y are independently selected from 0771. Each R is selected from the group consisting of —O— and NR' , then together R'' and R'' are -alkyl —H. lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and S S-alkyl- to form a cyclic group, or together R'' and R' lower acyl: are the group: (0772 with the provisos that: 0773 a) when G is selected from the group consisting of O— —S , —S(=O)— —S(=O) , —CH2—, H —C(O) and NR' : T is -A-B where A is selected Z from the group consisting of NR' , —O , —CH and - S - and B is selected H, from the group consisting of a bond and Substituted or unsub W stituted C-C alkyl; R is selected from the group consisting W of halogen, trifluoromethyl, substituted or unsubstituted C-C alkyl, substituted or unsubstituted aryl, substituted or wherein: unsubstituted heteroaryl, aryloxy, Substituted amide, Sulfone, 0760 V, W, and W are independently selected from the Sulfonamide and C-C, cycloalkyl, wherein said aryl, het group consisting of hydrogen, optionally Substituted alkyl, eroaryl or cycloalkyl ring(s) are attached or fused to the optionally substituted aralkyl, heterocycloalkyl, aryl, Substi aromatic; R is selected from the group consisting of hydro tuted aryl, heteroaryl, substituted heteroaryl, optionally sub gen, halogen, Substituted or unsubstituted C-C alkyl, Sub stituted 1-alkenyl, and optionally substituted 1-alkynyl: stituted or unsubstituted aryl, and substituted or unsubstituted 0761 or together V and Z are connected via an additional heteroaryl; R' and Rare each independently selected from 3-5 atoms to form a cyclic group containing 5-7 atoms, the group consisting of halogen, Substituted or unsubstituted wherein 0-1 atoms are heteroatoms and the remaining atoms C-C alkyl, and Substituted or unsubstituted C-Cs are carbon, Substituted with hydroxy, acyloxy, alkylthiocar cycloalkyl; R is selected selected from the group consisting bonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy of hydrogen, halogen, amino, hydroxyl. —O-C-C alkyl, attached to a carbon atom that is three atoms from both Y —SH and S C-C alkyl; and R is selected from the groups attached to the phosphorus; or group consisting of hydroxyl, optionally substituted —OC 0762 or together V and Z are connected via an additional C alkyl, and —OC(O)R; then X is not —P(O)(OH): 3-5 atoms to form a cyclic group, wherein 0-1 atoms are (0774 b) V, Z, W, Ware not all-H; and heteroatoms and the remaining atoms are carbon, that is fused (0775 c) when Z is R, then at least one of V, W, and W. to an aryl group at the beta and gamma position to the Y is not—H, alkyl, aralkyl, or heterocycloalkyl. attached to the phosphorus; 0776. In another aspect, when G is —O , T is —NH 0763 or together V and Ware connected via an additional CH. , R' and R are each chloro, R is iso-propyl, R is 3 carbonatoms to forman optionally Substituted cyclic group fluoro and R is —OH, then R is not hydrogen. In a further containing 6 carbon atoms and Substituted with one substitu aspect, when G is selected from the group consisting of oxy ent selected from the group consisting of hydroxy, acyloxy, gen, Sulfur, Sulfoxide, Sulfonyl, —CH2—, —C(O)— and alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycar NR' : T is -A-B where A is selected from the group bonyloxy, attached to one of said carbon atoms that is three consisting of NR ,-O-, -CH-and-S and B is atoms from a Y attached to the phosphorus: selected from the group consisting of a bond and Substituted 0764 or together Z and Ware connected via an additional or unsubstituted C-C alkyl; R is selected from the group 3-5 atoms to form a cyclic group, wherein 0-1 atoms are consisting of halogen, trifluoromethyl, Substituted or unsub heteroatoms and the remaining atoms are carbon, and V must stituted C-C alkyl, substituted or unsubstituted aryl, substi be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; tuted or unsubstituted heteroaryl, aryloxy, substituted amide, 0765 or together W and W are connected via an addi Sulfone, Sulfonamide and C-C cycloalkyl, wherein said tional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are aryl, heteroaryl or cycloalkyl ring(s) are attached or fused to heteroatoms and the remaining atoms are carbon, and V must the aromatic; R is selected from the group consisting of be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; hydrogen, halogen, Substituted or unsubstituted C-C alkyl, substituted or unsubstituted aryl, and substituted or unsubsti 0766 Z is selected from the group consisting of —CHR tuted heteroaryl; R' and Rare each independently selected *OH, CHROC(O)R’, CHROC(S)R’, CHROC(S) from the group consisting of halogen, Substituted or unsub OR, CHROC(O)SR, CHROCOR, OR, SR, stituted C-C alkyl, and Substituted or unsubstituted C-Cs —CHRN, -CHaryl, -CH(aryl)OH, -CH(CH=CR) cycloalkyl; and R is selected selected from the group con OH, -CH(C=CR)OH, -R, NR, OCOR', sisting of hydrogen, halogen, amino, hydroxyl. —O—C-C, OCOR', SCOR, SCOR, NHCOR, alkyl, -SH and —S C-C alkyl; then R is not hydroxyl, —NHCO.R, -CH-NHaryl, -(CH.) OR, and -(CH.) optionally substituted —OC-C alkyl, or —OC(O)R. SR; 0777. In one aspect, G is selected from the group consist 0767 q is an integer 2 or 3: ing of —O— and —CH2—. In a further aspect, G is —O—. 0768. Each R is selected from the group consisting of R' In another aspect, G is —S—. In a further aspect, G is and —H; —S(=O)—. In another aspect, G is —S(=O) . In a flirter 0769 Each R" is selected from the group consisting of aspect, G is —CH2—In another aspect, G is —CF -. In a alkyl, aryl, heterocycloalkyl, and aralkyl; further aspect, G is —CHF . In another aspect, G is 0770. Each R is independently selected from the group —C(O)—. In another aspect, G is —CH(OH)—. In a further consisting of —H, and alkyl, or together R and R' form a aspect, G is —NH-. In another aspect, G is —N(C-C, cyclic alkyl group; alkyl)-. US 2009/011 8236 A1 May 7, 2009 49

0778. In another aspect, T is selected from the group con Substituted—C-C alkyl. In a further aspect, R is optionally sisting of —(CR) , —O(CR” 2)(CR'2) , -NC)(CR) substituted—C(O)—C-C alkyl. In yet another aspect, R is (CR) , S(CR)(CR) , NR(CO) , and C(O)H. —CH2CHRR)-. In a further aspect, T is —(CR") . In 10782. In a further aspect, R' and R are the same and are another aspect, T is —CR'—CR(CR), . In a further selected from the group consisting of halogen, —C-C alkyl, aspect, Tis—(CR), CR”—CR -. In another aspect, T is —CF, and cyano. In yet another aspect, R' and Rare dif —(CR")—CR'—CR' (CR)-. In a further aspect, T is ferent and are selected from the group consisting of halogen, —O(CR)(CR), . In another aspect, T is S(CR) —C-C alkyl, -CF, and cyano. In an additional aspect, R' (CR), . In a further aspect, T is NM(CR)(CR), . and Rare each halogen. In another aspect, RandR are each In another aspect, T is N(R)C(O)(CR), . In a further optionally substituted—C-C alkyl. In a further aspect, R' aspect, T is —(CR),CHRRC)—. In another aspect, T is and Rare each optionally substituted—S C-C alkyl. In —C(O)(CR), . In a further aspect, T is —(CR),C another aspect, R' and R are each optionally substituted (O)—. In another aspect, T is —(CR)C(O)(CR), . In a —C-C alkenyl. In a further aspect, R' and R are each further aspect, T is (CR),C(O)(CR)—. In yet another optionally substituted—C-C alkynyl. In another aspect, R' aspect, T is C(O)NH(CR)(CR) . and Rare each—CF. In a further aspect, RandR are each 0779. In one aspect k is 0. In a further aspect, k is 1. In an —OCF. In another aspect, R' and R are each optionally additional aspect, k is 2. In a further aspect, k is 3. In yet substituted-O C-C alkyl. In a further aspect, RandR are another aspect, k is 4. In one aspect m is 0. In a further aspect, each cyano. In yet another aspect, Rand Rare each hydro m is 1. In an additional aspect, m is 2. In a further aspect, m is gen. In another aspect, R and R are each halogen. In a 3. In one aspect n is 0. In a further aspect, n is 1. In an further aspect, Rand Rare each - CF. In another aspect, additional aspect, n is 2. In one aspect, p is 0. In another Rand Rare each—OCF. In a further aspect, RandR are aspect, p is 1. each cyano. In another aspect, RandR are each optionally substituted—C-C alkyl. In a further aspect, RandR are 0780. In one aspect, each R" is hydrogen with the proviso each optionally substituted —C-C alkenyl. In another that when one R is attached to C through an O, S, or Natom, aspect, R and R are each optionally substituted —C-C2 then the other R' attached to the same C is a hydrogen, or alkynyl. In a further aspect, R and R are each optionally attached via a carbon atom. In another aspect, each R is substituted —(CR).aryl. In another aspect, R and R are optionally substituted —C-C alkyl with the proviso that each optionally substituted —(CR).cycloalkyl. In a further when one R is attached to C through an O, S, or Natom, then aspect, R and R are each optionally substituted —(CR) the other R' attached to the same C is a hydrogen, or attached heterocycloalkyl. In another aspect, RandR are each R". via a carbonatom. In a further aspect, each R" is halogen with In another aspect, R and R are each - SR". In a further the proviso that when one R is attached to C through an O, S, aspect, RandR are each - S(=O)R. In another aspect, R or N atom, then the other R' attached to the same C is a and Rare each - S(=O).R. In a further aspect, Rand R' hydrogen, or attached via a carbon atom. In another aspect, are each - S(=O)NR'R's. In another aspect, R and Rare each R" is —OH with the proviso that when one R is attached each –C(O)NR'R''. In a further aspect, R' and Rare each to C through an O, S, or Natom, then the other Rattached to —C(O)CR. In another aspect, RandR are each C(O)R. the same C is a hydrogen, or attached via a carbon atom. In a In a further aspect, R and R are each - N(R)C(O)R. In further aspect, each R" is optionally substituted—O C-C, another aspect, Rand Rare each - N(R)C(O)NR'R''. In a alkyl with the proviso that when one R is attached to C further aspect, R and R' are each - N(R)S(=O).R. In through an O, S, or Natom, then the other R' attached to the another aspect, RandR are each-N(R)S(=O)NR'R''. In same C is a hydrogen, or attached via a carbon atom. In a further aspect, Rand Rare each-NR/R3. another aspect, each R" is —OCF with the proviso that when 10783. In another aspect, R is selected from the group one R is attached to C through an O, S, or Natom, then the consisting of hydrogen, halogen, —C-C alkyl, cyano and other Rattached to the same C is a hydrogen, or attached via CF. In a further aspect, R is selected from the group con a carbon atom. In a further aspect, each R is optionally sisting of halogen, optionally Substituted —C-C alkyl, substituted—S C-C alkyl with the proviso that when one —CF, cyano, —C(O)NR'R'', optionally substituted R" is attached to C through an O, S, or Natom, then the other —(CR"), aryl, -SONR'R'', and -SO.R. R attached to the same C is a hydrogen, or attached via a (0784. In another aspect, each R" is optionally substituted carbon atom. In another aspect, each R" is NR'R' with the —C-C alkyl. In a further aspect, each R is optionally sub proviso that when one R is attached to C through an O, S, or stituted —C-C2 alkenyl. In another aspect, each R" is Natom, then the other Rattached to the same C is a hydro optionally substituted—C-C alkynyl. In a further aspect, gen, or attached via a carbonatom. In a further aspect, each R' each R" is optionally substituted —(CR),aryl. In another is optionally Substituted —C-C alkenyl with the proviso aspect, each R" is optionally substituted —(CR),cy that when one R is attached to C through an O, S, or Natom, cloalkyl. In a further aspect, each R" is optionally substituted then the other R' attached to the same C is a hydrogen, or —(CR), heterocycloalkyl. In another aspect, each R" is attached via a carbon atom. In another aspect, each R" is C(O)NR'R8. optionally substituted—C-C alkynyl with the proviso that 0785. In an additional aspect, R is optionally substituted when one R is attached to C through an O, S, or Natom, then —C-C alkyl. In another aspect, R is optionally substituted the other Rattached to the same C is a hydrogen, or attached —C-C alkenyl. In a further aspect, R is optionally substi via a carbon atom. tuted —C-C alynyl. In another aspect, R is optionally 0781. In one aspect, R is hydrogen. In an additional substituted—(CR), aryl. In a flirter aspect, R is optionally aspect, R is optionally substituted —C-C alkyl. In one substituted —(CR)cycloalkyl. In another aspect, R is aspect, R is hydrogen. In another aspect, R is optionally optionally substituted —(CR), heterocycloalkyl. US 2009/011 8236 A1 May 7, 2009 50

0786) In one aspect, R and R are each hydrogen. In an 0792. In one aspect, G is selected from the group consist additional aspect, R and Rs are each optionally substituted ing of —O— and —CH2—, T is selected from the group —C-C2alkyl. In another aspect, RandR are each option consisting of ally substituted—C-C alkenyl. In an additional aspect, R' and Rare each optionally Substituted—C-C alkynyl. In a —(CR), , O(CR'2)(CR) , N(CR)(CR) further aspect, R and Rs are each optionally substituted (CR') , S(CR',)(CR".) , NR(CO)—, and —(CR),aryl. In an additional aspect, R and R are each —CH-CH(NRR) : R* and R are each independently optionally substituted —(CR), cycloalkyl. In another selected from the group consisting of halogen, —C-C alkyl, aspect, R and Rs are each optionally substituted —(CR) —CF, and cyano; R' is selected from the group consisting of heterocycloalkyl. hydrogen, halogen, —C-C alkyl, cyano and CF; R is 0787. In an additional aspect, RandR may togetherform selected from the group consisting of —OH, - OC(O)R. an optionally Substituted heterocyclic ring, which may con –OC(O)CR', F, and -NHC(O)R: R is selected from tain a second heterogroup which is O. In another aspect, R the group consisting of halogen, optionally Substituted—C- and R may together form an optionally substituted hetero Calkyl, CFs, cyano, C(O)NR'R'', optionally substituted cyclic ring, which may contain a second heterogroup which is —(CR), aryl, -SONR/R3, and -SOR: R7 is selected NR. In another aspect, R and R may together form an from the group consisting of hydrogen, fluoro, chloro, amino, optionally substituted heterocyclic ring, which may contain a hydroxyl, and —O—CH; and X is selected from the group second heterogroup which is S. In one aspect, RandR may consisting together form an unsubstituted heterocyclic ring, which may contain a second heterogroup. In another aspect, the option of POH, -P(O) OCR OC(O)R. ally substituted heterocyclic ring may be substituted with 1 Substituent selected from the group consisting of optionally - P(O) OCR OC(O)ORT -P(O) N(H)CRC(O) substituted —C-C alkyl, -OR''. Oxo, cyano, —CF, ORI, optionally substituted phenyl, and C(O)OR". In further aspect, the optionally Substituted heterocyclic ring may be 0793 - P(O) N(H)CRC(O)ORT OR'' and substituted with 2 substituents selected from the group con -P(O) OCH(V)CHCHO I, wherein V is selected sisting of optionally substituted—C1-C4 alkyl, -OR. Oxo, from the group consisting of optionally Substituted aryl, aryl, cyano. —CF, optionally substituted phenyl, and —C(O) heteroaryl, and optionally substituted heteroaryl. OR". In another aspect, the optionally substituted heterocy 0794. In a further aspect, when G is —O , T is —CH2—, clic ring may be substituted with 3 substituents selected from R" and Rare chloro, R is iso-propyl, R is fluoro, and R is the group consisting of optionally Substituted—C-C alkyl, —OH, then R is not hydrogen. In another aspect, when G is —OR''. Oxo, cyano, -CFs, optionally substituted phenyl, selected from the group consisting of O—and —CH2—, T and —C(O)OR". In a further aspect, the optionally substi is -A-B - where A is selected from the group consisting of tuted heterocyclic ring may be substituted with 4 substituents NR' , —O , —CH2— and - S - and B is selected selected from the group consisting of optionally Substituted from the group consisting of a bond and Substituted or unsub —C-C alkyl, -OR''. Oxo, cyano. —CFs, optionally substi stituted C-C alkyl; R is selected from the group consisting tuted phenyl, and C(O)OR". of halogen, trifluoromethyl, substituted or unsubstituted 0788. In a further aspect, R is optionally substituted C-C alkyl, substituted or unsubstituted aryl, substituted or —C-C2 alkyl. In another aspect, R" is optionally substituted unsubstituted heteroaryl, aryloxy, Substituted amide, Sulfone, —C-C, alkenyl. In a further aspect, R" is optionally substi Sulfonamide and C-C, cycloalkyl, wherein said aryl, het tuted —Ca-Cia alkynyl. In another aspect, R" is optionally eroaryl or cycloalkyl ring(s) are attached or fused to the substituted—(CR),aryl. Inafurther aspect, R" is optionally aromatic; R is selected from the group consisting of hydro substituted —(CR), cycloalkyl. In another aspect, R" is gen, halogen, and Substituted or unsubstituted C-C alkyl, R' optionally substituted —(CR), heterocycloalkyl. and Rare each independently selected from the group con 0789. In one aspect, R is selected from the group consist sisting of halogen and Substituted or unsubstituted —C-C, ing of -OH,-OC(O)R, —OC(O)OR", –F, and - NHC alkyl; and R is selected from the group consisting of hydro (O)R. In an additional aspect, R" is optionally substituted gen, fluoro, chloro, amino, hydroxyl, and—OCHs; then R is —OC-C alkyl. In another aspect, R is —OC(O)R. In a not hydroxyl, optionally substituted —OC-Calkyl, or further aspect, R is OC(O)OR". In another aspect, R is OC(O)R. —F. In another aspect, R is NHC(O)R. Inafurtheraspect, 0795. In an additional aspect, Tis-N(H)C(O)–: R' and R is NHS(=O)R. In another aspect, R' is NHS(=O) Rare each independently selected from the group consisting R. In a further aspect, R is of iodo, bromo, chloro, methyl, and cyano; R is selected from NHC(S)NH(R' ). In another aspect, R is NHC(O)NH the group consisting of hydrogen and iodo; R is selected (R"). from the group consisting of H and OC(O)R: R is 0790. In one aspect, X is selected from the group consist selected from the group consisting of iodo, bromo, optionally ing of POH, -P(O) OCR OC(O)R’ -P(O)— Substituted—C-C alkyl, optionally Substituted —CH2aryl, OCROC(O)OR'', - P(O) N(H)CRC(O)CRT, optionally substituted —CH(OH)aryl, —C(O)-amido, - P(O) N(H)CRC(O)ORT OR'', and P(O) —S(=O)-amido, wherein the amido group is selected from OCH(V) CHCHO I, wherein V is selected from the group the group consisting of phenethylamino, piperidinyl, 4-met consisting of optionally Substituted aryl, aryl, heteroaryl, and hypiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and optionally substituted heteroaryl. indolinyl, and—SOR wherein R is selected from the group 0791) In another aspect, R is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, and consisting of hydrogen, fluoro, chloro, amino, hydroxyl, and 4-pyridyl; and R is selected from the group consisting of —O CH. hydrogen and fluoro. US 2009/011 8236 A1 May 7, 2009

0796. In an additional aspect, T is —N(H)C(O)—: G is (CH)C(O)OCHCH, -P(O) N(H)C(CH),C(O) —O : R and R are each chloro; R is hydrogen; R is OCHCH, -P(O) N(H)CH(CH)C(O)OCHCH-3, —OH: R is -iso-propyl; and R is fluoro. 4-methylenedioxyphenyl), —P(O) N(H)C(CH),C(O) 0797. In an additional aspect, T is N(H)C(O) ; G is OCHCH3.4-methylenedioxyphenyl), and —P(O)— —O : R* and R are each chloro; R is hydrogen; R is OCH(3-chlorophenyl)CHCHO . —OH: R is -iso-propyl; R is fluoro; X is selected from the (0804) Inafurther aspect, T is —CHCH. : RandR are group consisting of POH, -P(O)—OCHOC(O)-t-bu each independently selected from the group consisting of tyl, -P(O) OCHOC(O)O-i-propyl, -P(O) N(H) iodo, bromo, chloro, methyl, and cyano; R is selected from CH(CH)C(O)OCHCH, -P(O) N(H)C(CH),C(O) the group consisting of hydrogen and iodo; R is selected OCHCH, -P(O) N(H)CH(CH)C(O)OCHCH-3, from the group consisting of OH and —OC(O)R: R is 4-methylenedioxyphenyl, - P(O) N(H)C(CH),C(O) selected from the group consisting of iodo, bromo, optionally OCH2CH3.4-methylenedioxyphenyl, and —P(O)— Substituted C-C alkyl, optionally substituted —CHaryl, OCH(3-chlorophenyl)CHCH-O-). optionally substituted —CH(OH)aryl, —C(O)-amido, 0798. In another aspect, T is OCH ; R and Rare —S(—O)-amido, wherein the amido group is selected from each independently selected from the group consisting of the group consisting of phenethylamino, piperidinyl, 4-me iodo, bromo, chloro, methyl, and cyano; R is selected from thylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and the group consisting of hydrogen and iodo; R is selected indolinyl, and—SOR wherein R is selected from the group from the group consisting of OH, and —OC(O)R: R is consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, and selected from the group consisting of iodo, bromo, optionally 4-pyridyl; and R is selected from the group consisting of Substituted C-C alkyl, optionally Substituted —CH2aryl, hydrogen and fluoro. optionally substituted —CH(OH)aryl, —C(O)-amido, 0805. In another aspect, T is —CH2CH2—: G is —O—: —S(=O)-amido, wherein the amido group is selected from the group consisting of phenethylamino, piperidinyl, 4-me R" and Rare each chloro; R is hydrogen; R is OH: R is thylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and iso-propyl; and R is fluoro. 0806. In another aspect, T is —CH2CH2—: G is —O—: indolinyl, and—SOR wherein R is selected from the group R" and Rare each chloro; R is hydrogen; R is OH: R is consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, and iso-propyl; R is fluoro; and X is selected from the group 4-pyridyl; and R is selected from the group consisting of consisting of —POH, -P(O)—OCHOC(O)-t-butyl, hydrogen and fluoro. -P(O) OCHOC(O)O-i-propyl, -P(O) N(H)CH 0799. In another aspect, T is OCH : G is - O -; R' (CH)C(O)OCHCH - P(O) N(H)C(CH),C(O) and Rare each chloro; R is hydrogen; R is OH: R is OCHCH, -P(O) N(H)CH(CH)C(O)CCHCH-3, iso-propyl; and R is fluoro. 4-methylenedioxyphenyl), —P(O) N(H)C(CH),C(O) (0800. In another aspect, T is OCH ; G is —O ; R' OCHCH3.4-methylenedioxyphenyl). and Rare each chloro; R is hydrogen; R is OH: R is iso-propyl; R is fluoro; and X is selected from the group and - P(O)—OCH(3-chlorophenyl)CHCHO ). consisting of —POH, -P(O)—OCHOC(O)-t-butyl, (0807. In another aspect, T is NHCH. : R and Rare -P(O) OCHOC(O)O-i-propyl, -P(O) N(H)CH each independently selected from the group consisting of (CH)C(O)OCHCH, -P(O) N(H)C(CH),C(O) iodo, bromo, chloro, methyl, and cyano; R is selected from OCHCH, -P(O) N(H)CH(CH)C(O)OCHCH-3, the group consisting of hydrogen and iodo; R is selected 4-methylenedioxyphenyl), —P(O)—N(H)C(CH),C(O) from the group consisting of OH, and —OC(O)R: R is OCHCH3.4-methylenedioxyphenyl). selected from the group consisting of iodo, bromo, optionally and —P(O)—OCH(3-chlorophenyl)CHCHO . Substituted C-C alkyl, optionally substituted —CH2aryl, (0801. In an additional aspect, T is —CH2—, RandR are optionally substituted —CH(OH)aryl, —C(O)-amido, each independently selected from the group consisting of —S(=O)-amido, wherein the amido group is selected from iodo, bromo, chloro, methyl, and cyano; R is selected from the group consisting of phenethylamino, piperidinyl, 4-me the group consisting of hydrogen and iodo; R is selected thylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and from the group consisting of OH, and —OC(O)R: R is indolinyl, and—SOR wherein R is selected from the group selected from the group consisting of iodo, bromo, optionally consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, and Substituted C-C alkyl, optionally substituted —CHaryl, 4-pyridyl; and R is selected from the group consisting of optionally substituted —CH(OH)aryl, —C(O)-amido, hydrogen and fluoro. —S(=O)-amido wherein the amido group is selected from 0808. In yet another aspect, T is NHCH. : G is —O—: the group consisting of phenethylamino, piperidinyl, 4-me R" and R are each chloro; R is selected from the group thylpiperizinyl, morpholinyl, cyclohexylamino, anilinyl, and consisting of hydrogen and iodo Ris—OH: R is iso-propyl; indolinyl, and—SOR" wherein R is selected from the group and R is fluoro. consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, and (0809. In another aspect, T is NHCH-: G is - O -; R' 4-pyridyl; and R is selected from the group consisting of and Rare each bromo; R is selected from the group consist hydrogen and fluoro. ing of hydrogen and iodo Ris-OH: R is iso-propyl; and R' 0802. In an additional aspect, T is —CH2—, G is —O—: is fluoro. R" and Rare each chloro; R is hydrogen; R is OH: R is 0810. In another aspect, T is NHCH. : G is —O : R' i-propyl; and R is fluoro. and Rare each bromo; R is selected from the group consist 0803. In an additional aspect, T is —CH : G is —O : ing of hydrogen and iodo R is —OH: R is iso-propyl; R is R" and Rare each chloro; R is hydrogen; R is OH: R is fluoro; and X is selected from the group consisting of i-propyl; R is fluoro; and X is selected from the group con sisting of —POH, -P(O)—OCHOC(O)-t-butyl, -P(O) OCHOC(O)O-i-propyl, -P(O) N(H)CH US 2009/011 8236 A1 May 7, 2009 52

-P(O) N(H)CH(CH)C(O)OCH2CH3.4-methylene carbonatom; and X is attached to this ring by a direct bond to dioxyphenyl), -P(O) N(H)C(CH),C(O)OCHCH-3, a ring carbon, or by —CR)-bonded to a ring carbon or a ring 4-methylenedioxyphenyl, nitrogen; and - P(O)—OCH(3-chlorophenyl) CHCHO . 0824) R' is selected from the group consisting of hydro 0811. In a further aspect, X is —POH. gen, —C(O)C-C alkyl, -C-C alkyl, and —C-C-aryl; 0812. In a further aspect of the invention, the invention 0825 Rand Rare each independently selected from the relates to compounds of Formula VIII: group consisting of hydrogen, halogen, —CF, —OCF, cyano, optionally Substituted—C-C alkyl, optionally Sub stituted —C-C alkenyl, optionally Substituted —C-C2 Formula VIII alkynyl, optionally substituted —(CR), aryl, optionally R3 R8 R2 R6 Substituted —(CR), cycloalkyl, optionally Substituted —(CR), heterocycloalkyl, -OR. -SR, -S(=O)R, R5 G T-X S(=O).R., S(=O)NR'Rs, C(O)NR'Rs, C(O) OR, C(O)R, N(R)C(O)R, N(R)C(O)NR'Rs, N(R)S(=O).R, N(R)S(=O)NR'Rs, and NR: Rs: R4 R9 RI R7 (0826) Each R" is selected from the group consisting of optionally substituted—C-C alkyl, optionally substituted wherein: —C-C alkenyl, optionally Substituted —C-C alkynyl, 0813) G is selected from the group consisting of —O , optionally substituted —(CR),aryl, optionally substituted —S , —S(=O) s S(=O) s Se s CH s —(CR), cycloalkyl, optionally substituted —(CR).het CF, , —CHF , —C(O)—, —CH(OH)—, —CH(C-C, erocycloalkyl, and –C(O)NR'R'': alkyl)-, -CH(C-C alkoxy)-, —C(=CH-)— —NH-, and 0827. Each R is selected from the group consisting of —N(C-C alkyl)-; optionally Substituted—C-C alkyl, optionally Substituted 0814 T is selected from the group consisting of (CR) —C-C alkenyl, optionally Substituted —C-C alkynyl, , —CR'—CR (CR), , —(CR), CR”—CR” , optionally substituted —(CR), aryl, optionally substituted —(CR) CR-CR (CR)— —O(CR)(CR), , —(CR), cycloalkyl, and optionally Substituted —(CR) —S(CR)(CR")—, N(R)(CR)(CR), , – N(R)C heterocycloalkyl: (O)(CR), , —(CR), CH(NRR) , C(O)(CR), , (0828 RandR are each independently selected from the —(CR"),C(O) , (CR")C(O)(CR), , –(CR"),C(O) group consisting of hydrogen, optionally substituted —C- (CR",)—, and –C(O)NH(CR')(CR") ; Calkyl, optionally Substituted—C-Calkenyl, optionally 08.15 k is an integer from 0-4: Substituted —C-C alkynyl, optionally Substituted 08.16 m is an integer from 0-3: —(CR),aryl, optionally substituted —(CR), cycloalkyl, 0817 n is an integer from 0-2: and optionally substituted —(CR), heterocycloalkyl, or R 0818 p is an integer from 0-1; and R may together form an optionally substituted hetero 0819. Each R" is independently selected from the group cyclic ring, said heterocyclic ring may contain a second het consisting of hydrogen, optionally Substituted—C-C alkyl, erogroup within the ring selected from the group consisting of halogen, —OH, optionally Substituted —O—C-C alkyl, O, NR, and S, wherein said optionally substituted heterocy —OCF, optionally substituted S C-C alkyl, NRR, clic ring may be substituted with 0-4 substituents selected optionally substituted —C-C alkenyl, and optionally sub from the group consisting of optionally Substituted—C-C, stituted—C-C alkynyl; with the proviso that when one R is alkyl, -OR. Oxo, cyano. —CF, optionally substituted phe attached to C through an O, S, or Natom, then the other R' nyl, and –C(O)OR"; attached to the same C is a hydrogen, or attached via a carbon (0829. Each R" is selected from the group consisting of atom; optionally substituted—C-C alkyl, optionally substituted 0820 Each R is independently selected from the group —C-C alkenyl, optionally Substituted —C-C alkynyl, consisting of hydrogen and optionally substituted —C-C, optionally substituted —(CR),aryl, optionally substituted alkyl: —CR), cycloalkyl, and optionally substituted —(CR) 0821. Each R is independently selected from the group heterocycloalkyl; consisting of hydrogen and optionally substituted —C-C, 0830 R is selected from the group consisting of —OH, alkyl, optionally substituted —C(O)—C-C alkyl, and optionally substituted —OC-C alkyl, —OC(O)R. —OC C(O)H: (O)OR, F, NHC(O)R, NHS(—OR, NHS(—O) 0822 R', R. R. R. R. and Rare each independently R, NHC(=S)NH(R'), and NHC(O)NH(R'); selected from the group consisting of hydrogen, halogen, 0831 X is P(O)YR''Y'R'" ; optionally Substituted —C-C alkyl, optionally Substituted 0832 Y and Y are each independently selected from the —S C-C alkyl, optionally substituted —C-C alkenyl, group consisting of O—, and —NR'—, when Y and Y are optionally Substituted —C-C alkynyl. —CF, —OCF, —O—, R'' attached to —O—is independently selected from optionally substituted-O-C-C alkyl, and cyano; with the the group consisting of —H, alkyl, optionally substituted proviso that at least one of R' and R is not hydrogen; aryl, optionally Substituted heterocycloalkyl, optionally Sub 0823) or Rand T are taken together along with the car stituted CH-heterocycloaky1 wherein the cyclic moiety con bons they are attached to form a ring of 5 to 6 atoms 0 to 2 tains a carbonate or thiocarbonate, optionally substituted heteroatoms independently selected from NR' , —O , -alkylaryl, -C(R),OC(O)NR, NR C(O) R', and —S , with the proviso that when there are 2 heteroat - C(R) OC(O)R’, C(R) O C(O)OR, C(R) oms in the ring and both heteroatoms are different than nitro OC(O)SR, -alkyl-S C(O)R’, -alkyl-S-S-alkylhydroxy, gen then both heteroatoms have to be separated by at least one and -alkyl-S S S-alkylhydroxy: US 2009/011 8236 A1 May 7, 2009

0833 when Y and Y are NR' , then R'' attached to 0842 Z is selected from the group consisting of —CHR —NR'—is independently selected from the group consisting *OH, CHROC(O)R’, CHROC(S)R’, CHROC(S) of -H, -IC(R), COOR, C(R)-COOR, C(R), OR, CHROC(O)SR, CHROCOR, OR, SR, C(O)SR', and -cycloalkylene-COOR'; —CHRN, -CHaryl, -CH(aryl)OH, -CH(CH=CR) 0834 when Yis-O- and Y is NR', then R'' attached to OH, -CH(C=CR)OH, R, NR, OCOR', —O—is independently selected from the group consisting of –OCOR', SCOR, SCOR, NHCOR, —H, alkyl, optionally substituted aryl, optionally substituted —NHCO.R, -CH-NHaryl, -CH), OR, and -(CH.) heterocycloalkyl, optionally substituted CH-heterocy SR; cloakyl wherein the cyclic moiety contains a carbonate or 0843 q is an integer 2 or 3: thiocarbonate, optionally substituted -alkylaryl, —C(R)-C 0844. Each R is selected from the group consisting of R' (O)NR, NR C(O) R', C(R), OC(O)R’, and —H; —C(R) O C(O)OR, C(R),OC(O)SR, -alkyl-S-C 0845 Each R" is selected from the group consisting of (O)R’, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alky alkyl, aryl, heterocycloalkyl, and aralkyl; lhydroxy; and R'' attached to NR— is independently 0846. Each R is independently selected from the group selected from the group consisting of -H, -IC(R), consisting of —H, and alkyl, or together R and R form a COOR, C(R)-COOR. -IC(R), C(O)SR', and -cy cyclic alkyl group; cloalkylene-COOR: 0847 Each R is selected from the group consisting of 0835 or when Y and Y are independently selected from —H. lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and —O— and NR' , then together R'' and R'' are -alkyl lower acyl. S S-alkyl- to form a cyclic group, or together R'' and R' 0848 with the provisos that: are the group: 0849 a) V, Z, W, Ware not all-H; and 0850 b) when Zis-R, then at least one of V, W, and W. is not—H, alkyl, aralkyl, or heterocycloalkyl. H 0851. In one aspect, when G is —O , T is —CH2—, R' and Rare each bromo, R is iso-propyl, R' is hydrogen, and Z R is OH, then X is not P(O)(OH) or P(O)(OCHCH). In H another aspect, when G is -O-, T is -(CH2). , R' and Rare independently halogen, alkyl of 1 to 3 carbons, and W cycloalkyl of 3 to 5 carbons, R is alkyl of 1 to 4 carbons or W cycloalkyl of 3 to 7 carbons, R is hydrogen, and R is -OH, then X is not - P(O)(OH), or - P(O)(O lower alkyl). In a wherein: further aspect, when Gis-O-, R is NHC(O)R, NHS 0836 V, W, and W are independently selected from the (=O) R, NHC(S)NH(R'), or NHC(O)NH(R'), T is group consisting of hydrogen, optionally Substituted alkyl, —(CH), , —CH=CH-. —O(CH) , or optionally substituted aralkyl, heterocycloalkyl, aryl, Substi - NH(CH) , then X is not-P(O)(OH), or -P(O)(OH) tuted aryl, heteroaryl, substituted heteroaryl, optionally sub NH. stituted 1-alkenyl, and optionally substituted 1-alkynyl: 0852. In one aspect, G is selected from the group consist 0837 or together V and Z are connected via an additional ing of —O— and —CH2—. In a further aspect, G is —O—. 3-5 atoms to form a cyclic group containing 5-7 atoms, In another aspect, G is —S—. In a further aspect, G is wherein 0-1 atoms are heteroatoms and the remaining atoms —S(=O)—. In another aspect, G is —S(=O)—. In a fur are carbon, Substituted with hydroxy, acyloxy, alkylthiocar ther aspect, G is —CH2—. In another aspect, G is —CF-. bonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy In a further aspect, G is —CHF . In another aspect, G is attached to a carbon atom that is three atoms from both Y —C(O)—. In another aspect, G is —CH(OH)—. In a further groups attached to the phosphorus; or aspect, G is —NH-. In another aspect, G is —N(C-C, 0838 or together V and Z are connected via an additional alkyl)-. In yet another aspect, G is —Se—. In another aspect, 3-5 atoms to form a cyclic group, wherein 0-1 atoms are G is —CH(C-C alkyl)-. In another aspect, Gis —CH(C-C, heteroatoms and the remaining atoms are carbon, that is fused alkoxy)-. In another aspect, G is —C(=CH-)—, to an aryl group at the beta and gamma position to the Y 0853. In another aspect, T is selected from the group con attached to the phosphorus; sisting of (CR), O(CR'2)(CR'2) , N(R)(CR) 0839 or together V and Ware connected via an additional (CR) , S(CR)(CR) , NR(CO) , and 3 carbonatoms to forman optionally Substituted cyclic group —CH-CH(NRR)—. In a further aspect, T is —(CR), . containing 6 carbon atoms and Substituted with one substitu In another aspect, Tis-CR'—CR' (CR), . Inafurther ent selected from the group consisting of hydroxy, acyloxy, aspect, T is —(CR), CR'—CR -. In another aspect, T is alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycar —(CR")—CR'—CR' (CR)-. In a further aspect, T is bonyloxy, attached to one of said carbon atoms that is three —O(CR)(CR), . In another aspect, T is S(CR) atoms from a Y attached to the phosphorus: (CR), . In a further aspect, T is N(CR)(CR), . In 0840 or together Z and Ware connected via an additional another aspect, T is —N(R)C(O)(CR), . In a further 3-5 atoms to form a cyclic group, wherein 0-1 atoms are aspect, T is —(CR), CH(NRR)—. In another aspect, T is heteroatoms and the remaining atoms are carbon, and V must —C(O)(CR), . In a further aspect, T is —(CR),C be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; (O)—. In another aspect, T is —(CR")C(O)(CR)ft. In a 0841 or together W and W are connected via an addi further aspect, T is —(CR),C(O)(CR)—. In yet another tional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are aspect, T is C(O)NH(CR)(CR) . heteroatoms and the remaining atoms are carbon, and V must 0854. In one aspect k is 0. In a further aspect, k is 1. In an be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; additional aspect, k is 2. In a further aspect, k is 3. In yet US 2009/011 8236 A1 May 7, 2009 54 another aspect, k is 4. In one aspect m is 0. In a further aspect, each optionally substituted-O C-C alkyl. In a further m is 1. In an additional aspect, m is 2. In a further aspect, m is aspect, R. R. R. R. R. and Rare each cyano. 3. In one aspect n is 0. In a further aspect, n is 1. In an 0860. In one aspect, Rand T are taken together along with additional aspect, n is 2. In one aspect, p is 0. In another the carbons they are attached to form a ring of 5 to 6 atoms aspect, p is 1. containing 0 to 2 unsaturations and 0 to 2 heteroatoms inde 0855. In one aspect, each R" is hydrogen with the proviso pendently selected from —NR , —O—, and - S - with that when one R is attached to C through an O, S, or Natom, the proviso that when there are 2 heteroatoms in the ring and then the other R attached to the same C is a hydrogen, or both heteroatoms are different than nitrogen then both het attached via a carbon atom. In another aspect, each R" is eroatoms have to be separated by at least one carbon atom; optionally substituted —C-C alkyl with the proviso that and X is attached to this ring to either a carbon or a nitrogen when one R is attached to C through an O, S, or Natom, then by either —CR)— or —(O)— or a bond if X is attached the other Rattached to the same C is a hydrogen, or attached directly to a carbon atom. In one aspect, Rand T are taken via a carbonatom. In a further aspect, each R" is halogen with together along with the carbons they are attached to form a the proviso that when one R is attached to C through an O, S, ring of 5 to 6 atoms containing 0 unsaturations. In another or N atom, then the other R' attached to the same C is a aspect, R and T are taken together along with the carbons hydrogen, or attached via a carbon atom. In another aspect, they are attached to form a ring of 5 to 6 atoms containing 1 each R" is —OH with the proviso that when one R is attached unsaturation. R and T are taken together along with the to C through an O, S, or Natom, then the other Rattached to carbons they are attached to form a ring of 5 to 6 atoms the same C is a hydrogen, or attached via a carbon atom. In a containing 2 unsaturations. In one aspect, 0 to 2 heteroatoms further aspect, each R" is optionally substituted—O C-C, are —NR -. In another aspect, 0 to 2 heteroatoms are alkyl with the proviso that when one R is attached to C —O—. In another aspect, 0 to 2 heteroatoms are —S—. through an O, S, or Natom, then the other R' attached to the 0861. In one aspect, R is hydrogen. In another aspect, R is same C is a hydrogen, or attached via a carbon atom. In —C(O)C1-C4 alkyl. In another aspect, Ris-C-C alkyl. In another aspect, each R" is —OCF with the proviso that when a further aspect, R is —C-C-aryl. one R is attached to C through an O, S, or Natom, then the 0862. In yet another aspect, RandR are each hydrogen. other Rattached to the same C is a hydrogen, or attached via In another aspect, R and R are each halogen. In a further a carbon atom. In a further aspect, each R is optionally aspect, RandR are each —CF. In another aspect, R and substituted—S C-C alkyl with the proviso that when one Rare each —OCF. In a further aspect, Rand Rare each R" is attached to C through an O, S, or Natom, then the other cyano. In another aspect, Rand Rare each optionally sub R attached to the same C is a hydrogen, or attached via a stituted—C-C alkyl. In a further aspect, RandR are each carbon atom. In another aspect, each R" is NR'R' with the optionally Substituted —C-C alkenyl. In another aspect, proviso that when one R is attached to C through an O, S, or R and Rare each optionally substituted—C-C alkynyl. Natom, then the other Rattached to the same C is a hydro In a further aspect, Rand Rare each optionally substituted gen, or attached via a carbonatom. In a further aspect, each R' —(CR), aryl. In another aspect, Rand Rare each option is optionally substituted —C-C alkenyl with the proviso ally substituted —(CR).cycloalkyl. In a further aspect, R that when one R is attached to C through an O, S, or Natom, and R are each optionally substituted CR"), heterocy then the other R' attached to the same C is a hydrogen, or cloalkyl. In another aspect, R and R are each —OR". In attached via a carbon atom. In another aspect, each R" is another aspect, RandR are each - SR". In a further aspect, optionally substituted—C-C alkynyl with the proviso that Rand Rare each–S(=O)R. In another aspect, RandR when one R is attached to C through an O, S, or Natom, then are each - S(=O).R. In a further aspect, Rand Rare each the other R' attached to the same C is a hydrogen, or attached —S(=O)NR'R's. In another aspect, R and R' are each via a carbon atom. —C(O)NR'R''. In a further aspect, RandR are each–C(O) 0856. In one aspect, R is hydrogen. In an additional OR". In another aspect, R and Rare each –C(O)R. In a aspect, R is optionally substituted—C-C alkyl. further aspect, R' and Rare each - N(R)C(O)R. In another 0857. In one aspect, R is hydrogen. In another aspect, R aspect, Rand Rare each - N(R)C(O)NR'R''. In a further is optionally substituted—C-C alkyl. In a further aspect, R aspect, R and R are each - N(R)S(=O).R. In another is optionally substituted—C(O)—C-C alkyl. In yet another aspect, RandR are each-N(R)S(=O)NR'R''. Inafurther aspect, R is —C(O)H. aspect, R and Rare each - NR/R3. 0858. In a further aspect, R' and Rare the same and are 0863. In another aspect, R is selected from the group selected from the group consisting of halogen, —C-C alkyl, consisting of hydrogen, halogen, —C-C alkyl, cyano and —CF, and cyano. In yet another aspect, R' and Rare dif CF. In a further aspect, R' is selected from the group con ferent and are selected from the group consisting of halogen, sisting of halogen, optionally Substituted —C-C alkyl, —C-C alkyl, -CFs, and cyano. In an additional aspect, R' —CFs, cyano, -q(O)NR'R'', optionally substituted —(CR) and Rare each halogen. In another aspect, R. R. R. R. R. aryl, -SONR'Rs, and -SO.R. and R are each optionally substituted —C-C alkyl. In a 10864. In another aspect, each R" is optionally substituted further aspect, R. R. R. R. R. and Rare each optionally —C-C2 alkyl. In a further aspect, each R" is optionally substituted—S C-C alkyl. In another aspect, R', R. R. substituted —C-C, alkenyl. In another aspect, each R" is R. R. and Rare each optionally substituted—C-C alk optionally substituted—C-C alkynyl. In a further aspect, enyl. In a further aspect, R. R. R. R. R. and Rare each each R" is optionally substituted —(CR),aryl. In another optionally Substituted—C-C alkynyl. aspect, each R" is optionally substituted —(CR),cy 0859. In another aspect,R,R,R,R,R, and Rare each cloalkyl. In a further aspect, each R" is optionally substituted —CF. In a further aspect, R. R. R. R. R. and Rare each —(CR).heterocycloalkyl. In another aspect, each R" is –OCF. In another aspect, R. R. R. R. R. and Rare C(O)NR'R8. US 2009/011 8236 A1 May 7, 2009

0865. In an additional aspect, R is optionally substituted above permutations may be specifically set forth as for inclu —C-C alkyl. In another aspect, R is optionally substituted sion or specifically may be excluded from the present inven —C-C alkenyl. In a further aspect, R is optionally Substi tion. tuted —C-C alkynyl. In another aspect, R is optionally 0871. In an additional aspect, this invention relates to For substituted—(CR), aryl. Inafurther aspect, R is optionally mulas I, II, III, or VIII wherein X is P(O)YR''Y'R''. substituted —(CR)cycloalkyl. In another aspect, R is 0872. In one aspect, Y and Y are each independently optionally substituted —(CR).heterocycloalkyl. selected from the group consisting of —O—, and —NR'—. 0866. In one aspect, Rand R are each hydrogen. In an In another aspect, Y and Y are each independently selected additional aspect, R and Rs are each optionally substituted from the group consisting of —O—, and —NR'—, when Y —C-C2 alkyl. In another aspect, RandR are each option and Y are —O , R'' attached to —O— is —H, alkyl. In ally substituted—C-C, alkenyl. In an additional aspect, R another aspect, Yand Y are each independently selected from and Rare each optionally Substituted—C-C alkynyl. In a the group consisting of O—, and —NR' ; when Y and Y further aspect, R and Rs are each optionally substituted are —O R'' attached to - O - is optionally substituted —(CR), aryl. In an additional aspect, R and R are each aryl. In another aspect, Y and Y are each independently optionally substituted —(CR), cycloalkyl. In another selected from the group consisting of —O—, and —NR'—; aspect, R and Rs are each optionally substituted —(CR) when Y andYare-O , R'' attached to —O—is optionally heterocycloalkyl. substituted heterocycloalkyl. In a further aspect, Y and Y are 0867. In an additional aspect, RandR may togetherform each independently selected from the group consisting of an optionally Substituted heterocyclic ring, which may con —O , and NR' ; when Y andYare —O , R'' attached tain a second heterogroup which is O. In another aspect, R to —O— is optionally substituted CH-heterocycloakyl. In and R may together form an optionally substituted hetero one aspect, the cyclic moiety contains a carbonate or thiocar cyclic ring, which may contain a second heterogroup which is bonate. In another aspect, the cyclic moiety contains option NR. In another aspect, R and R may together form an ally Substituted -alkylaryl. In another aspect, the cyclic moi optionally substituted heterocyclic ring, which may contain a ety contains a C(R),OC(O)NR. In another aspect, the second heterogroup which is S. In one aspect, RandR may cyclic moiety contains—NR C(O)—R'. In another aspect, together form an unsubstituted heterocyclic ring, which may the cyclic moiety contains —C(R). OC(O)R’. In another contain a second heterogroup. In another aspect, the option aspect, the cyclic moiety contains —C(R) O—C(O)OR”. ally substituted heterocyclic ring may be substituted with 1 In a further aspect, the cyclic moiety contains —C(R)OC Substituent selected from the group consisting of optionally (O)SR. In another aspect, the cyclic moiety contains -alkyl substituted —C-C alkyl, -OR''. Oxo, cyano, —CFs, S C(O)R’. In another aspect, the cyclic moiety contains optionally substituted phenyl, and —C(O)OR". In further -alkyl-S-S-alkylhydroxy. In a further aspect, the cyclic moi aspect, the optionally Substituted heterocyclic ring may be ety contains -alkyl-S-S-S-alkylhydroxy. substituted with 2 substituents selected from the group con 0873. In yet another aspect, Y and Y are - NR' . In sisting of optionally substituted—C1-C4 alkyl, -OR. Oxo, another aspect, whenY and Y are NR' , then R'' attached cyano. —CF, optionally substituted phenyl, and —C(O) to —NR' is —H. In a further aspect, when Y and Y are OR". In another aspect, the optionally substituted heterocy NR' , then R'' attached to NR is -IC(R), clic ring may be substituted with 3 substituents selected from COOR. In another aspect, when Y and Y are - NR' , then the group consisting of optionally Substituted—C-C alkyl, R'' attached to NR' is C(R)-COOR. In a further —OR''. Oxo, cyano, -CFs, optionally substituted phenyl, aspect, when Y and Y are NR' , then R'' attached to and —C(O)OR". In a further aspect, the optionally substi NR—is-C(R), C(O)SR. In another aspect, when Y tuted heterocyclic ring may be substituted with 4 substituents and Y are NR' , then R'' attached to NR— is -cy selected from the group consisting of optionally Substituted cloalkylene-COOR. —C-C alkyl, -OR''. Oxo, cyano. —CFs, optionally substi 0874) In one aspect, Y is - O - and Y is NR. In another tuted phenyl, and C(O)OR". aspect, when Y is —O— and Y is NR', then R'' attached to 0868. In a further aspect, R" is optionally substituted —O— is —H. In a further aspect, when Y is —O— and Y is —C-C2 alkyl. In another aspect, R" is optionally substituted NR', then R'' attached to —O— is alkyl. In another aspect, —C-C2 alkenyl. In a further aspect, R" is optionally substi when Y is - O - and Y is NR, then R'' attached to -O- tuted —C-C2alkynyl. In another aspect, R" is optionally is optionally substituted aryl. In a further aspect, when Y is substituted—(CR),aryl. Inafurther aspect, R" is optionally —O—and Y is NR', then R'' attached to —O is optionally substituted heterocycloalkyl. In another aspect, when Y is substituted —(CR), cycloalkyl. In another aspect, R" is —O—and Y is NR', then R'' attached to —O is optionally optionally substituted —(CR), heterocycloalkyl. Substituted CH-heterocycloakyl. In one aspect, the cyclic 0869. In one aspect, R is selected from the group consist moiety contains a carbonate or thiocarbonate. In another ing of -OH, -OC(O)R, OC(O)CR', F, and NHC aspect, the cyclic moiety contains optionally Substituted (O)R. In an additional aspect, R is optionally substituted -alkylaryl. In another aspect, the cyclic moiety contains —OC-C alkyl. In another aspect, R is —OC(O)R. In a —C(R)OC(O)NR. In another aspect, the cyclic moiety further aspect, R is —OC(O)OR". In another aspect, R is contains —NR C(O)—R''. In another aspect, the cyclic —F. In another aspect, Ris—NHC(O)R. Inafurtheraspect, moiety contains—C(R). OC(O)R’. In another aspect, the R is NHS(=O)R. In another aspect, R is NHS(=O) cyclic moiety contains—C(R), O C(O)OR". In a further R. In a further aspect, R is aspect, the cyclic moiety contains —C(ROC(O)SR. In NHC(=S)NHR'. ). In another aspect, R is NHC(O)NH another aspect, the cyclic moiety contains -alkyl-S C(O)R’. (R'). In another aspect, the cyclic moiety contains -alkyl-S-S- 0870. Each of the individual species of compounds of alkylhydroxy. In a further aspect, the cyclic moiety contains Formula III which can be generated by making all of the -alkyl-S-S-S-alkylhydroxy. US 2009/011 8236 A1 May 7, 2009 56

0875. In another aspect, when Y is - O - and Y is NR', groups attached to the phosphorus. Inafurther aspect, the ring and R'' attached to NR is H. In a further aspect, when is substituted with aryloxycarbonyloxy attached to a carbon Y is - O - and Y is NR', and R'' attached to NR is atom that is three atoms from both Y groups attached to the —IC(R), COOR. In another aspect, when Y is - O - phosphorus. and Y is NR', and R'' attached to NR is C(R) 0884. In yet another aspect, together V and Z are con COOR. In a further aspect, when Y is - O - and Y is NR7, nected via an additional 3-5 atoms to form a cyclic group, and R' attached to NR' is -IC(R), C(O)SR. In wherein 0-1 atoms are heteroatoms and the remaining atoms another aspect, when Y is —O— and Y is NR', and R' are carbon, that is fused to an aryl group at the beta and attached to NR— is -cycloalkylene-COOR. gamma position to the Y attached to the phosphorus. 0876. In another aspect, Y and Y are independently 0885. In a further aspect, together V and Ware connected selected from O and NR' , then together R'' and R' via an additional 3 carbon atoms to form an optionally Sub are -alkyl-S-S-alkyl- to form a cyclic group. stituted cyclic group containing 6 carbon atoms and Substi 0877. In one aspect, Y and Y are independently selected tuted with one substituent. In one aspect, the substituent is from —O— and NR'—and together R'' and R'' are the hydroxyl that is attached to one of said carbon atoms that is group: three atoms from a Y attached to the phosphorus. In another aspect, the Substituent is acyloxy 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 alkoxycar bonyloxy that is attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus. In another H. aspect, the Substituent is alkylthiocarbonyloxy that is attached to one of said carbon atoms that is three atoms from W a Y attached to the phosphorus. In another aspect, the Sub W stituent is aryloxycarbonyloxy that is attached to one of said carbon atoms that is three atoms from a Y attached to the 0878. In a further aspect, V is hydrogen. In another aspect, phosphorus. V is optionally substituted alkyl. In a further aspect, V is 0886. In another aspect, together Z and W are connected optionally substituted aralkyl. In another aspect, V is hetero via an additional 3-5 atoms to form a cyclic group, wherein cycloalkyl. In another aspect, V is aryl. In a further aspect, V 0-1 atoms are heteroatoms and the remaining atoms are car is substituted aryl. bon, and V must be aryl, substituted aryl, heteroaryl, or sub 0879. In another aspect, V is heteroaryl. In a further aspect, stituted heteroaryl. V is substituted heteroaryl. In another aspect, V is optionally 0887. In yet another aspect, together W and W are con substituted 1-alkenyl. In a further aspect, V is optionally nected via an additional 2-5 atoms to form a cyclic group, substituted 1-alkynyl. wherein 0-2 atoms are heteroatoms and the remaining atoms 0880. In a further aspect, W is hydrogen. In, another are carbon, and V must be aryl, substituted aryl, heteroaryl, or aspect, W is optionally substituted alkyl. In a further aspect, substituted heteroaryl. W is optionally substituted aralkyl. In another aspect, W is 0888. In one aspect, Z is —CHROH. In another aspect, Z heterocycloalkyl. In another aspect, W is aryl. In a further is CHROC(O)R’. In a further aspect, Z is CHROC(S) aspect, W is substituted aryl. R". In another aspect, Z is —CHROC(S)OR. In a further 0881. In another aspect, W is heteroaryl. In a further aspect, Z is —CHROC(O)SR. In another aspect, Z is aspect, W is substituted heteroaryl. In another aspect, W is - CHROCOR'. In a further aspect, Z is OR. In another optionally substituted 1-alkenyl. In a further aspect, W is aspect, Z is —SR. In a further aspect, Z is —CHRN. optionally substituted 1-alkynyl. 0889. In another aspect, Z is —CHaryl. In a further 0882. In a further aspect, W' is hydrogen. In another aspect, Z is —CH(aryl)OH. In another aspect, Z is —CH aspect, W is optionally substituted alkyl. In a further aspect, (CH=CR)OH. In another aspect, Z is CH(C=CR)OH. W is optionally substituted aralkyl. In another aspect, W is In a further aspect, Z is —R. In another aspect, Z is NR. heterocycloalkyl. In another aspect, W' is aryl. In a further In a further aspect, Z is —OCOR'. In another aspect, Z is aspect, W is substituted aryl. In another aspect, W is het —OCOR'. In a further aspect, Z is SCOR”. In another eroaryl. In a further aspect, W is substituted heteroaryl. In aspect, Z is —SCOR”. In a further aspect, Z is —NHCOR. another aspect, W' is optionally substituted 1-alkenyl. In a In another aspect, Z is NHCOR. In a further aspect, Z is further aspect, W' is optionally substituted 1-alkynyl. CH-NHaryl. In another aspect, Z is —(CH), OR. In a 0883. In one aspect, together V and Z are connected via an further aspect, Z is (CH),SR. additional 3-5 atoms to form a cyclic group containing 5-7 (0890. In one aspect R'' is not hydrogen. In one aspect, q is atoms, wherein 0-1 atoms are heteroatoms and the remaining 2. In a further aspect, q is 3. atoms are carbon. In one aspect, the ring is substituted with 0891. In one aspect, R is alkyl. In another aspect, R is hydroxyl attached to a carbon atom that is three atoms from aryl. In a further aspect, R is heterocycloalkyl. In another both Y groups attached to the phosphorus. In another aspect, aspect, R” is aralkyl. the ring is Substituted with acyloxy attached to a carbonatom 0892. In one aspect, R is —H. In another aspect, R is that is three atoms from both Y groups attached to the phos alkyl. In yet another aspect, together R and R form a cyclic phorus. In a further aspect, the ring is Substituted with alky alkyl group. lthiocarbonyloxy attached to a carbonatom that is three atoms (0893. In one aspect, R is H. In another aspect, R is from both Y groups attached to the phosphorus. In another lower alkyl. In another aspect, R is acyloxyalkyl. In another aspect, the ring is substituted with alkoxycarbonyloxy aspect, Risalkoxycarbonyloxyalkyl. In another aspect, R is attached to a carbon atom that is three atoms from both Y lower acyl. US 2009/011 8236 A1 May 7, 2009 57

0894. In one aspect, the present invention excludes 0900 5) - P(O)NH-CH(CH)C(O)CCHCH throughout unsubstituted lower alkyl diesters of X when X is 0901 6) - P(O)NH C(CH),C(O)OCHCH POH, e.g., where X is —P(O)(OCH2CH). 0902 7) - P(O)(OCHs), (0903) 8) -P(O)(O-CH(3-chlorophenyl)CHCH-O) Specific Compounds (0904. 9) -P(O)(O-CH(4-pyridyl)CHCH-O) 0895. In one aspect the following compounds are included Variable V: in the invention but the compounds are not limited to these illustrative compounds. The compounds are shown without (0905. 1)-CH depiction of Stereochemistry since the compounds are bio 0906. 2) OCH logically active as the diastereomeric mixture or as a single (0907 3)-CH, CH, Stereoisomer. Compounds named in Table 2 are designated by 0908. 4) NHCH numbers assigned to the variables of formulas V-VII using the (0909, 5) NH(CO) following convention: V.V.V.V. 0910 6) —CH2—CH(NH)—(R-configuration) 0911 7) —CH2—CH(NH)—(S-configuration) (0912. 8)-CH=CH- (trails) Formula V V3 0913 9)-null Variable V: HO O V2-VI (0914) 1) - Omethyl 0915. 2) iodo (0916. 3) bromo v4 V3 (0917 4) chloro Formula VI (0918 5) fluoro V3 0919 6) methyl 0920) 7) trifluoromethyl 0921) 8) cyano HO CH V2-VI 0922 9). OCF, Variable V: v4 V3 Formula VII 0923. 1) iodo 0924. 2) CH(CH), V3 0925, 3) CH 0926 4) CH 0927. 5) - C(O)NHCH HO SO V2-VI 0928 6)-CH(OH)(4-fluorophenyl) 0929 7) – SO(4-fluorophenyl) v4 V3 0930) 8) – SO(N-piperazinyl) 0931. 9) bromo In another aspect additional compounds are listed in Table 2 using Formula V. VI or VII. For example, the compound Variable V': 1.3.6.7 from Formula V represents the compound of Formula 0896) 1) P(O)(OH), V wherein V' is 1, i.e., of group V' is 1, i.e., of group -P(O) 0897 2) - P(O)IO CHOC(O)C(CH), (OH); V is 3, i.e., of group —CH, CH. : V is 6, i.e., of (0898 3) -P(O)IO CHOC(O)CH(CH), group methyl; and V* is 7, i.e., of group - SO(4-fluorophe 0899 4) - P(O)IO CHOC(O)CCHCH nyl).

TABLE 2 .1.1.1 1.1.1.2 .1.1.3 .1.1.4 11.5 .1.1.6 11.7 .1.1.8 .1.1.9 .1.2.1 .1.2.2 1.1.2.3 .1.2.4 12.5 .1.2.6 12.7 .1.2.8 .1.2.9 .1.3.1 .1.3.2 .1.3.3 1.1.3.4 13.5 .1.3.6 1.3.7 13.8 13.9 .1.4.1 .1.4.2 1.4.3 1.4.4 1.14.5 .1.4.6 1.4.7 1.4.8 1.4.9 1.5.1 15.2 15.3 .1.5.4 15.5 11.5.6 1.S.7 15.8 1.59 .1.6.1 .1.6.2 .1.6.3 .1.6.4 16.5 16.6 116.7 .1.6.8 16.9 1.7.1 17.2 1.7.3 1.7.4 1.7.5 1.7.6 1.7.7 11.7.8 17.9 .1.8.1 .1.8.2 18.3 .1.8.4 18.5 .1.8.6 18.7 18.8 11.8.9 .1.9.1 .1.9.2 19.3 .1.9.4 19.5 1.96 19.7 1.98 .1.9.9 1.2.1.1 .2.1.2 .2.1.3 .2.1.4 2.1.5 .2.1.6 2.17 .2.1.8 .2.1.9 .2.2.1 1.2.2.2 .2.2.3 .2.2.4 2.25 .2.2.6 22.7 .2.2.8 22.9 .2.3.1 2.32 1.2.3.3 .2.3.4 2.3.5 23.6 2.3.7 23.8 23.9 .2.4.1 .2.4.2 .2.4.3 1.2.4.4 .2.4.5 .2.4.6 24.7 .2.4.8 .2.4.9 2.5.1 25.2 2.5.3 2.5.4 12.5.5 2.56 2.5.7 25.8 25.9 .2.6.1 .2.6.2 2.6.3 .2.6.4 26.5 126.6 2.6.7 26.8 26.9 2.7.1 27.2 .2.7.3 27.4 2.7.5 .2.7.6 1.2.7.7 2.78 2.7.9 2.8.1 2.8.2 2.83 2.8.4 2.8.5 28.6 2.8.7 1.28.8 2.8.9 .2.9.1 29.2 2.93 .2.9.4 2.95 2.96 2.9.7 2.98 12.9.9 .3.1.1 .3.1.2 3.13 .3.1.4 3.15 .3.1.6 3.17 3.1.8 US 2009/011 8236 A1 May 7, 2009 58

TABLE 2-continued

3.19 .3.2.1 .3.2.2 3.23 .3.2.4 3.2.5 3.26 3.2.7 32.8 3.29 3.31 3.32 3.3.3 .3.3.4 3.35 33.6 3.3.7 3.38 33.9 .3.4.1 .3.4.2 .3.4.3 .3.4.4 34.5 .3.4.6 34.7 .3.4.8 3.49 35.1 3.5.2 3.5.3 3.54 3.S.S 3.56 3.5.7 3.S.8 3.S.9 .3.6.1 36.2 3.6.3 .3.6.4 36.5 3.6.6 3.6.7 3.68 36.9 3.7.1 3.7.2 .3.7.3 3.74 3.7.5 3.7.6 3.7.7 37.8 .3.7.9 38.1 38.2 38.3 .3.8.4 3.85 38.6 38.7 3.8.8 38.9 3.91 3.9.2 3.93 3.94 3.95 3.96 39.7 39.8 3.9.9 4.1.1 .4.1.2 4.1.3 4.1.4 4.1.5 4.1.6 4.1.7 4.1.8 4.1.9 .4.2.1 4.2.2 .4.2.3 4.2.4 4.2.5 4.2.6 4.2.7 .4.2.8 4.2.9 4.3.1 4.3.2 4.3.3 .4.3.4 4.3.5 4.3.6 4.3.7 4.3.8 4.3.9 .4.4.1 .4.4.2 .4.4.3 .4.4.4 .4.4.5 .4.4.6 .4.4.7 .4.4.8 .4.4.9 .4.5.1 4.5.2 4.5.3 .4.5.4 45.5 45.6 45.7 45.8 45.9 .4.6.1 .4.6.2 .4.6.3 .4.6.4 46.5 .4.6.6 46.7 .4.6.8 .4.6.9 4.7.1 4.7.2 4.7.3 4.7.4 4.7.5 4.7.6 4.7.7 4.7.8 4.7.9 4.8.1 4.8.2 4.8.3 .4.8.4 48.5 4.8.6 4.8.7 4.8.8 48.9 4.9.1 4.9.2 49.3 .4.9.4 4.95 4.9.6 4.9.7 49.8 4.99 5.1.1 5.1.2 51.3 .5.1.4 S.1.5 5.1.6 S.1.7 5.1.8 5.19 5.2.1 5.2.2 S.2.3 .5.2.4 S.2.5 5.2.6 S.2.7 5.2.8 5.2.9 5.3.1 S.3.2 .5.3.3 53.4 S3.5 5.36 53.7 .5.3.8 S.3.9 .5.4.1 .5.4.2 5.43 .5.44 5.45 54.6 S.4.7 54.8 5.4.9 S.S.1 S.S.2 S.S.3 5.54 5.5.5 S.S.6 5.5.7 S.S.8 S.S.9 5.6.1 56.2 56.3 56.4 S.6.5 56.6 S.6.7 56.8 56.9 S.7.1 S.7.2 .5.7.3 S.7.4 5.7.5 S.7.6 5.7.7 S.7.8 S.7.9 5.8.1 5.8.2 5.83 58.4 S8.5 58.6 S8.7 58.8 5-8.9 5.9.1 59.2 5.93 5.94 S.9.5 59.6 S.9.7 59.8 S.9.9 .6.1.1 .6.1.2 .6.1.3 .6.1.4 6.15 .6.1.6 6.17 .6.1.8 6.1.9 .6.2.1 .6.2.2 6.23 .6.2.4 6.25 .6.2.6 6.2.7 6.2.8 6.2.9 6.3.1 6.3.2 6.3.3 6.3.4 6.3.5 6.3.6 6.3.7 6.3.8 6.3.9 .6.4.1 .6.4.2 6.4.3 .6.4.4 6.45 6.4.6 6.4.7 6.4.8 6.4.9 6.5.1 6.5.2 6.53 6.54 6.S.S 65.6 6.5.7 65.8 6.5.9 .6.6.1 .6.6.2 6.6.3 .6.6.4 6.65 .6.6.6 66.7 6.6.8 6.6.9 .6.7.1 .6.7.2 .6.7.3 .6.7.4 .6.7.5 .6.7.6 .6.7.7 .6.7.8 6.79 .6.8.1 6.82 6.8.3 .6.8.4 6.8.5 6.86 6.8.7 6.8.8 6.8.9 6.9.1 6.9.2 6.9.3 .6.9.4 6.95 6.9.6 6.9.7 6.98 6.9.9 .7.1.1 .7.1.2 .7.1.3 .7.1.4 .7.1.5 71.6 .7.1.7 .7.1.8 .7.1.9 7.2.1 7.2.2 7.2.3 7.2.4 7.2.5 7.2.6 7.2.7 7.2.8 7.2.9 7.3.1 7.3.2 7.3.3 7.34 7.3.5 7.3.6 7.3.7 7.3.8 7.3.9 .7.4.1 7.4.2 7.43 .7.4.4 7.45 74.6 7.4.7 7.48 7.4.9 7.5.1 7.5.2 7.5.3 7.5.4 7.5.5 7.5.6 7.5.7 7.58 7.5.9 7.6.1 7.6.2 7.6.3 7.6.4 7.6.5 7.6.6 7.6.7 7.6.8 7.6.9 7.7.1 7.7.2 7.7.3 7.7.4 7.75 7.7.6 7.77 77.8 7.7.9 78.1 7.82 7.8.3 78.4 7.8.5 7.86 7.8.7 78.8 7.8.9 7.91 7.9.2 7.9.3 7.94 7.9.5 79.6 79.7 7.9.8 7.9.9 .8.1.1 .8.1.2 8.13 .8.1.4 8.15 .8.1.6 8.17 8.1.8 .8.19 .8.2.1 .8.2.2 8.23 .8.2.4 8.25 82.6 8.2.7 82.8 8.29 8.31 8.32 8.33 .8.3.4 8.3.5 8.36 8.3.7 8.3.8 83.9 .8.4.1 .8.4.2 .84.3 .8.44 84.5 .8.4.6 8.4.7 .84.8 8.49 85.1 8.5.2 8.5.3 8.54 8.S.S 85.6 8.5.7 85.8 8.59 .8.6.1 .8.6.2 .8.6.3 .8.6.4 86.5 .8.6.6 .8.6.7 .8.6.8 .8.6.9 8.7.1 8.7.2 8.7.3 8.74 8.7.5 87.6 8.7.7 8.78 8.7.9 88.1 8.82 8.8.3 .8.8.4 8.85 88.6 88.7 88.8 88.9 8.9.1 8.9.2 89.3 8.9.4 89.5 8.9.6 89.7 8.98 8.9.9 .9.1.1 .9.1.2 9.13 .9.14 9.15 91.6 9.17 9.18 91.9 .9.2.1 92.2 .9.23 .9.2.4 9.25 92.6 92.7 9.28 92.9 9.31 9.32 93.3 9.34 9.3.5 9.36 93.7 9.38 93.9 .9.4.1 .9.4.2 9.43 .9.4.4 9.45 .9.4.6 94.7 9.48 94.9 9.51 95.2 9.S.3 9.54 9.S.S 9.5.6 9.S.7 9.58 9.S.9 96.1 9.6.2 96.3 .9.6.4 9.6.5 96.6 96.7 96.8 96.9 9.7.1 9.7.2 9.7.3 9.7.4 9.7.5 9.7.6 9.7.7 9.7.8 9.7.9 98.1 98.2 98.3 9.84 98.5 98.6 98.7 98.8 98.9 99.1 9.9.2 99.3 9.94 99.5 99.6 99.7 99.8 99.9 2.1.1.1 2.1.1.2 2.1.1.3 2.1.1.4 2.1.1.5 2.1.1.6 2.1.1.7 2.1.1.8 2.1.1.9 2.1.2.1 2.1.2.2 2.1.2.3 2.1.2.4 2.1.2.5 2.1.2.6 2.1.2.7 2.1.2.8 2.1.2.9 2.1.3.1 2.1.3.2 2.1.3.3 2.1.3.4 2.1.3.5 2.1.3.6 2.1.3.7 2.13.8 2.1.3.9 2.1.4.1 2.1.4.2 2.1.4.3 2.1.4.4 2.1.45 2.1.4.6 2.14.7 2.1.4.8 2.1.4.9 2.1.5.1 2.1.5.2 2.1.5.3 2.1.5.4 2.1.S.S 2.1.5.6 2.1.5.7 2.1.5.8 2.1.5.9 2.1.6.1 2.1.6.2 2.1.6.3 2.1.6.4 2.1.6.5 2.1.6.6 2.1.6.7 2.1.6.8 2.1.6.9 2.17.1 2.17.2 2.17.3 2.17.4 2.17.5 2.17.6 2.17.7 2.17.8 2.17.9 2.1.8.1 2.1.8.2 2.1.83 2.1.8.4 2.18.5 2.18.6 2.18.7 2.18.8 2.18.9 2.19.1 2.1.9.2 2.1.93 2.1.9.4 21.9.5 2.1.96 21.9.7 2.1.98 2.1.99 2.2.1.1 2.2.1.2 2.2.1.3 2.2.1.4 2.2.1.5 2.2.1.6 2.2.1.7 2.2.1.8 2.2.1.9 2.2.2.1 2.2.2.2 2.2.23 2.2.2.4 2.2.2.5 2.2.2.6 2.2.2.7 2.2.2.8 2.2.2.9 2.2.3.1 2.23.2 22.3.3 2.2.3.4 2.2.3.5 22.3.6 2.2.3.7 2.23.8 2.23.9 2.2.4.1 2.2.4.2 2.2.4.3 2.2.4.4 2.2.45 2.2.4.6 2.24.7 2.2.4.8 2.2.4.9 2.2.5.1 2.2.5.2 2.2.5.3 2.2.5.4 2.2.S.S 2.2.5.6 2.2.5.7 2.25.8 2.2.5.9 2.2.6.1 2.2.6.2 2.2.6.3 2.2.6.4 2.26.5 2.2.6.6 2.26.7 2.26.8 2.26.9 2.2.7.1 2.2.7.2 2.2.7.3 2.2.7.4 2.2.7.5 2.2.7.6 2.2.7.7 2.2.7.8 2.2.7.9 2.2.8.1 2.2.8.2 2.28.3 2.2.8.4 2.28.5 22.86 2.28.7 22.8.8 2.28.9 2.29.1 2.292 2.29.3 2.2.9.4 2.29.5 2.29.6 2.2.9.7 2.29.8 2.29.9 2.3.1.1 2.3.1.2 2.3.1.3 2.3.1.4 2.3.1.5 2.3.1.6 2.3.1.7 2.3.1.8 2.3.1.9 2.3.2.1 2.3.2.2 2.32.3 2.3.2.4 2.3.2.5 2.3.2.6 2.3.2.7 2.3.2.8 2.3.2.9 2.3.3.1 2.3.3.2 2.3.3.3 2.3.3.4 2.3.3.5 2.3.3.6 2.3.3.7 2.338 233.9 2.3.4.1 2.3.4.2 2.3.4.3 2.3.4.4 2.3.4.5 2.3.4.6 2.3.4.7 2.348 2.3.4.9 23.5.1 2.3.5.2 2.3.5.3 US 2009/011 8236 A1 May 7, 2009 59

TABLE 2-continued

2.35.4 2.35.5 2.35.6 2.357 23.5.8. 23.5.9 2.3.6.1 2.3.6.2 2.3.6.3 2.3.6.4 2.3.6.5 2.3.6.6 2.3.6.7 2.3.6.8, 2.3.6.9 2.3.7.1 2.3.7.2 2.3.7.3 2.37.4 2.3.7.5 2.3.7.6 2.3.7.7 2.3.7.8 2.3.7.9 2.38.1 2.38.2 238.3 2.38.4 2.38.5 2.38.6 2.38.7 2.38.8 2.38.9 23.91 2.39.2 23.9.3 2.39.4 23.9.5 2.3.96 2.39.7 2.3.9.8 2.3.9.9 2.4.1.1 2.4.1.2 2.4.1.3 2.4.1.4 2.4.1.5 2.4.1.6 2.4.1.7 2.4.1.8 2.4.1.9 2.4.2.1 2.4.2.2 2.4.2.3 2.4.2.4 2.4.2.5 2.4.2.6 2.4.2.7 2.4.2.8 2.4.2.9 2.4.3.1 2.4.3.2 2.4.3.3 2.4.3.4 2.4.3.5 2.4.3.6 2.4.3.7 2.4.3.8 2.4.3.9 2.4.4.1 2.4.4.2 2.4.4.3 2.4.4.4 2.4.4.5 2.4.4.6 2.4.4.7 2.4.4.8 2.4.4.9 2.4.5.1 2.4.5.2 2.45.3 24.54 2.45.5 2.45.6 2.45.7 24.5.8. 24.59 2.4.6.1 2.4.6.2 2.4.6.3 2.46.4 2.4.6.5 2.4.6.6 2.4.6.7 2.4.6.8, 2.4.6.9 24.7.1. 24.7.2 24.7.3 2.47.4 24.7.5 2.47.6 2.47.7 24.7.8 24.7.9 24.8.1 2.48.2 248.3 24.84 2.48.5 248.6 2.48.7 2.48.8 24.89 24.9.1 2.4.9.2 24.9.3 249.4 24.95 2.4.9.6 2.4.9.7 2.4.9.8 24.99 2.5.1.1 2.5.1.2 2.5.13 2.5.14 2.5.1.5 2.5.1.6 2.5.1.7 2.5.1.8 2.5.19 2.5.2.1 2.5.22 2.5.23 2.5.2.4 2.5.25 2.5.2.6 2.5.27 2.5.2.8 2.5.2.9 2.5.3.1 2.5.3.2 2.5.3.3 2.5.3.4 2.5.3.5 2.5.3.6 2.5.3.7 2.5.3.8 2.5.3.9 25.4.1 2.5.4.2 2.5.4.3 2.5.44 2.5.45 2.54.6 2.54.7 2.5.48 25.4.9 25.5.1 2.S.S.2 2.S.S.3 2.S.S.4 2.S.S.S 2.S.S.6 2.S.S.7 2.S.S.8 2.S.S.9 2.S.6.1 2.5.6.2 2.S.6.3 2.56.4 2.S.6.5 2.S.6.6 2.5.6.7 2.S.6.8 2.56.9 2.5.7.1 2.5.7.2 2.5.7.3 2.5.7.4 2.5.7.5 2.5.7.6 2.5.7.7 2.5.7.8 2.5.7.9 2.5.8.1 2.5.8.2 2.5.8.3 2.5.8.4 2.5.8.5 2.5.8.6 2.5.8.7 2.5.8.8 2.5.8.9 2.59.1 2.5.9.2 2.5.9.3 2.5.94 2.5.9S 2.59.6 2.59.7 2.59.8 25.99 2.6.1.1 2.6.1.2 2.6.13 2.6.14 2.6.1.5 2.6.16 26.17 2.6.1.8 2.6.19 2.6.2.1 2.6.2.2 2.6.2.3 2.6.2.4 2.6.2.5 2.6.2.6 2.6.2.7 2.6.2.8 2.6.29 2.6.3.1 2.6.32 2.6.3.3 2.6.3.4 2.63.5 2.6.3.6 2.6.3.7 2.6.38 2.6.3.9 2.6.4.1 2.6.4.2 2.6.4.3 2.6.4.4 2.6.4.5 2.6.4.6 2.6.4.7 2.6.4.8 2.6.4.9 26.5.1 2.6.5.2 2.6.5.3 26.54 2.6.55 2.6.5.6 2.65.7 26.5.8. 26.59 2.6.6.1 26.6.2 2.6.6.3 2.6.6.4 26.6.5 2.6.6.6 2.66.7 2.66.8. 26.6.9 2.6.7.1 2.6.7.2 2.6.7.3 2.6.7.4 2.6.7.5 2.6.7.6 2.6.7.7 2.6.7.8 2.6.7.9 26.8.1. 26.82 2.6.83 26.8.4 26.85 2.6.8.6 2.68.7 26.88 2.68.9 2.6.9.1 2.6.9.2 2.6.9.3 2.6.94 26.9.5 2.6.9.6 2.6.9.7 26.98 2.6.99 2.7.1.1 2.7.1.2 2.7.1.3 2.7.14 2.7.15 2.7.1.6 2.7.17 2.7.1.8 2.7.1.9 27.2.1 2.7.2.2 2.72.3 2.7.2.4 2.72.5 2.7.26 2.72.7 2.72.8 2.7.2.9 2.7.3.1 2.7.3.2 2.7.3.3 2.73.4 2.7.3.5 2.7.3.6 2.7.3.7 2.73.8 2.73.9 274.1 2.74.2 2.74.3 2.74.4 2.74.5 27:46 2.74.7 2.74.8 2.74.9 2.7.5:1 2.7.5.2 2.7.5.3 2.7.54 2.7.S.S 2.75.6 2.75.7 2.75.8 2.7.5.9 2.76.1 2.76.2 2.76.3 2.76.4 2.76.5 2.76.6 2.76.7 276.8 2.76.9 2.77.1 2.7.7.2 2.77.3 2.77.4 2.77.5 2.77.6 2.77.7 2.77.8 2.77.9 2.7.8.1 2.7.82 2.78.3 2.7.84 2.7.8.5 2.78.6 2.78.7 2.78.8 2.78.9 2.7.9.1 2.7.9.2 2.7.9.3 2.79.4 2.79.5 2.79.6 2.79.7 27.98 2.79.9 2.81.1 2.8.1.2 2.81.3 2.8.1.4 2.8.1.5 2.8.1.6 2.8.17 2.81.8 2.8.19 2.8.2.1 2.8.2.2 2.8.2.3 2.8.2.4 2.8.25 2.8.2.6 2.8.27 2.8.2.8 2.8.2.9 2.83.1 2.83.2 2.83.3 28.34 2.835 28.36 2.83.7 2.83.8 2.83.9 2.84.1 28.4.2 2.84.3 2.84.4 2.84.5 2.84.6 2.84.7 2.84.8 2.84.9 28.5.1 2.85.2 2.85.3 2.85.4 2.85.5 2.85.6 2.85.7 2.85.8 2.85.9 2.8.6.1 2.8.6.2 2.8.6.3 2.8.6.4 2.86.5 2.86.6 2.8.6.7 2.86.8 2.8.6.9 2.87.1 28.7.2 2.87.3 2.87.4 2.87.5 2.87.6 2.87.7 28.7.8 2.87.9 2.88.1 2.8.8.2 2.88.3 2.88.4 2.88.5 2.88.6 2.88.7 2.88.8 2.88.9 2.89.1 2.89.2 2.89.3 2.89.4 2.89.5 2.89.6 2.89.7 2.89.8 2.89.9 29.1.1 2.9.1.2 2.9.13 2.9.14 2.91.5 2.9.1.6 2.9.17 2.91.8 2.91.9 2.92.1 2.9.2.2 2.92.3 2.92.4 2.92.5 2.92.6 2.92.7 29.28 2.92.9 2.93.1 2.93.2 2.93.3 2.93.4 2.93.5 2.93.6 2.93.7 29.38 2.93.9 2.94.1 2.94.2 2.94.3 2.9.44 2.94.5 2.94.6 2.94.7 2.94.8 2.94.9 2.95.1 2.95.2 2.95.3 2.95.4 2.95.5 2.95.6 2.95.7 2.95.8 2.95.9 2.9.6.1 2.96.2 2.96.3 2.96.4 2.96.5 2.96.6 2.96.7 2.96.8 2.96.9 2.9.7.1 2.9.7.2 2.9.7.3 2.9.7.4 2.97.5 2.97.6 2.97.7 2.97.8 2.9.79 2.98.1 2.98.2 2.98.3 2.98.4 2.98.5 2.98.6 2.98.7 29.8.8 2.98.9 2.99.1 29.9.2 2.99.3 29.94 2.99.5 2.99.6 2.99.7 2.99.8. 29.99 3.1.1.1 3.11.2 3.11.3 3.1.1.4 3.11.5 3.1.1.6 3.11.7 3.11.8 3.11.9 3.1.2.1 3.12.2 3.1.2.3 3.1.2.4 3.12.5 3.12.6 3.1.2.7 3.1.2.8, 3.12.9 3.1.3.1 3.1.3.2 3.133 3.13.4 3.1.3.5 3.1.3.6 3.1.37 313.8 3.13.9 3.14.1 3.14.2 3.14.3 3.14.4 3.14.5 3.14.6 3.14.7 3.14.8 3.14.9 3.15.1 3.15.2 3.15.3 3.15.4 3.15.5 3.15.6 3.15.7 3.15.8 3.15.9 3.1.6.1 3.1.6.2 3.1.6.3 3.1.6.4 3.16.5 3.1.6.6 3.1.6.7 3.1.6.8, 3.1.6.9 3.17.1 3.17.2 3.17.3 3.17.4 3.17.5 3.17.6 3.17.7 3.17.8 3.17.9 3.18.1 3.18.2 3.18.3 3.18.4 3.18.5 3.18.6 3.18.7 3.18.8 3.18.9 3.19.1 3.19.2 3.19.3 3.19.4 3.19.5 3.19.6 3.19.7 3.19.8 31.99 3.2.1.1 3.2.1.2 3.2.1.3 3.2.1.4 3.2.1.5 3.2.1.6 3.21.7 3.2.18 32.19 3.2.2.1 3.2.2.2 3.22.3 3.2.2.4 3.2.2.5 3.22.6 3.22.7 3.22.8 322.9 3.23.1 3.232 32.3.3 3.23.4 3.23.5 3.23.6 3.23.7 3.238 3.23.9 3.24.1 32.4.2 3.24.3 3.24.4 3.24.5 3.24.6 3.24.7 3.24.8 3.24.9 3.25.1 3.25.2 3.2.5.3 3.25.4 3.25.5 3.25.6 3.25.7 3.25.8 3.25.9 32.6.1 32.6.2 32.6.3 3.26.4 3.26.5 3.26.6 3.2.6.7 3.2.6.8, 3.2.6.9 3.2.7.1 3.2.7.2 3.2.7.3 3.2.7.4 3.2.7.5 3.2.7.6 3.2.7.7 3.27.8 3.27.9 3.28.1 32.8.2 328.3 3.28.4 3.28.5 3.28.6 3.28.7 3.28.8 3.28.9 3.29.1 3.29.2 32.93 3.29.4 3.29.5 3.29.6 3.29.7 3.29.8 32.99 3.3.1.1 3.3.1.2 3.3.1.3 3.31.4 3.31.5 3.3.1.6 3.31.7 3.31.8 3.31.9 3.3.2.1 3.32.2 3.32.3 332.4 3.3.2.5 3.32.6 3.32.7 3.3.2.8, 3.32.9 3.3.3.1, 33.32 3.333 33.34 33.3.5 33.3.6 3.33.7 3.33.8 3.33.9 3.3.4.1 3.34.2 3.34.3 3.34.4 3.34.5 3.34.6 3.34.7 3.34.8 3.34.9 3.35.1 33.5.2 3.35.3 33.54 3.3.S.S 3.35.6 3.35.7 3.35.8 3.35.9 3.3.6.1 3.3.6.2 3.3.6.3 3.3.6.4 3.3.6.5 3.3.6.6 3.3.6.7 3.3.6.8, 3.3.6.9 3.3.7.1 3.3.7.2 3.3.7.3 3.3.7.4 3.3.7.S 3.3.7.6 3.37.7 3.3.7.8 3.3.7.9 3.38.1 3.38.2 3.38.3 3.38.4 3.38.S 3.38.6 3.38.7 US 2009/011 8236 A1 May 7, 2009 60

TABLE 2-continued

3.38.8 3.38.9 3.39.1 33.9.2 33.9.3 3.39.4 3.39.5 33.9.6 3.39.7 33.9.8 3.39.9 34.1.1 3412 34.13 34.14 34.15 34.1.6 3.41.7 3.4.18 3.4.19 3.42.1 34.2.2 3.42.3 34.24 34.25 34.2.6 3.42.7 34.2.8, 3.42.9 34.3.1 3.43.2 3.433 34.34 34.35 3.43.6 3.43.7 3.438 3.43.9 3.4.4.1 34.42 3.443 3.4.4.4 3.44.5 34.46 344.7 3.44.8 3.4.4.9, 3.45.1 34.52 3.45.3 3.45.4 34.55 345.6 3.45.7 3.45.8 3.45.9 34.6.1 34.6.2 34.6.3 3.46.4 34.6.5 3.46.6 3.46.7 34.6.8, 3.46.9 34.7.1 34.7.2 34.7.3 34.74 34.75 3.47.6 3.47.7 3.47.8 34.79 34.8.1 3.48.2 3.48.3 3.48.4 34.85 34.86 3.48.7 3.48.8 3.48.9 34.9.1 34.9.2 34.9.3 34.94 34.9.5 34.96 3.4.9.7 3.49.8 34.99 3.5.1.1 35.1.2 3.5.1.3 3.5.1.4 3.5.1.5 3.5.1.6 3.5.1.7 3.5.1.8 3.5.1.9 3.5.2.1 3.5.2.2 3.5.2.3 3.5.2.4 3.5.2.S 3.5.2.6 3.5.2.7 3.5.2.8, 3.5.2.9 3.5.3.1 3.5.3.2 3.5.3.3 3.5.3.4 3.5.3.5 3.5.3.6 3.5.3.7 3.5.3.8 3.5.3.9 3.5.4.1 35.4.2 3.54.3 3.5.44 3.5-4.5 3.54.6 3.5-4.7 3.54.8 35.4.9 3.5.5.1 35.5.2 3.S.S.3 3.S.S.4 3.S.S.S 3.S.S.6 3.S.S.7 3.S.S.8 3.S.S.9 3.S.6.1 3.S.6.2 3.S.6.3 3.S.6.4 3.S.6.S 3.S.6.6 3.5.6.7 3.S.6.8, 3.S.6.9 3.5.7.1 3.5.7.2 3.5.7.3 3.5.7.4 3.5.7.5 3.5.7.6 3.5.7.7 3.5.7.8 3.5.7.9 3.5.8.1 3.5.8.2 3.5.8.3 3.5.8.4 3.5.8.5 3.5.8.6 3.5.8.7 3.5.8.8 3.5.8.9 3.5.9.1 35.9.2 3.5.9.3 3.S.9.4 3.5.9S 3.5.9.6 3.59.7 3.59.8 3.59.9 36.1.1 3.6.1.2 36.13 3.6.1.4 3.6.1.5 3.6.16 3.6.17 3.6.18, 3.6.19 3.6.2.1 3.6.2.2 3.6.2.3 3.6.2.4 3.6.2.5 3.6.2.6 3.6.27 3.6.2.8 3.6.2.9 36.31 3.6.32 36.33 36.34 36.35 36.36 3.6.3.7 3.6.38. 36.39 36.4.1 36.4.2 36.4.3 36.4.4 36.45 3.6.46 3.64.7 3.6.4.8 36.4.9, 36.5.1 36.5.2 36.5.3 36.5.4 36.55 36.56 36.5-7 3.6.58. 36.5.9 36.6.1 36.6.2 3.6.6.3 36.64 3.6.6.5 36.66 3.6.6.7 3.6.6.8, 3.66.9 3.6.7.1 3.6.7.2 3.6.7.3 3.6.7.4 3.6.7.5 3.6.7.6 3.6.7.7 3.6.7.8 3.6.7.9 36.81 36.8.2 36.83 36.84 36.8.5 36.86 3.6.8.7 3.6.88 36.8.9 36.9.1 36.9.2 36.9.3 36.94 36.95 36.9.6 3.6.9.7 3.6.9.8 36.99 3.7.1.1 3.7.1.2 3.7.1.3 37.14 37.15 3.7.1.6 3.7.1.7 3.7.1.8 3.7.1.9 3.7.2.1 3.7.2.2 3.7.2.3 3.7.2.4 37.2.S 3.7.2.6 3.7.2.7 3.7.2.8, 3.7.2.9 37.3.1, 37.3.2 3.7.33 37.3.4 3.73.S 37.3.6 3.737 37.3.8 37.3.9 3.74.1 37.4.2 3.7-4.3 37.44 3.7-4.5 3.74.6 3.74.7 3.74.8 37.49 3.7.5.1, 37.5.2 3.7.5.3 37.54 3.7.S.S 3.7.5.6 3.75.7 3.75.8 3.75.9 3.7.6.1 3.7.6.2 3.7.6.3 3.7.6.4 3.7.6.S 3.7.6.6 3.7.6.7 3.7.6.8, 3.7.6.9 3.77.1 37.7.2 3.77.3 37.74 37.7.S 3.77.6 3.77.7 3.77.8 3.77.9 3.7.8.1 3.78.2 37.83 3.78.4 3.78.S 3.78.6 3.78.7 3.78.8 3.78.9 3.7.9.1 37.9.2 37.9.3 37.94 37.9.5 3.79.6 37.9.7 37.9.8 37.99 3.8.1.1 38.1.2 38.13 38.14 3.8.1.5 3.8.1.6 3.81.7 3.8.18, 3.8.19 3.8.2.1 38.2.2 3.823 38.2.4 38.25 3.8.2.6 3.8.2.7 3.8.2.8, 3.8.2.9 38.31 38.3.2 383.3 38.34 38.35 3.83.6 38.3.7 38.38. 3.83.9 38.4.1 38.4.2 38.43 38.4.4 3.84.5 38.4.6 3.84.7 3.8-4.8 38.4.9, 3.8.S.1 38.5.2 38.5.3 38.54 3.8.S.S 3.85.6 3.8.S.7 3.85.8 38.59 3.8.6.1 3.8.6.2 3.8.6.3 38.64 3.8.6.5 3.8.6.6 3.8.6.7 3.8.6.8, 3.8.6.9 38.7.1 3.8.7.2 3.87.3 3.8.7.4 3.87.5 3.8.7.6 3.87.7 3.87.8 3.8.7.9 3.88.1 38.82 3.88.3 3.884 3.88.5 3.88.6 3.88.7 3.88.8 3.88.9 38.9.1 389.2 38.93 3.89.4 3.89.5 3.89.6 3.89.7 38.98 3.89.9 3.9.1.1 39.1.2 3.913 3.9.14 3.915 3.9.1.6 3.9.17 39.18, 3.9.19 3.9.2.1 3.922 39.2.3 3.92.4 3.9.25 3.9.2.6 3.92.7 3.9.2.8, 3.92.9 39.3.1 393.2 3.93.3 39.34 3.93.5 3.936 39.37 39.38 39.39 39.4.1 39.4.2 3.94.3 39.4.4 3.9.45 394.6 3.94.7 3.9.4.8 3.94.9 3.9.S.1 39.5.2 3.9.5.3 3.9.S.4 3.9.S.S 3.9.S.6 3.95.7 3.9.S.8 3.95.9 39.6.1 39.6.2 39.6.3 39.64 3.9-6.5 3.96.6 3.9.6.7 39.6.8, 3.96.9 39.7.1 39.7.2 3.9.7.3 39.7.4 3.9.7.S. 39.7.6 3.97.7 39.7.8 39.7.9 3.9.8.1 39.8.2 39.8.3 39.8.4 3.98.5 3.98.6 3.98.7 3.98.8 39.8.9 3.99.1 39.9.2 3.99.3 39.94 39.95 39.96 3.9.9.7 3.99.8 399.9 4.1.1.1 4.1.1.2 4.1.1.3 4.1.1.4 4.1.1.5 4.1.1.6 4.1.1.7 4.1.1.8 4.1.1.9 4.1.2.1 4.1.2.2 4.1.2.3 4.1.2.4 4.1.2.5 4.1.2.6 4.1.2.7 4.1.2.8, 4.1.2.9 4.1.3.1 4.1.3.2 4.1.3.3 4.1.3.4. 4.1.3.5 4.1.3.6 4.1.3.7 4.1.3.8 4.1.3.9 4.1.4.1 4.1.4.2 4.1.4.3 4.1.4.4 4.1.4.5 4.1.4.6 4.14.7 41.48 4.14.9 4.1.5.1. 4.15.2 4.15.3 4.15.4 4.15.5 4.1.5.6 4.15.7 4.1.5.8 4.1.5.9 4.1.6.1 4.1.6.2 4.1.6.3 4.1.6.4 4.1.6.5 4.1.6.6 4.1.6.7 4.1.6.8 4.1.6.9 41.7.1. 4.17.2 41.73 4.17.4 4.17.5 4.17.6 4.17.7 4.17.8 4.17.9 4.1.8.1. 4.1.8.2 4.1.8.3 4.1.8.4 4.1.8.5 4.1.8.6 4.1.8.7 4.1.8.8 4.1.8.9 4.1.9.1 4.1.9.2 4.1.9.3 4.1.9.4 4.1.9.5 4.1.9.6 4.1.9.7 4.1.9.8 4.1.9.9 4.2.1.1 4.2.1.2 4.2.1.3 4.2.1.4 4.2.1.5 4.2.1.6 4.2.1.7 4.2.1.8 4.2.1.9 4.2.2.1 4.2.2.2 4.2.2.3 4.2.2.4 4.2.2.5 4.2.2.6 4.2.2.7 4.2.2.8, 4.2.2.9 4.2.3.1 4.2.3.2 4.2.3.3 4.2.3.4 4.2.3.5 4.2.3.6 4.2.3.7 4.2.3.8 4.2.3.9 4.2.4.1 4.2.4.2 4.2.4.3 4.2.4.4 4.2.4.5 4.2.4.6 4.2.4.7 4.2.48 4.2.4.9 4.2.5.1 4.2.5.2 4.2.5.3 4.2.5.4 4.2.5.5 4.2.5.6 4.2.5.7 4.25.8 4.2.5.9 4.2.6.1 4.2.6.2 4.2.6.3 4.2.64 4.2.6.5 42.6.6 42.6.7 4.2.6.8, 4.2.6.9 4.2.7.1 4.2.7.2 4.2.7.3 4.2.7.4 4.2.7.5 4.2.7.6 4.2.7.7 4.2.7.8 4.2.7.9 4.28.1 42.8.2 4.28.3 42.84 4.28.5 42.86 4.28.7 4.28.8 4.28.9 42.9.1 42.92 4.2.9.3 4.294 42.95 4:29.6 42.9.7 4.2.9.8 4.29.9 4.3.1.1 4.3.1.2 4.3.1.3 4.3.1.4 4.3.1.5 4.3.1.6 4.3.1.7 4.3.1.8 4.3.1.9 4.3.2.1 4.3.2.2 4.3.23 4.3.24 4.3.25 4.3.2.6 4.3.2.7 4.3.2.8, 4.3.2.9 4.3.3.1 4.3.3.2 4.3.3.3 4.3.34 4.3.3.5 4.3.3.6 4.3.3.7 4.3.3.8 4.3.3.9 4.3.4.1 4.3.4.2 4.3.4.3 4.3.4.4 4.3.4.5 4.34.6 4.3.4.7 43.48 4.3.4.9 43.5.1 4.352 43.5.3 4.35.4 4.35.5 4.356 4.35.7 435.8 4.35.9 4.3.6.1 4.3.6.2 4.3.6.3 4.3.6.4 4.3.6.5 4.3.6.6 4.3.6.7. 4.3.6.8, 4.3.6.9 4.3.7.1. 4.3.7.2 4.3.7.3 4.3.7.4 4.3.7.5 4.3.7.6 4.3.7.7 4.3.7.8 43.79 43.8.1 43.8.2, 43.83 4.38.4 4.385 43.8.6 438.7 4.38.8 4.38.9 439.1 43.9.2 43.93 4.3.94 4.39.5 4.3.96 43.9.7 43.98 4.399 4.4.1.1 4.4.1.2 4.4.1.3 4.4.1.4 4.4.1.5 4.4.1.6 4.4.1.7 4.4.1.8 4.4.1.9 4.4.2.1 4.4.2.2 4.4.2.3 4.4.2.4 4.4.2.5 4.4.2.6 4.4.2.7 4.4.2.8, 4.4.2.9 4.4.3.1 4.4.3.2 US 2009/011 8236 A1 May 7, 2009 61

TABLE 2-continued

4.4.3.3 4.4.34 4.4.3.5 4.4.3.6 4.4.3.7 4.4.3.8 44.3.9 4.4.4.1 4.4.4.2 4.4.4.3 4.4.4.4 4.4.4.5 4.4.4.6 4.4.4.7 4.4.4.8 4.4.4.9 4.4.5.1 4.4.5.2 4.4.5.3 4.4.5.4 4.4.5.5 4.4.5.6 4.4.5.7 4.4.5.8 4.4.5.9 4.4.6.1 4.4.6.2 4.4.6.3 4.4.6.4 4.4.6.5 4.4.6.6 4.4.6.7 4.4.6.8, 4.4.6.9 4.4.7.1 4.4.7.2 4.4.7.3 4.4.7.4 4.4.7.5 4.4.7.6 4.4.7.7 4.4.7.8 4.4.7.9 4.4.8.1 4.4.8.2 4.4.8.3 4.4.8.4 4.4.8.5 4.4.8.6 4.4.8.7 4.4.8.8 4.4.8.9 4.4.9.1 4.4.9.2 4.4.9.3 4.4.9.4 4.4.9.5 4.4.9.6 4.4.9.7 4.4.9.8 4.4.9.9 4.5.1.1 4.5.1.2 4.5.1.3 4.5.1.4 4.5.1.5 4.5.1.6 4.5.1.7 4.5.1.8 4.5.19 4.5.2.1 4.5.2.2 4.5.23 4.5.24 4.5.25 4.5.2.6 4.5.2.7 4.5.2.8, 4.5.2.9 4.5.3.1 4.5.3.2 45.33 45.34 4.5.3.5 4.5.3.6 4.5.3.7 4.5.3.8 4.5.3.9 4.54.1 4.54.2 45.4.3 4.54.4 45.45 4.54.6 4.5-4.7 4.5.48 4.54.9 45.5.1 4.552 455.3 45.54 4.55.5 45.5.6 4.55.7 45.58, 4.55.9 4.56.1 4.5.6.2 45.6.3 4.56.4 45.6.5 4.56.6 4.5.6.7 4.568 45.69 4.5.7.1 4.5.7.2 45.73 45.74 4.5.7.5 4.5.7.6 4.5.7.7 4.5.7.8 4.5.7.9 4.5.8.1 4.5.8.2, 4.5.8.3 4.5.8.4 4.5.8.5 4.5.8.6 4.5.8.7 4.5.8.8 4.5.8.9 4.59.1 45.92 4.59.3 45.94 4.5.9.5 4.59.6 4.59.7 4.5.9.8 4.5.9.9 4.6.1.1 4.6.1.2 4.6.1.3 4.6.1.4 4.6.1.5 4.6.1.6 4.6.1.7 4.6.1.8 4.6.1.9 4.6.2.1 4.6.2.2 4.6.2.3 4.6.2.4 4.6.2.5 4.6.2.6 4.6.2.7 4.6.2.8, 4.6.2.9 46.31 46.32 46.3.3 46.34 46.35 46.3.6 46.37 46.38 46.39 46.4.1 4.6.4.2 4.6.4.3 4.6.4.4 4.6.4.5 4.6.4.6 4.6.4.7 4.6.4.8 4.6.4.9 4.6.5.1 4.6.5.2 46.5.3 46.54 46.5.5 46.5.6 46.57 4.65.8 46.5.9 46.6.1 46.6.2 46.6.3 46.6.4 46.6.5 46.6.6 46.6.7. 46.6.8, 4.66.9 46.7.1 4.6.7.2 46.7.3 4.6.7.4 4.6.7.5 4.6.7.6 4.6.7.7 4.6.7.8 46.7.9 46.8.1 46.82 46.8.3 46.84 46.85 46.86 4.68.7 46.8.8 46.8.9 46.9.1 46.9.2 46.93 46.9.4 46.9.5 46.96 46.9.7 4.69.8 46.9.9 4.7.1.1 4.7.1.2 4.7.1.3 4.7.1.4 4.7.15 4.7.1.6 4.7.1.7 4.7.1.8 4.7.1.9 47.2.1 4.7.2-2 47.23 4.7.24 4.7.25 4.7.2.6 4.7.2-7 4.7.2-8 4.7.2.9 4.7.3.1 4.7.32 4.7.33 4.7.34 4.7.3.5 4.7.3.6 4.7.3.7 4.7.38, 4.7.3.9 4.7.4.1 47.4.2 47.4.3 4.7.4.4 4.7.45 47.46 4.74.7 4.7.48 474.9 4.7.51 4.7.5.2 4.7.5.3 4.7.5.4 4.7.S.S 4.7.5.6 4.75.7 4.7.5.8 4.7.5.9 4.7.6.1 4.7.6.2 4.7.6.3 4.7.6.4 4.7.6.5 4.76.6 4.7.6.7 4.7.6.8, 4.76.9 4.77.1 47.7.2 477.3 4.77.4 4.77.5 4.77.6 4.77.7 47.78 4.77.9 4.781 4.7.8.2, 4.78.3 4.7.84 4.7.8.5 4.786 4.78.7 4.78.8 47.89 4.79.1 4.7.92 4.7.9.3 4.7.94 4.79.5 4.7.9.6 4.7.9.7 4.7.9.8 4.79.9 4.8.1.1 4.8.1.2 48.13 4.8.1.4 4.8.1.5 4.8.1.6 4.8.1.7 4.8.18, 4.8.19 4.8.2.1 48.22 48.23 48.24 48.25 4.8.2.6 4.8.2.7 4.8.2.8, 4.8.2.9 48.3.1 4-83.2 48.33 48.34 4.83.5 4.8.3.6 4.83.7 48.38 4.8.3.9 4.8.4.1 4.8.4.2 4.84.3 4.8.4.4 4.8.4.5 4.8.4.6 4.8.4.7 4.8.4.8 4.8.4.9 48.5.1 48.52 48.5.3 48.54 48.55 4.85.6 4.85.7 48.58 4.85.9 4.8.6.1 4.8.6.2 4.8.6.3 4.8.6.4 4.8.6.5 4.8.6.6 4.8.6.7 4.8.6.8, 4.8.6.9 4.8.7.1 4.8.7.2 4.8.7.3 4.8.74 4.8.75 4.8.76 4.8.77 4.8.7.8 4.879 48.8.1 4.882 48.83 4.88.4 4.88.5 4.88.6 4.88.7 48.88, 4.88.9 489.1 48.92 4.89.3 48.94 48.9.5 4.89.6 48.9.7 4.89.8 48.99 49.11 49.1.2 49.13 4.9.14 4.9.15 4.9.16 4.91.7 4.9.18, 4.9.19 4.9.21 4.9.2.2 4.9.23 4.9.24 4.9.25 4.92.6 4.9.27 4.9.2.8, 4.92.9 4.93.1 49.32 4.93.3 49.34 4.93.5 4.93.6 4.93.7 4.93.8 4.93.9 49.4.1 4.94.2 4.94.3 4.94.4 4.94.5 49.4.6 4.94.7 49.4.8 4.94.9 4.9.51 49.5.2 4.95.3 4.95.4 4.95.5 4.95.6 4.95.7 4.95.8 49.59 4.9.6.1 49.6.2 49.6.3 4.96.4 4.9-6.5 4.96.6 4.96.7 49.6.8, 4.96.9 49.7.1 4.9.7.2 49.7.3 4.97.4 4.97.5 49.76 4.97.7 4.97.8 4.97.9 4.98.1 49.8.2 4.98.3 4.984 4.98.5 4.98.6 4.98.7 4.98.8 4.9-8.9 49.9.1 49.9.2 4.99.3 4.99.4 4.995 4.99.6 4.99.7 49.98 4.99.9 5.1.1.1 5.1.1.2 5.1.1.3 5.1.1.4 5.1.1.5 5.1.1.6 5.1.1.7 5.1.1.8 5.1.1.9 5.1.2.1 5.1.2.2 5.1.2.3 5.1.2.4 5.1.25 5.1.2.6 5.1.2.7. 5.1.2.8, 5.1.29 S.1.3.1 5.1.3.2 5.1.3.3 5.13.4 5.1.3.5 5.13.6 5.1.3.7 5.13.8 5.13.9 51.4.1 5.14.2 5.14.3 5.14.4 5.14.5 5.14.6 5.14.7 S.148 S.14.9 S.1.5.1 S.1.5.2 S.1.5.3 S.1.5.4 S.1.S.S. S.1.5.6 S.1.5.7. S.1.5.8 5.1.5.9 5.1.6.1 5.1.6.2 5.1.6.3 5.1.6.4 5.1.6.5 5.1.6.6 5.1.6.7. 5.1.6.8, 5.1.6.9 S.17.1 S.1.7.2 S.17.3 S.174 S.17.5 S.17.6 S.17.7 S.17.8 S.17:9 S.1.8.1 5.18.2 5.18.3 5.18.4 518.5 5.18.6 5.18.7 5.18.8 S18.9 5.19.1 5.192 5.19.3 5.19.4 5.1.9.5 5.19.6 5.19.7 5.19.8 5.19.9 5.2.1.1 S.212 52.13 5.2.1.4 52.15 5.2.1.6 5.2.1.7 5.2.1.8 5.2.1.9 5.2.2.1 5.2.2.2 5.22.3 5.2.2.4 S.2.2.5 S.2.2.6 S.2.2.7 S.2.2.8 S.2.29 S.23.1 S.23.2 S.2.3.3 S.234 S.2.3.5 5.2.3.6 5.23.7 S.23.8 52.39 5.24.1 5.242 5.24.3 5.24.4 52.45 5.24.6 S.2.47 S.2.48 S.2.49 S.2.5.1 S.2.5.2 S.2.5.3 S.2.5.4 52.S.S. S.2.5.6 S.2.5.7 5.2.5.8 5.25.9 52.6.1 52.6.2 52.6.3 5.26.4 52.6.5 52.6.6 52.6.7. 52.6.8 S.2.6.9 S.2.7.1 S.2.7.2 S.2.7.3 S.2.7.4 52.7.5 S.2.7.6 S.2.7.7 S.2.7.8 S.2.7.9 5.2.8.1 52.8.2, 52.8.3 5.28.4 52.8.5 5.28.6 5.28.7 52.8.8 52.8.9 52.9.1 S.2.9.2 S.2.9.3 S.2.9.4 52.9.S. S.2.96 S.2.9.7 S.2.9.8 S.2.9.9 5.3.1.1 5.3.1.2 5.3.1.3 S.3.1.4 5.3.1.5 5.3.1.6 5.3.1.7 5.3.1.8 S.3.1.9 5.3.2.1 5.3.2.2 S.3.2.3 5.3.2.4 5.3.2.S 5.3.2.6 S.3.2.7. 5.3.2.8 S.3.2.9 5.3.3.1 S.3.3.2 5.3.3.3 5.3.3.4 5.3.3.5 5.3.3.6 5.3.3.7 S.3.3.8 S.3.3.9 5.3.4.1 S.3.4.2 5.3.4.3 5.3.4.4 5.3.4.5 5.3.4.6 5.3.4.7 5.3.4.8 S.34.9 S-3.5.1 S3.5.2 5.3.5.3 S3.5.4 5.3.SS S-3.S.6 5.3.5.7. 5.35.8 S.3.S.9 5.3.6.1 S.3.6.2 5.3.6.3 5.3.6.4 5.3.6.S. S.3.6.6 S.3.6.7 5.3.6.8 S.3.6.9 5.3.7.1 S.3.7.2 5.3.7.3 5.3.7.4 5.3.7.S. S.3.7.6 5.3.7.7 5.3.7.8 5.3.7.9 5.38.1 S.3.8.2, 53.83 5.3.8.4 5.38.5 5.38.6 5.38.7 S.38.8 S.3.8.9 5.3.9.1 5.3.9.2 5.3.9.3 5.3.94 5.3.9.S 5.3.96 S.3.9.7 5.3.9.8 S3.99 S.4.1.1 54.12 S.4.13 S.4.14 54.15 5.4.1.6 54.17 5.4.18 5.4.19 54.2.1 5.4.2.2 54.23 5.4.2.4 5.4.2.5 5.4.2.6 5.4.2.7. 54.2.8, 5.42.9 54.3.1 54.32 5.4.3.3 5.434 5.4.3.5 5.4.3.6 5.4.3.7 5.43.8 54.39 5.4.4.1 5.4.4.2 544.3 5.4.4.4 5.445 S.4.4.6 5.4.4.7 5.448 S.4.4.9, 5.45.1 5.45.2 54.5.3 5.454 5.45.5 5.45.6 5.45.7 54.5.8 54.59 5.4.6.1 5.4.6.2 5.4.6.3 5.46.4 5.4.6.5 5.46.6

US 2009/011 8236 A1 May 7, 2009 63

TABLE 2-continued

6.5.1.2 6.5.13 6.5.1.4 6.5.1.5 6.5.1.6 6.5.1.7 6.5.1.8 6.5.19 6.5.2.1 6.5.2.2 6.5.23 6.5.2.4 6.5.2.5 6.5.2.6 6.5.2.7 6.5.2.8, 6.5.2.9 6.5.3.1 6.5.3.2. 6.5.3.3 6.5.3.4 6.5.3.5 6.5.3.6 6.5.3.7 6.5.3.8 6.5.3.9 6.54.1 6.5.4.2 6.543 6.5.44 6.5.45 6.54.6 6.5.47 6.5.48 6.5.4.9 6.55.1 6.55.2 6.5.5.3 6.55.4 6.55.5 6.5-5.6 6.55.7 6.558 6.55.9 6.5.6.1 6.5-6.2. 6.5.6.3 6.5.6.4 6.5.6.5 6.5.6.6 6.5.6.7 6.5.6.8, 6.5.6.9 6.5.7.1 6.5.7.2 6.5.7.3 6.5.7.4 6.5.7.5 6.5.7.6 6.5.7.7 6.5.7.8 6.5.7.9 6.5.8.1 6.5.8.2. 6.5.8.3 6.5.8.4 6.5.8.5 6.5.8.6 6.5.8.7 6.5.8.8 6.5-8.9 6.59.1 6.5.9.2 6.5.93 6.5.94 6.5.9.5 6.59.6 6.5.9.7 6.5.98 6.5.9.9 6.6.1.1 6.6.1.2. 6.6.13 6.6.1.4 6.6.1.5 6.6.16 6.617 6.6.18, 6.6.19 6.6.2.1 6.6.2.2 6.6.2.3 6.6.2.4 6.625 6.6.2.6 6.6.2.7 6.6.2.8, 6.6.29 66.31 6.6.32 66.33 6.6.3.4 6.6.35 6.63.6 6.6.3.7 6.63.8 6.6.39 66.4.1 66.4.2 6.6.43 66.4.4 6.64.5 6.6.46 6.64.7 6.6.4.8 6.64.9 6.6.5.1, 6.6.5.2. 6.6.5.3 6.6.54 6.6.5.5 6.65.6 6.6.5.7 6.658 6. 6.5.9 66.6.1 6.6.6.2. 6.6.6.3 6.66.4 6.6.65 6.6. 6.6 6.66.7 6.6.6.8, 6.66.9 6.6.7.1 6.6.7.2 6.6.7.3 6.6.7.4 6.6.7.5 6.6.7.6 6.6.7.7 6.6.7.8 6.6.7.9 6.68.1 6.6.8.2. 6.68.3 6.68.4 6.6.8.5 6.68.6 6.6.8.7 6.6.8.8 6.68.9 6.6.9.1 6.69.2 6.6.9.3 6.69.4 6.6.9.5 6.6.9.6 6.6.9.7 6.6-9.8 6.6.9.9 6.7.1.1 6.7.1.2. 6.7.1.3 6.7.1.4 6.7.1.5 6.7.1.6 6.7.1.7 6.7.1.8 6.7.1.9 6.7.2.1 6.7.22 6.7.2.3 6.7.24 6.7.25 6.7.2.6 6.7.27 6.7.2.8, 6.72.9 6.7.3.1 6.7.3.2. 6.7.33 6.7.34 6.7.3.5 6.7.3.6 6.7.3.7 6.7.3.8 6.7.3.9 6.7.4.1 6.7.4.2 6.7.4.3 6.74.4 6.7.45 6.74.6 6.74.7 6.74.8 6.74.9 6.7.5:1 6.75.2 6.7.5.3 6.7.5.4 6.7.S.S 6.7.5.6 6.75.7 6.7.58 6.75.9 6.7.6.1 6.7.6.2. 6.7.6.3 6.7.6.4 6.7.6.5 6.7.6.6 6.7.6.7 6.7.6.8, 6.7.6.9 6.77.1 6.7.7.2 6.7.7.3 6.7.74 6.7.7.5 6.7.7.6 6.7.7.7 6.7.7.8 6.7.7.9 6.7.8.1 6.7.8.2. 6.7.8.3 6.7.8.4 6.7.8.5 6.7.8.6 6.7.8.7 6.7.8.8 6.7.8.9 6.7.9.1 6.7.9.2 6.7.9.3 6.7.94 6.7.9.5 6.7.9.6 6.7.9.7 6.79.8 6.7.99 6.8.1.1 6.8.1.2 6.8.1.3 6.8.1.4 6.8.1.5 6.8.1.6 6.8.1.7 6.8.1.8 6.8.19 6.8.2.1 6.8.2.2 6.8.2.3 6.8.2.4 6.8.2.5 6.8.2.6 6.8.2.7 6.8.2.8, 6.8.2.9 6.8.3.1, 6.8.3.2. 6.8.33 6.83.4 6.8.35 6.83.6 6.83.7 6.8.3.8 6.83.9 6.8.4.1 6.8.4.2 6.84.3 6.8.44 6.84.5 6.8.4.6 6.84.7 6.848, 6.8.49 6.8.5.1, 6.8.5.2 6.8.5.3 6.85.4 6.8.55 6.85.6 6.8.57 6.85.8 6.85.9 6.8.6.1 6.8.6.2. 6.8.6.3 6.8.6.4 6.8.6.5 6.8.6.6 6.8.6.7 6.8.6.8, 6.8.6.9 6.87.1 6.8.7.2 6.87.3 6.8.74 68.75 6.87.6 6.8.7.7 6.87.8 6.8.79 6.88.1 6.88.2 6.8.8.3 6.884 6.8.85 6.88.6 6.88.7 6.8.8.8 6.88.9 6.8.9.1 6.89.2 6.89.3 6.8.9.4 6.89.5 6.8.9.6 68.9.7 6.89.8 6.8.9.9 6.9.1.1 6.9.1.2 6.9.13 6.9.14 6.9.1.5 6.9.1.6 6.9.17 6.9.18, 6.9.19 6.9.21 6.9.2.2 6.9.23 6.9.2.4 6.9.25 6.9.2.6 6.92.7 6.9.28 6.92.9 6.931 6.9.32 6.933 6.9.34 6.93.5 6.9.36 6.93.7 6.93.8 6.93.9 6.9.4.1 6.94.2 6.9.43 6.94.4 6.9.45 6.94.6 6.94.7 6.9.4.8 6.94.9 6.9.51 6.95.2 6.95.3 6.95.4 6.95.5 6.9.56 6.95.7 6.9.58 6.95.9 6.9.6.1 6.9.6.2 6.9.6.3 6.96.4 6.9.6.5 6.96.6 6.9.6.7 6.9.6.8, 6.96.9 6.9.7.1 6.9.7.2 6.9.7.3 6.97.4 6.9.75 6.9.7.6 6.97.7 6.9.78 6.97.9 6.9.8.1 6.9.8.2. 6.98.3 6.9.84 6.98.5 6.98.6 6.98.7 6.98.8 6.98.9 6.9-9.1 6.9.9.2 6.9.9.3 6.9.94 6.9.95 6.99.6 6.99.7 6.9.9.8 6.99.9 7.1.1.1 7.1.1.2 7.1.1.3 7.1.1.4 7.1.1.5 7.1.16 7.11.7 7.1.1.8 7.1.1.9 7.1.2.1 7.1.2.2 7.1.2.3 7.1.2.4 7.1.2.5 7.1.2.6 7.1.2.7 7.1.2.8, 7.1.2.9 7.1.3.1 7.1.3.2 7.1.3.3 7.1.3.4 7.1.3.5 7.1.3.6 7.1.3.7 7.1.3.8 7.1.3.9 7.14.1 7.14.2 7.1-4.3 7.14.4 7.14.5 7.14.6 7.14.7 7.14.8 7.14.9 7.1.5.1 7.1.5.2 7.1.5.3 7.1.5.4 7.1.S.S 7.1.5.6 7.1.5.7 7.1.5.8 7.1.5.9 7.1.6.1 7.16.2 7.1.6.3 7.16.4 7.16.5 7.16.6 7.1.6.7 7.1.6.8, 7.16.9 7.17.1 7.17.2 7.17.3 7.17.4 7.17.S 7.17.6 7.17.7 7.17.8 7.17.9 7.1.8.1 7.1.8.2 7.1.83 7.18.4 7.18.5 7.18.6 7.18.7 7.18.8 7.18.9 7.19.1 7.1.9.2 7.19.3 7.1.94 7.1.9S 7.1.9.6 7.1.9.7 7.19.8 7.19.9 7.2.1.1 7.2.1.2 7.2.1.3 7.2.1.4 7.2.1.5 7.2.1.6 7.2.1.7 7.2.1.8 7.2.1.9 7.2.2.1 7.2.2.2 7.223 7.2.2.4 7.2.2.5 7.2.2.6 7.2.2.7 7.2.2.8, 7.2.2.9 7.2.3.1 7.2.3.2 7.2.3.3 7.2.34 7.2.3.5 7.2.3.6 7.2.3.7 7.2.38 7.2.39 7.2.4.1 72.42 7.2.43 7.24.4 7.2.45 72.46 7.24.7 7.2.48 7.2.49 7.2.5.1 7.2.5.2 7.2.5.3 7.2.5.4 7.2.S.S 7.2.5.6 7.2.5.7 7.2.5.8 7.2.5.9 7.2.6.1 7.2.6.2 7.2.6.3 7.26.4 7.26.5 726.6 7.26.7 7.2.6.8, 7.26.9 7.2.7.1 7.2.7.2 7.2.7.3 7.2.7.4 7.2.7.5 7.2.7.6 7.2.7.7 7.2.7.8 7.2.7.9 7.2.8.1 7.2.8.2 7.2.8.3 7.2.84 7.2.8.S 7.28.6 7.2.8.7 7.2.8.8 7.28.9 7.2.9.1 7.2.9.2 7.2.93 7.2.9.4 7.2.9S 7.2.9.6 7.2.9.7 7.2.9.8 7.2.9.9 7.3.1.1 7.3.1.2 7.3.1.3 7.3.1.4 7.3.1.5 7.3.1.6 7.3.1.7 7.3.1.8 7.3.1.9 7.3.2.1 7.3.2.2 7.3.2.3 7.3.2.4 7.3.2.5 7.3.2.6 7.3.2.7 7.3.2.8 7.3.2.9 7.3.3.1 7.3.3.2 7.3.3.3 7.3.3.4 7.3.3.S 7.3.3.6 7.3.3.7 7.3.3.8 7.3.3.9 7.3.4.1 7.3.4.2 7.3.4.3 7.3.4.4 7.3.4.S 7.3.4.6 7.3.4.7 7.3.4.8 7.3.4.9 7.3.5.1, 73.5.2 7.3.5.3 7.35.4 7.3.S.S 7.3.5.6 7.3.5.7 7.3.S.8 7.3.S.9 7.3.6.1 7.3.6.2 7.3.6.3 7.3.6.4 7.3.6.5 7.3.6.6 7.3.6.7 7.3.6.8 7.3.6.9 7.3.7.1 7.3.7.2 7.3.7.3 7.3.7.4 7.3.7.5 7.3.7.6 7.3.7.7 7.3.7.8 7.3.7.9 7.3.8.1 7.3.8.2 7.38.3 7.3.8.4 7.3.8.5 7.3.8.6 7.3.8.7 7.38.8 7.3.8.9 7.3.9.1 7.3.9.2 7.3.9.3 7.3.94 7.3.9.S 7.3.96 7.3.9.7 7.3.9.8 7.3.9.9 7.4.1.1 7.4.1.2 7.4.13 74.14 7.4.15 7.4.1.6 7.4.17 7.4.18 7.4.19 7.4.2.1 74.2.2 74.23 7.4.24 742.5 7.4.2.6 7.4.2.7 7.4.2.8, 7.42.9 7.4.31 7.4.3.2 74.3.3 7.4.34 7.4.35 743.6 7.4.3.7 7.4.38 7.4.39 7.4.4.1 7.4.4.2 7.4.4.3 7.4.4.4 7.4.4.5 7.4.4.6 7.447 7.4.4.8 7.4.4.9 7.45.1 7.45.2 74.5.3 7.4.54 7.45.5 74.56 7.45.7 7.4.5.8 7.45.9 7.4.6.1 7.4.6.2 7.4.6.3 7.4.6.4 7.4.6.5 7.4.6.6 7.4.6.7 7.4.6.8 7.4.6.9 7.4.7.1 74.7.2 74.7.3 7.4-7.4 74.7.5 74.7.6 7.4-7.7 74.7.8 7.4-7.9 74.8.1 74.82 7.48.3 74.84 7.48.5 748.6 7.4.8.7 7.48.8 7.4.89 7.4.9.1 7.4.9.2 7.4.9.3 7.4.9.4 7.4.9.5 7.4.9.6 7.4.9.7 7.4.9.8 7.4.9.9 7.5.1.1 7.5.1.2 7.5.1.3 7.5.1.4 7.5.1.S 7.5.1.6 7.5.1.7 7.5.1.8 7.5.1.9 7.5.2.1 7.5.2.2 7.5.23 7.5.2.4 7.5.2.S 7.5.2.6 7.5.2.7 7.5.2.8 7.5.2.9 7.5.3.1 7.5.3.2 7.5.3.3 7.5.3.4 7.5.3.5 7.5.3.6 7.5.3.7 7.5.3.8 7.5.3.9 7.5.4.1 7.5.4.2 7.5.4.3 7.5.44 7.5.45

US 2009/011 8236 A1 May 7, 2009 66

TABLE 2-continued

9.6.2.5 9.6.2.6 9.6.2.7 9.6.2.8 9.6.29 96.3.1 9.6.32 96.3.3 96.34 9.6.3.5 96.36 9.6.3.7 96.38 9.63.9 9.6.4.1 96.42 96.43 9.6.4.4 9.64.5 9.6.46 96.47 9.64.8 96.49 96.5.1 96.5.2 96.5.3 9.654 96.S.S 9.65.6 9.6.S.7 96.5.8 9.65.9 9.6.6.1 9.662 9.6.6.3 9.66.4 9.66.5 9-6. 6.6 9.66.7 9.6.68 9.6.6.9 9.6.7.1 9.6.7.2 9.6.7.3 9.6.7.4 9.6.7.5 9.6.7.6 9.6.7.7 9.6.7.8 9.6.7.9 96.8.1 9.68.2 96.8.3 96.84 96.85 96.86 9.68.7 96.8.8 9.68.9 96.9.1 96.9.2 96.9.3 96.9.4 96.9.5 96.96 96.9.7 96.98 96.9.9 9.7.1.1 9.7.1.2 9.7.1.3 9.7.1.4 9.7.1.5 9.7.1.6 9.7.1.7 9.7.1.8 9.7.1.9 9.7.2.1 9.7.2.2 9.7.2.3 9.7.2.4 9.7.2.5 9.7.2.6 9.7.2.7 9.7.2.8 9.7.2.9 9.7.3.1 9.7.3.2 9.7.3.3 9.7.34 9.7.3.5 9.7.3.6 9.7.3.7 9.7.3.8 9.7.3.9 9.7.4.1 9.7.4.2 97.43 97.44 9.7.4.5 9.7.46 9.7.4.7 9.7.48 97.49 9.7.5.1 9.7.5.2 9.7.5.3 9.7.5.4 9.7.5.5 9.7.S.6 9.7.5.7 9.7.58 9.7.5.9 9.7.6.1 9.7.62 9.7.6.3 9.7.6.4 9.7.6.5 9.7.6.6 9.7.6.7 9.7.6.8 9.7.6.9 9.7.7.1 9.7.7.2 9.7.7.3 9.7.7.4 9.7.7.5 9.7.7.6 9.7.7.7 9.7.7.8 9.7.7.9 9.7.8.1 9.7.8.2 9.7.83 9.7.84 9.7.8.5 9.7.86 9.7.8.7 9.7.8.8 9.7.8.9 9.7.9.1 9.7.9.2 9.7.9.3 97.94 9.7.9.5 9.7.9.6 9.7.9.7 9.7.9.8 9.7.9.9 9.8.1.1 9.8.1.2 9.8.1.3 9.8.1.4 98.15 9.8.1.6 98.17 9.8.1.8 9.8.19 9.8.2.1 9.8.2.2 98.23 9.824 9.82.5 9.82.6 9.8.2.7 9.8.2.8 9.82.9 98.31 98.32 98.33 98.34 9.83.5 98.36 98.3.7 98.38 98.39 9.84.1 98.4.2 9.84.3 98.44 98.45 9.84.6 98.4.7 9.84.8 98.4.9 9.85.1 9.85.2 98.5.3 98.54 9.8.S.S 98.5.6 9.85.7 9.85.8 98.59 9.8.6.1 9.8.6.2 9.8.6.3 9.8.6.4 9.8.6.5 9.8.6.6 9.8.6.7 9.8.6.8 9.8.6.9 98.71 9.8.7.2 98.7.3 9.87.4 98.7.5 9.87.6 9.8.7.7 98.7.8 9.87.9 9.88.1 98.82 98.83 9.88.4 9.88.5 9.88.6 9.88.7 9.88.8 9.88.9 9.89.1 98.9.2 98.93 98.94 98.9.5 9.89.6 98.9.7 98.98 98.99 99.1.1 99.1.2 99.13 99.14 99.15 99.1.6 9.91.7 99.1.8 9.91.9 9.9.2.1 99.2.2 9.9.23 9.9.2.4 9.9.25 99.26 9.9.2.7 9.9.28 99.2.9 99.31 9.93.2 99.3.3 9.93.4 9.93.5 99.36 9.93.7 99.38 9.93.9 9.94.1 9.94.2 9.94.3 9.94.4 9.94.5 9.94.6 9.94.7 9.94.8 9.94.9 9.951 99.5.2 9.95.3 99.54 99.S.S 9.956 9.95.7 99.5.8 9.9.S.9 99.6.1 99.6.2 99.6.3 99.6.4 99.6.5 99.6.6 9.96.7 99.6.8 99.6.9 9.9.7.1 99.7.2 9.9.7.3 99.74 9.97.5 9.9.7.6 99.7.7 9.97.8 9.9.7.9 99.8.1 99.82 9.98.3 99.84 99.8.5 99.86 9.98.7 99.8.8 9.9-8.9 9.99.1 99.9.2 9.99.3 9.99.4 9.99.5 99.96 9.99.7 99.98 99.99

0932. In another aspect the following compounds are included in the invention but the compounds are not limited to -continued these illustrative compounds. The compounds are shown Formula XIII without depiction of stereochemistry since the compounds are biologically active as the diastereomeric mixture or as a single stereoisomer. Compounds included are designated by numbers assigned to the variables of formulas XI-XIII using HO SO V2-VI the following convention: V1,V2.V3.V4. V5.V6. Each indi vidual compound from 1.1.1.1.1.1 to 9.9.9.9.9.9 (e.g., 2.3.4. 5.6.7. or 8.7.3.5.2.1) is included in the present invention as an individual species and may be specifically set forthas such for inclusion or may be specifically excluded from the present invention. As the understanding is to what is included is clear Variable V: from the description thus, a Table is not included so as to not 0933 1) P(O)(OH), unduly lengthen the specification. 0934 2) -P(O)IO CHOC(O)C(CH), 0935 3) P(O)IO CHOC(O)CH(CH), 0936 4) -P(O)IO CHOC(O)OCHCH.), Formula XI 0937) 5) - P(O)NH-CH(CH)C(O)CCHCH 0938 6) -P(O)NH C(CH),C(O)OCHCH.), 0939 7) - P(O)(OCH), (0940) 8) -P(O)(O-CH(3-chlorophenyl)CHCH-O) HO (0941 9) -P(O)(O-CH(4-pyridyl)CHCH-O) Variable V: Formula XII (0942. 1)-CH 0943 2) OCH (0944 3) —CH CH (0945. 4) NHCH HO CH V2-VI 0946 5) - NH(CO) 0947 6) —CH2—CH(NH)— (R-configuration) 0948 7) —CH2—CH(NH)— (S-configuration) (0949 8)-CH=CH- (trans) 0950 9)-null US 2009/011 8236 A1 May 7, 2009 67

Variable V: -continued 0951 1) —OCH Formula XV 0952 2) iodo V5 V3 V7- Vl 0953 3) bromo N

0954 4) chloro HO O NH 0955 5) fluoro 0956 6) methyl 0957) 7) trifluoromethyl v4 V3 0958 8) cyano 0959 9). OCF, Variable V7: 0960| Variable V: 0961 1) iodo 0980) 1)-CH 0981) 2)-null 0962 2) CH(CH), 0982. The present invention provides for compounds of 0963 3) -(3-trifluoromethylphenoxy) Formula I including but not limited to wherein: 0964 4) -(3-ethylphenyl) 0965 5) - C(O)NH-CH CH-phenyl Phosphonic Acids 0966 6) —CH(OH)(4-fluorophenyl) 0983. G is - O Tis-CH-CH(NH) , R is I, R is 0967 7) —SO(4-fluorophenyl) I, R is I, R is -H, R is -OH, X is - POH: 0968 8) -(4-fluorobenzyl) 0984) G is-O. T is CH-CH(NH) , R' is I, R is 9) -1-ethyl-propyl –I, R is I, R is I, R is -OH, X is - POH: 0969 0985 G is - O Tis-CH , R is I, R is I, R is I, R is -H, R is -OH, X is - POH: Variable V and V 0986 G is - O Tis-N(H)C(O) , R is CH, R is 0970) 1) hydrogen —CH R is CH(OH) (4-fluorophenyl), R is H, R is - OH, X is - POH: 0971 2) iodo 0987 G is —CH , T is —OCH , R is CH, R is 0972 3) bromo —CH, R is i-propyl, R is -H, R is -OH, X is - POH: 0973 4) chloro 0988 G is - O Tis-CH , R' is - C1, R is - C1, R 0974 5) fluoro is i-propyl, R is —H, R is —OH, X is —POH: 0975 6) methyl 0989 Gis-O-, Tis–OCH R is I, R is - I, R 0976 7) trifluoromethyl is i-propyl, R is -H, R is -OH, X is POH: 8) cyano 0977 BSPOM 0978 9). OCH, 0979. In another aspect the following compounds are 0990 G is - O Tis-CH-CH(NH) , R is I, R is included in the invention but the compounds are not limited to –I, R is I, R is -H, R is -OH, X is -P(O)— these illustrative compounds. The compounds are shown OCHOC(O)C(CH)); without depiction of stereochemistry since the compounds 0991 G is-O. T is CH-CH(NH) , R" is I, R is are biologically active as the diastereomeric mixture or as a I, Ris-I, Ris-I, Ris-OH, X is P(O) OCHOC single stereoisomer. Compounds included are designated by (O)C(CH): numbers assigned to the variables of formulas XIV and XV 0992 G is - O Tis-CH , R' is I, R is I, R is using the following convention: V.V.V.V.V.V.V7 Each –I, R is -H, R is -OH, X is -P(O) OCHOC(O)C individual compound from 1.1.1.1.1.1.1 to 9.9.9.9.9.9.2 (e.g., (CH3)2. 2.3.4.5.6.7.1 or 8.7.3.5.2.1.1) is included in the present inven 0993 G is -O-, T is N(H)C(O) , R is CH, R is tion as an individual species and may be specifically set forth —CH, R is CH(OH)(4-fluorophenyl), R is -H, R is as such for inclusion or may be specifically excluded from the - OH, X is -P(O) OCHOC(O)C(CH): present invention. As the understanding is to what is included 0994) G is —CH2—, T is —OCH , R' is CH, R is is clear from the description thus, a Table is not included so as —CH R is i-propyl, R is -H, R is -OH, X is -P(O) to not unduly lengthen the specification OCHOC(O)C(CH): 0995 Gis O Tis-CH R is C1, Riis C1, R is i-propyl, R is -H, R is -OH, X is -P(O) OCHOC Formula XIV (O)C(CH): 0996) Gis-O-, Tis–OCH R is I, R is - I, R is i-propyl, R is -H, R is -OH, X is POH: HO O Carbonates 0997 G is O T is CH-CH(NH) , R is I, R is –I, R is I, R is -H, R is -OH, X is -P(O)— OCHOC(O)OCH(CH):

US 2009/011 8236 A1 May 7, 2009 69 tatin (ZOCOR; see U.S. Pat. Nos. 4,444,784; 4.450,171, ably CI-1011, of which the chemical name is 2,6-diisopropy 4.820,850: 4,916,239), pravastatin (PRAVACHOL: see U.S. lphenyl-N-(2,4,6-tr-iisopropylphenyl)acetylsulfamate, and Pat. Nos. 4,346,227; 4,537,859: 4,410,629; 5,030,447 and in the present invention CI-1011 including a pharmacologi 5,180,589), lactones of pravastatin (see U.S. Pat. No. 4,448, cally acceptable salt/co-crystal, ester or prodrug thereof, a 979), fluvastatin (LESCOL: see U.S. Pat. Nos. 5,354,772: compound having the general formula (I) including a phar 4,911, 165; 4,739,073: 4,929,437; 5,189,164; 5,118.853; macologically acceptable salt/co-crystal, ester or prodrug 5,290,946; 5,356,896), lactones of fluvastatin, atorvastatin thereof disclosed in EP 421-441 (U.S. Pat. No. 5,120,738) (LIPITOR; see U.S. Pat. Nos. 5.273,995; 4,681,893; 5,489, {preferably F-1394, of which the chemical name is (1S,2S)- 691; 5,342.952), lactones of atorvastatin, cerivastatin (also 2-3-(2,2-dimet-hylpropyl)-3-nonylureidocyclohexan-1-yl known as rivastatin and BAYCHOL; see U.S. Pat. No. 5,177, 3-(4R) N-(2.2.5.5-tetramethyl-1, -3-dioxane-4-carbonyl) 080, and European Application No. EP-491226A), lactones aminopropionate, and in the present invention F-1394 of cerivastatin, rosuvastatin (Crestor; see U.S. Pat. Nos. including a pharmacologically acceptable salt/co-crystal, 5,260,440 and RE37314, and European Patent No. ester or prodrug thereof: a compound including a pharma EP521471), lactones of rosuvastatin, itavastatin, nis vastatin, cologically acceptable salt/co-crystal, ester or prodrug visastatin, atavastatin, bervastatin, compactin, dihydrocom thereof disclosed in the Japanese Patent Publication (Kohyo) pactin, dalvastatin, fluindostatin, pitivastatin, mevastatin (see 2000-500771 (WO97/19918, U.S. Pat. No. 5,990, 173) {pref U.S. Pat. No. 3,983,140), and Velostatin (also referred to as erably F-12511, of which the chemical name is (S)-2',3',5'- synvinolin). Other examples of HMG-CoA reductase inhibi trimethyl-4'-hydroxy-alpha.-dodecylthio-alpha.-phenylac tors are described in U.S. Pat. Nos. 5,217,992; 5,196,440; eta-nilide, and in the present invention F-12511 including a 5,189, 180; 5,166.364; 5,157,134; 5,110,940; 5,106,992: pharmacologically acceptable salt/co-crystal, ester or pro 5,099,035; 5,081,136; 5,049,696; 5,049,577; 5,025,017; drug thereof.; a compound having the general formula (I) 5,011,947; 5,010,105: 4,970,221: 4,940,800; 4.866,058: including a pharmacologically acceptable salt/co-crystal, 4,686,237; 4,647,576: European Application Nos. ester or prodrug thereof disclosed in the Japanese Patent 0142146A2 and 0221025A1; and PCT Application Nos. WO Publication (Kokai) Hei 10-195037 (EP 790240, U.S. Pat. 86/03488 and WO 86/07054. Also included are pharmaceu No. 5,849,732) preferably T-2591, of which the chemical tically acceptable forms of the above. All of the above refer name is 1-(3-t-butyl-2-hydroxy-5-methoxyphenyl)-3-(2-cy ences are incorporated herein by reference. clohexylethyl)-3-(4-diethylaminophenyl)urea, and in the 1027 Non-limiting examples of suitable bile acid seques present invention T-2591 including a pharmacologically trants include cholestyramine (a styrene-divinylbenzene acceptable salt/co-crystal, ester or prodrug thereof.; a com copolymer containing quaternary ammonium cationic groups pound having the general formula (I) including a pharmaco capable of binding bile acids, such as QUESTRAN or QUES logically acceptable salt/co-crystal, ester or prodrug thereof TRAN LIGHT cholestyramine which are available from disclosed in WO 96/26948 preferably FCE-28654, of which Bristol-Myers Squibb), colestipol (a copolymer of diethylen the chemical name is 1-(2,6-diisopropylphenyl)-3-(4R,5R)- etriamine and 1-chloro-2,3-epoxypropane, Such as COLES 4.5-di-methyl-2-(4-phosphonophenyl)-1,3-dioxolan-2-ylm TID tablets which are available from Pharmacia), coleseve ethylurea, including a pharmacologically acceptable salt/co lam hydrochloride (such as WelChol Tablets (poly crystal, ester or prodrug thereof: a compound having the (allylamine hydrochloride) cross-linked with general formula (I) or a pharmacologically acceptable salt epichlorohydrin and alkylated with 1-bromodecane and thereof disclosed in the specification of WO 98/54153 (EP (6-bromohexyl)-trimethylammonium bromide) which are 987254) {preferably K-10085, of which the chemical name is available from Sankyo), water soluble derivatives such as N-2,4-bis(methylthio)-6-methyl-3-pyridyl-2-4-2-(ox 3.3-ioene, N-(cycloalkyl)alkylamines and poliglusam, aZolo4,5-b]pyridine-2-ylthio)ethylpiperazin-1-yl)aceta insoluble quaternized polystyrenes, Saponins and mixtures mide, including a pharmacologically acceptable salt/co-crys thereof. Other useful bile acid sequestrants are disclosed in tal, ester or prodrug thereof: a compound having the general PCT Patent Applications Nos. WO 97/11345 and WO formula (I) disclosed in WO92/09572 (EP559898, U.S. Pat. 98/57652, and U.S. Pat. Nos. 3,692,895 and 5,703,188 which No. 5,475,130) preferably HL-004, of which the chemical are incorporated herein by reference. Suitable inorganic cho name is N-(2,6-diisopropylphenyl)-2-tetradecylthioaceta lesterol sequestrants include bismuth Salicylate plus montmo mide.; a compound having the general formula (I) including rillonite clay, aluminum hydroxide and calcium carbonate a pharmacologically acceptable salt/co-crystal, ester or pro antacids. drug thereof disclosed in the Japanese Patent Publication 1028. In the above description, a fibrate base compound is (Kokai) Hei 7-82232 (EP 718281) {preferably NTE-122, of a medicament for inhibiting synthesis and secretion of trig which the chemical name is trans-1,4-bis 1-cyclohexyl-3-(4- lycerides in the liver and activating lipoprotein lipase, thereby dimethylaminophenyl)urei-domethylcyclohexane, and in lowering the triglyceride level in the blood. Examples include the present invention NTE-122 includes pharmacologically bezafibrate, beclobrate, binifibrate, ciprofibrate, clinofibrate, acceptable salts of NTE-122.; a compound including a phar clofibrate, clofibric acid, ethofibrate, fenofibrate, gemfibrozil, macologically acceptable salt/co-crystal, ester or prodrug nicofibrate, pirifibrate, ronifibrate, simfibrate and theofibrate. thereof disclosed in the Japanese Patent Publication (Kohyo) Such an ACAT inhibitor includes, for example: a compound Hei 10-510512 (WO 96/10559) {preferably FR-186054, of having the general formula (I) disclosed in WO92/09561 which the chemical name is 1-benzyl-1-3-(pyrazol-3-yl) preferably FR-129169, of which the chemical name is N-(1, benzyl-3-2,4-bis(methylthio)-6-methylpyridi-n-3-ylurea, 2-diphenylethyl)-2-(2-octyloxyphenyl)acetamide; a com and in the present invention FR-186054 including a pharma pound having the general formula (I) including a pharmaco cologically acceptable salt/co-crystal, ester or prodrug logically acceptable salt/co-crystal, ester or prodrug thereof thereof: a compound having the general formula (I) includ disclosed in the Japanese Patent Publication (Kohyo) Hei ing a pharmacologically acceptable salt/co-crystal, ester or 8-510256 (WO 94/26702, U.S. Pat. No. 5,491,172) {prefer prodrug thereof disclosed in WO 96/09287 (EP 0782986, US 2009/011 8236 A1 May 7, 2009 70

U.S. Pat. No. 5,990,150) preferably N-(1-pentyl-4,6-dim or the like), including a pharmacologically acceptable salt/ ethylindolin-7-yl)-2,2-dime-thylpropaneamide, and in the co-crystal, ester or prodrug thereof: a carboxylic acid present invention including a pharmacologically acceptable derivative having the general formula (I), including a phar salt/co-crystal, ester or prodrug thereof; and a compound macologically acceptable salt/co-crystal, ester or prodrug having the general formula (I) including a pharmacologically thereof disclosed in the Japanese Patent Publication (Kokai) acceptable salt/co-crystal, ester or prodrug thereof disclosed Hei 5-78328 (U.S. Pat. No. 5,616,599) {preferably olm in WO 97/12860 EP 0866059, U.S. Pat. No. 6,063,806) pref esartan, of which the chemical name is (5-methyl-2-oxo-1,3- erably N-(1-octyl-5-carboxymethyl-4,6-dimethylindolin-7- dioxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-pr yl)-2,2-dimethylpropaneamide, including a pharmacologi opyl-1-2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl cally acceptable salt/co-crystal, ester or prodrug thereof. imidazole-5-carboxylate, and in the present invention The ACAT inhibitor preferably is a compound selected from olmesartan includes carboxylic acid derivatives thereof, phar the group consisting of FR-129169, CI-1011, F-1394, macologically acceptable esters of the carboxylic acid deriva F-12511, T-2591, FCE-28654, K-10085, HL-004, NTE-122, tives (CS-866 or the like), including a pharmacologically FR-186054, N-(1-octyl-5-carboxymethyl-4,6-dimet-hylin acceptable salt/co-crystal, ester or prodrug thereof; and a dolin-7-yl)-2,2-dimethylpropaneamide (hereinafter referred compound having the general formula (I), including a phar as compoundA), and N-(1-pentyl-4,6-dimethylindolin-7-yl)- macologically acceptable salt/co-crystal, ester or prodrug 2,2-dimethylpropan-eamide (hereinafter referred as com pound B), including a pharmacologically acceptable salt/co thereof disclosed in the Japanese Patent Publication (Kokai) crystal, ester or prodrug thereof. The ACAT inhibitor more Hei 4-346978 (U.S. Pat. No. 5,591,762, EP 502,314) {pref preferably is a compound selected from the group consisting erably telmisartan, of which the chemical name is 4-2-n- of CI-1011, F-12511, N-(1-octyl-5-carboxymethyl-4,6- propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimi dime-thylindolin-7-yl)-2,2-dimethylpropaneamide (com dazol-1-yl)-methylbiphenyl-2-carboxylate, including a pound A), and N-(1-pentyl-4,6-dimethylindolin-7-yl)-2.2- pharmacologically acceptable salt/co-crystal, ester or pro dimethylpropaneamide (compound B), including a drug thereof. The angiotensin II receptor antagonist prefer pharmacologically acceptable salt/co-crystal, ester or pro ably is losartan, irbesartan, Valsartan, candesartan, olm drug thereof; most preferred is N-(1-octyl-5-carboxymethyl esartan, or telmisartan; more preferred is losartan or 4,6-dimethylindolin-7-yl)-2,2-ditnethylpropanea-mide olmesartan; and most preferred is olmesartan. (compound A). 1030. In addition to being useful in treating or preventing 1029. An angiotensin II receptor antagonist includes, for certain diseases and disorders, combination therapy with example, a biphenyltetrazole compound orbiphenylcarboxy compounds of this invention may be useful in reducing the lic acid derivative Such as: a compound having the general dosage of the second drug or agent (e.g., atorvastatin). formula (I) including a pharmacologically acceptable salt/co 1031. In addition, the compounds of the present invention crystal, ester or prodrug thereof disclosed in the Japanese can be used in combination with an apolipoprotein B secre Patent Publication (Kokai) Sho 63-23868 (U.S. Pat. No. tion inhibitor and/or microsomal triglyceride transfer protein 5,138,069) {preferably losartan, of which the chemical name (MTP) inhibitor. Some apolipoprotein B secretion inhibitors is 2-butyl-4-chloro-1-2'-(1H-tetrazol-5-yl)biphe-nyl-4-ylm and/or MTP inhibitors are disclosed in U.S. Pat. No. 5,919, ethyl)-1H-imidazol-5-methanol, and in the present invention 795. losartan including a pharmacologically acceptable salt/co 1032. Any HMG-CoA reductase inhibitor may be crystal, ester or prodrug thereof; a compound having the employed as an additional compound in the combination general formula (I) including a pharmacologically acceptable therapy aspect of the present invention. The term HMG-CoA salt/co-crystal, ester or prodrug thereof disclosed in the Japa reductase inhibitor refers to a compound that inhibits the nese Patent Publication (Kohyo) Hei 4-506222 (WO biotransformation of hydroxymethylglutaryl-coenzyme A to 91/14679) preferably irbesartan, of which the chemical mevalonic acid as catalyzed by the enzyme HMG-CoA name is 2-N-butyl-4-spirocyclopentane-1-2'-(1H-tetrazol reductase. Such inhibition may be determined readily by one 5-yl)bi-phenyl-4-ylmethyl-2-imidazoline-5-one, and in the of skill in the art according to standard assays (e.g., Methods present invention irbesartan including a pharmacologically of Enzymology, 71; 455-509 (1981); and the references cited acceptable salt/co-crystal, ester or prodrug thereof; a com therein). A variety of these compounds are described and pound having the general formula (I), an ester thereof, includ referenced below. U.S. Pat. No. 4,231,938 discloses certain ing a pharmacologically acceptable salt/co-crystal, ester or compounds isolated after cultivation of a microorganism prodrug thereof disclosed in the Japanese Patent Publication belonging to the genus Aspergillus, such as lovastatin. Also (Kokai) Hei 4-235149 (EP 433983) {preferably valsartan, of U.S. Pat. No. 4,444,784 discloses synthetic derivatives of the which the chemical name is (S)- N-Valeryl-N-2'-(1H-tetra aforementioned compounds, such as simvastatin. Addition Zol-5-yl)biphenyl-4-ylmethylvaline, and in the present ally, U.S. Pat. No. 4,739,073 discloses certain substituted invention Valsartan including a pharmacologically acceptable indoles, such as fluvastatin. Further, U.S. Pat. No. 4,346,227 salt/co-crystal, ester or prodrug thereof; a carboxylic acid discloses ML-236B derivatives, such as pravastatin. In addi derivative having the general formula (I), including a phar tion, EP 491,226 teaches certain pyridyldihydroxyheptenoic macologically acceptable salt/co-crystal, ester or prodrug acids, such as rivastatin. Also, U.S. Pat. No. 4,647,576 dis thereof disclosed in the Japanese Patent Publication (Kokai) closes certain 6-2-(substituted-pyrrol-1-yl)-alkyl-pyran-2- Hei 4-364171 (U.S. Pat. No. 5,196,444) {preferably cande ones such as atorvastatin. Other HMG-CoA reductase inhibi Sartan, of which the chemical name is 1-(cyclohexyloxycar tors will be known to those skilled in the art. Examples of bonyloxy)ethyl 2-ethoxy-1-2'-(1H-etrazol-5-yl)biphen-yl currently or previously marketed products containing HMG 4-ylmethyl)-1H-benzimidazole-7-carboxylate, and in the CoA reductase inhibitors include cerivastatin Na, rosuvasta present invention candesartan including a pharmacologically tin Ca, fluvastatin, atorvastatin, lovastatin, pravastatin Na and acceptable salt/co-crystal, ester or prodrug thereof (TCV-116 simvastatin. US 2009/011 8236 A1 May 7, 2009

1033) Any HMG-CoA synthase inhibitor may be used as variety of these compounds are described and referenced an additional compound in the combination therapy aspect of below; however, other ACAT inhibitors will be known to this invention. The term HMG-CoA synthase inhibitor refers those skilled in the art. U.S. Pat. No. 5,510,379 discloses to a compound that inhibits the biosynthesis of hydroxymeth certain carboxysulfonates, while WO 96/26948 and WO ylglutaryl-coenzyme A from acetyl-coenzyme A and 96/10559 both disclose urea derivatives having ACAT inhibi acetoacetyl-coenzyme A, catalyzed by the enzyme HMG tory activity. CoA synthase. Such inhibition may be determined readily by 1037. Any compound having activity as a squalene Syn one of skill in the art according to standard assays (e.g., thetase inhibitor can serve as an additional compound in the Methods of Enzymology 35: 155-160 (1975); and Methods of combination therapy aspect of the instant invention. The term Enzymology, 110: 19-26 (1985); and the references cited squalene synthetase inhibitor refers to compounds that inhibit therein). A variety of these compounds are described and the condensation of two molecules of fameSylpyrophosphate referenced below. U.S. Pat. No. 5,120,729 discloses certain to form squalene, a reaction that is catalyzed by the enzyme beta-lactam derivatives. U.S. Pat. No. 5,064,856 discloses squalene synthetase. Such inhibition is readily determined by certain spiro-lactone derivatives prepared by culturing the those skilled in the art according to standard methodology microorganism MF5253. U.S. Pat. No. 4,847,271 discloses (Methods of Enzymology 15:393-454 (1969); and Methods of certain oxetane compounds such as 11-(3-hydroxymethyl-4- Enzymology 110: 359-373 (1985); and references cited oxo-2-oxetayl)-3,5,7-trimethyl-2,4-undecadienoic acid therein). A Summary of squalene synthetase inhibitors has derivatives. Other HMG-CoA synthase inhibitors useful in been complied in Curr: Op. Ther Patents, 861-4, (1993). EP0 the methods, compositions and kits of the present invention 567 026 A1 discloses certain 4.1-benzoxazepine derivatives will be known to those skilled in the art. as squalene synthetase inhibitors and their use in the treat 1034 Any compound that decreases HMG-CoA reduc ment of hypercholesterolemia and as fungicides. EP 0 645 tase gene expression may be used as an additional compound 378 A1 discloses certain seven- or eight-membered hetero in the combination therapy aspect of this invention. These cycles as squalene synthetase inhibitors and their use in the agents may be HMG-CoA reductase transcription inhibitors treatment and prevention hypercholesterolemia and fungal that block the transcription of DNA or translation inhibitors infections. EPO 645377 A1 discloses certain benzoxazepine that prevent translation of mRNA coding for HMG-CoA derivatives as squalene synthetase inhibitors useful for the reductase into protein. Such inhibitors may either affect tran treatment of hypercholesterolemia or coronary sclerosis. EP Scription or translation directly, or may be biotransformed 0 611 749A1 discloses certain substituted amic acid deriva into compounds that have the aforementioned attributes by tives useful for the treatment of arteriosclerosis. EPO 705 607 one or more enzymes in the cholesterol biosynthetic cascade A2 discloses certain condensed seven- or eight-membered or may lead to the accumulation of an isoprene metabolite that heterocyclic compounds useful as antihypertriglyceridemic has the aforementioned activities. Such regulation is readily agents. WO96/09827 discloses certain combinations of cho determined by those skilled in the art according to standard lesterol absorption inhibitors and cholesterol biosynthesis assays (Methods of Enzymology, 110:9-19 (1985)). Several inhibitors including benzoxazepine derivatives and benzothi such compounds are described and referenced below; how azepine derivatives. EP 0701 725 A1 discloses a process for ever, other inhibitors of HMG-CoA reductase gene expres preparing certain optically-active compounds, including ben sion will be known to those skilled in the art, for example, Zoxazepine derivatives, having plasma cholesterol and trig U.S. Pat. No. 5,041,432 discloses certain 15-substituted lyceride lowering activities. lanosterol derivatives that are inhibitors of HMG-CoA reduc 1038. Other compounds that are currently or previously tase gene expression. Other oxygenated Sterols that Suppress marketed for hyperlipidemia, including hypercholester the biosynthesis of HMG-CoA reductase are discussed by E. olemia, and which are intended to help prevent or treat ath I. Mercer (Prog. Lip. Res., 32:357-416 (1993)). erosclerosis, include bile acid sequestrants. Such as colestipol 1035 Any compound having activity as a CETP inhibitor HCl and cholestyramine; and fibric acid derivatives, such as can serve as the second compound in the combination therapy clofibrate, fenofibrate, and gemfibrozil. These compounds aspect of the instant invention. The term CETP inhibitor can also be used in combination with a compound of the refers to compounds that inhibit the cholesteryl ester transfer present invention. protein (CETP) mediated transport of various cholesteryl 1039. It is also contemplated that the compounds of the esters and triglycerides from HDL to LDL and VLDL. A present invention be administered with a lipase inhibitor and/ variety of these compounds are described and referenced or a glucosidase inhibitor, which are typically used in the below; however, other CETP inhibitors will be known to treatment of conditions resulting from the presence of excess those skilled in the art. U.S. Pat. No. 5,512,548 discloses triglycerides, free fatty acids, cholesterol, cholesterol esters certain polypeptide derivatives having activity as CETP or glucose including, inter alia, obesity, hyperlipidemia, inhibitors, while certain CETP-inhibitory rosenonolactone hyperlipoproteinemia, Syndrome X, and the like. derivatives and phosphate-containing analogs of cholesteryl 1040. In a combination with a compound of the present ester are disclosed in J. Antibiot., 49(8): 815-816 (1996), and invention, any lipase inhibitor or glucosidase inhibitor may be Bioorg Med. Chem. Lett., 6:1951-1954 (1996), respectively. employed. In one aspect lipase inhibitors comprise gastric or 1036) Any ACAT inhibitor can serve as an additional com pancreatic lipase inhibitors. In a further aspect glucosidase pound in the combination therapy aspect of this invention. inhibitors comprise amylase inhibitors. Examples of glucosi The term ACAT inhibitor refers to a compound that inhibits dase inhibitors are those inhibitors selected from the group the intracellular esterification of dietary cholesterol by the consisting of acarbose, adiposine, Voglibose, miglitol, enzyme acyl CoA: cholesterol acyltransferase. Such inhibi emiglitate, camiglibose, tendamistate, trestatin, pradimi tion may be determined readily by one of skill in the art cin-Q and salbostatin. Examples of amylase inhibitors according to standard assays, such as the method of Heideret include tendamistat and the various cyclic peptides related al. described in Journal of Lipid Research, 24:1127 (1983). A thereto disclosed in U.S. Pat. No. 4,451,455, AI-3688 and the US 2009/011 8236 A1 May 7, 2009 72 various cyclic polypeptides related thereto disclosed in U.S. 1047. The pancreatic lipase inhibitor WAY-121898, Pat. No. 4,623,714, and trestatin, consisting of a mixture of 4-phenoxyphenyl-4-methylpiperidin-1-yl-carboxylate, and trestatin A, trestatin B and trestatin C and the various treha the various carbamate esters and pharmaceutically acceptable lose-containing aminosugars related thereto disclosed in U.S. salts related thereto, are disclosed in U.S. Pat. Nos. 5,512, Pat. No. 4,273,765. 565; 5,391,571 and 5,602,151. 1041. A lipase inhibitor is a compound that inhibits the 1048. The lipase inhibitor Bay-N-3176, N-3-trifluorom metabolic cleavage of dietary triglycerides into free fatty ethylphenyl-N'-3-chloro-4-trifluoromethylphenylurea, and acids and monoglycerides. Under normal physiological con the various urea derivatives 65 related thereto, are disclosed in ditions, lipolysis occurs via a two-step process that involves U.S. Pat. No. 4,405,644. acylation of an activated serine moiety of the lipase enzyme. 1049. The pancreatic lipase inhibitor valilactone, and a This leads to the production of a fatty acid-lipase hemiacetal process for the preparation thereof by the microbial cultiva intermediate, which is then cleaved to release a diglyceride. tion of Actinomycetes strain MG 147CF, are disclosed in Following further deacylation, the lipase-fatty acid interme Kitahara, et al., J. Antibiotics, 40(11): 1647-50 (1987). diate is cleaved, resulting in free lipase, a monoglyceride and 1050. The lipase inhibitoresteracin, and certain processes a fatty acid. The resultant free fatty acids and monoglycerides for the preparation thereof by the microbial cultivation of are incorporated into bile acid phospholipid micelles, which Streptomyces strain ATCC 31336, are disclosed in U.S. Pat. are subsequently absorbed at the level of the brush border of Nos. 4,189,438 and 4,242,453. the small intestine. The micelles eventually enter the periph 1051. The pancreatic lipase inhibitors ebelactone A and eral circulation as chylomicrons. Accordingly, compounds, ebelactone B, and a process for the preparation thereof by the including lipase inhibitors that selectively limit or inhibit the microbial cultivation of Actinomycetes strain MG7-G1, are absorption of ingested fat precursors are useful in the treat disclosed in Umezawa, et al., J. Antibiotics, 33, 1594-1596 ment of conditions including obesity, hyperlipidemia, hyper (1980). The use of ebelactones A and B in the suppression of lipoproteinemia, Syndrome X, and the like. monoglyceride formation is disclosed in Japanese Kokai 08-143457, published Jun. 4, 1996. 1042 Pancreatic lipase mediates the metabolic cleavage 1052. The lipase inhibitor RHC 80267, cyclo-O,O'-(1,6- of fatty acids from triglycerides at the 1- and 3-carbon posi hexanediyl)-bis-(iminocarbonyl) dioxime, and the various tions. The primary site of the metabolism of ingested fats is in bis(iminocarbonyl)dioximes related thereto may be prepared the duodenum and proximal jejunum by pancreatic lipase, as described in Petersen et al., Liebig's Annalem, 562: 205-29 which is usually secreted in vast excess of the amounts nec (1949). essary for the breakdown of fats in the upper small intestine. 1053. The ability of RHC 80267 to inhibit the activity of Because pancreatic lipase is the primary enzyme required for myocardial lipoprotein lipase is disclosed in Carroll et al., the absorption of dietary triglycerides, inhibitors have utility Lipids, 27 305-7 (1992) and Chuang et al., J. Mol. Cell. in the treatment of obesity and the other related conditions. Cardiol., 22: 1009-16 (1990). 1043 Gastric lipase is an immunologically distinct lipase 1054. In another aspect of the present invention, the com that is responsible for approximately 10 to 40% of the diges pounds of Formula I can be used in combination with an tion of dietary fats. Gastric lipase is secreted in response to additional anti-obesity agent. The additional anti-obesity mechanical stimulation, ingestion of food, the presence of a agent in one aspect is selected from the group consisting of a fatty meal or by sympathetic agents. Gastric lipolysis of 3-adrenergic receptoragonist, a cholecystokinin-A agonist, a ingested fats is of physiological importance in the provision monoamine reuptake inhibitor, a sympathomimetic agent, a offatty acids needed to trigger pancreatic lipase activity in the Serotoninergic agent, a dopamine agonist, a melanocyte intestine and is also of importance for fat absorption in a stimulating hormone receptor agonist or mimetic, a melano variety of physiological and pathological conditions associ cyte-stimulating hormone receptor analog, a cannabinoid ated with pancreatic insufficiency. See, for example, C. K receptor antagonist, a melanin concentrating hormone Abrams, et al., Gastroenterology 92: 125 (1987). antagonist, leptin, a leptin analog, a leptin receptor agonist, a 1044. A variety of lipase inhibitors are known to one of galanin antagonist, a lipase inhibitor, a bombesin agonist, a ordinary skill in the art. However, in the practice of the meth neuropeptide-Yantagonist, a thyromimetic agent, dehydroe ods, pharmaceutical compositions, and kits of the instant piandrosterone or an analog thereof, a glucocorticoid recep invention, generally lipase inhibitors are those inhibitors that tor agonist or antagonist, an orexin receptor antagonist, a are selected from the group consisting of lipstatin, tetrahy urocortin binding protein antagonist, a glucagon-like pep drolipstatin (orlistat), FL-386, WAY-121898, Bay-N-3176, tide-1 receptor agonist, and a ciliary neurotrophic factor. valilactone, esterastin, ebelactone A, ebelactone B and RHC 1055. In an additional aspect the anti-obesity agents com 8O267. prise those compounds selected from the group consisting of 1045. The pancreatic lipase inhibitors lipstatin, 2S,3S, SS, Sibutramine, fenfluramine, dexfenfluramine, bromocriptine, 7Z.10Z)-5-(S)-2-formamido-4-methyl-valeryloxy-2- phentermine, ephedrine, leptin, phenylpropanolamine pseu hexyl-3-hydroxy-7.1 (t-hexadecan oic acid lactone, and tet doephedrine, 4-2-(2-6-aminopyridin-3-yl)-2(R)-hydroxy rahydrolipostatin (orlistat), 2S, 3S, 55)-5-(S)-2-formamido ethylamino)ethoxyphenyl)acetic acid, 4-2-(2-6-ami 4-methyl-Valeryloxy-2-hexyl-3-hydroxy-hexadecanoic acid nopyridin-3-yl)-2(R)-hydroxyethylamino)ethoxy lactone, and the variously substituted N-formylleucine phenylbenzoic acid, 4-2-(2-6-aminopyridin-3-yl)-2(R)- derivatives and stereoisomers thereof, are disclosed in U.S. hydroxyethylamino)ethoxyphenylpropionic acid, and {4- Pat. No. 4,598,089. 2-(2-6-aminopyridin-3-yl)-2(R)-hydroxyethylamino) 1046. The pancreatic lipase inhibitor FL-386, 1-4-(2-me ethoxyphenoxyacetic acid. thylpropyl)cyclohexyl-2-(phenylsulfonyl)oxy-ethanone, 1056. In one aspect, the present invention concerns the and the variously substituted sulfonate derivatives related prevention or treatment of diabetes, including impaired glu thereto, are disclosed in U.S. Pat. No. 4,452,813. cose tolerance, insulin resistance, insulin dependent diabetes US 2009/011 8236 A1 May 7, 2009

mellitus (Type I) and non-insulin dependent diabetes mellitus Suring the inhibition of glucose production by isolated hepa (NIDDM or Type II). Also included in the prevention or tocytes or in a perfused liver, or by measuring blood glucose treatment of diabetes are the diabetic complications, such as lowering in normal or diabetic animals (e.g., Vincent M F. neuropathy, nephropathy, retinopathy or cataracts. Erion MD, Gruber HE, Van den Berghe, Diabetologia. 1996, 1057. In one aspect the type of diabetes to be treated by the 39(10): 1148-55: Vincent MF, Marangos PJ, Gruber HE, Van compounds of the present invention is non-insulin dependent den Berghe G. Diabetes 1991 40(10): 1259-66). In some diabetes mellitus, also known as Type II diabetes or NIDDM. cases, in vivo metabolic activation of a compound may be 1058 Diabetes can be treated by administering to a patient required to generate the FBPase inhibitor. This class of com having diabetes (Type I or Type II), insulin resistance, pounds may be inactive in the enzyme inhibition screen, may impaired glucose tolerance, or any of the diabetic complica or may not be active in hepatocytes, but is active in vivo as tions such as neuropathy, nephropathy, retinopathy or cata evidenced by glucose lowering in the normal, fasted rat and/ racts, a therapeutically effective amount of a compound of the or in animal models of diabetes. present invention. It is also contemplated that diabetes be 1062. A variety of FBPase inhibitors are described and treated by administering a compound of the present invention referenced below; however, other FBPase inhibitors will be along with other agents that can be used to prevent or treat known to those skilled in the art. Gruber et al. U.S. Pat. No. diabetes. 5,658,889 described the use of inhibitors of the AMP site of 1059 Representative agents that can be used to treat dia FBPase to treat diabetes: WO 98/39344 and U.S. Pat. No. betes in combination with a compound of the present inven 6.284,748 describe purine inhibitors: WO 98/39343 and U.S. tion include insulin and insulin analogs (e.g., LysPro insulin); Pat. No. 6,110,903 describe benzothiazole inhibitors to treat GLP-1 (7-37) (insulinotropin) and GLP-1 (7-36)-NH. diabetes: WO 98/39342 and U.S. Pat. No. 6,054,587 describe Agents that enhance insulin secretion, e.g., eblorpropamide, indole inhibitors to treat diabetes; and WO 00/14095 and U.S. glibenclamide, tolbutamide, tolaZamide, acetohexamide, Pat. No. 6,489.476 describe heteroaromatic phosphonate glypizide, glimepiride, repaglinide, nateglinide, meglitinide; inhibitors to treat diabetes. Other FBPase inhibitors are biguanides: metformin, phenformin, buformin; A2-antago described in Wright SW, Carlo AA, Carty M D et al., J Med nists and imidazolines: midaglizole, isaglidole, deriglidole, Chem. 200245(18):3865-77 and WO99/47549. idazoxan, efaroxan, fluparoxan; other insulin secretagogues 1063. The compounds of the present invention can also be linogliride, A-4166; glitaZones: ciglitaZone, pioglitaZone, used in combination with Sulfonylureas Such as arnaryl, aly englitazone, troglitazone, dargilitazone, BR 149653; fatty acid buride, glucotrol, chlorpropamide, diabinese, tolaZamide, oxidation inhibitors: clomoxir, etomoxir; a-glucosidase tolinase, acetohexamide, glipizide, tolbutamide, orinase, inhibitors: acarbose, miglitol, emiglitate, Voglibose, MDL25, glimepiride, DiaBeta, micronase, glibenclamide, and gli 637, camiglibose, MDL-73.945; -3-agonists: BRL 35135, clazide. BRL 37344, RO 16-87.14, ICI D7114, CL 316,243; phos 1064. The compounds of the present invention can also be phodiesterase inhibitors: -386,398; lipid-lowering agents used in combination with antihypertensive agents. Any anti benfluorex; antiobesity agents: fenfiuramine; Vanadate and hypertensive agent can be used as the second agent in Such Vanadium complexes (e.g., bis(cysteinamide N-octyl)oxova combinations. Examples of presently marketed products con nadium) and peroxovanadium complexes; amylin antago taining antihypertensive agents include calcium channel nists; glucagon antagonists; gluconeogenesis inhibitors; blockers, such as Cardizem, Adalat, Calan, Cardene, Covera, Somatostatin analogs; antilipolytic agents: nicotinic acid, Dilacor, DynaCirc, Procardia XL, Sular, Tiazac, Vascor, Ver acipimox, WAG 994. Also contemplated to be used in com elan, Isoptin, Ninotop, Norvasc, and Plendil, angiotensin bination with a compound of the present invention are pram converting enzyme (ACE) inhibitors, such as Accupril, lintide (symlinTM), AC 2993 and nateglinide. Any agent or Altace, Captopril, Lotensin, Mavik, Monopril, Prinivil, combination of agents can be administered as described Univasc, Vasotec and Zestril. above. 1065. Examples of compounds that may be used in com 1060. In addition, the compounds of the present invention bination with the compounds of the present invention to pre can be used in combination with one or more aldose reductase vent or treat osteoporosis include: anti-resorptive agents inhibitors, DPPIV inhibitor, glycogen phosphorylase inhibi including progestins, polyphosphonates, bisphosphonate(s), tors, sorbitol dehydrogenase inhibitors, NHE-1 inhibitors estrogen agonists/antagonists, estrogen, estrogen/progestin and/or glucocorticoid receptor antagonists. combinations, Premarin, estrone, estriol or 17.alpha.- or 1061 Any compound having activity as a fructose-1,6- 17.beta.-ethynyl estradiol); progestins including algestone bisphosphatase (FBPase) inhibitor can serve as the second acetophenide, altrenogest, amadinone acetate, anagestone compound in the combination therapy aspect of the instant acetate, chlormadinone acetate, cingestol, clogestone acetate, invention (e.g., 2-Amino-5-isobutyl-4-2-5-(N,N'-bis(S)- clomegestone acetate, dehnadinone acetate, desogestrel, 1-ethoxycarbonyl)ethyl)phosphonamidofuranylthiazoles). dimethisterone, dydrogesterone, ethynerone, ethynodiol FBPase is a key regulatory enzyme in gluconeogenesis, the diacetate, etonogestrel, fluorogestone acetate, gestaclone, metabolic pathway by which the liver synthesizes glucose gestodene, gestonorone caproate, gestrinone, haloprogester from 3-carbon precursors. The term FBPase inhibitor refers one, hydroxyprogesterone caproate, levonorgestrel, lynestre to compounds that inhibit FBPase enzyme activity and nol, medrogestone, medroxyprogesterone acetate, thereby block the conversion of fructose-1,6-bisphosphate, melengestrol acetate, methynodiol diacetate, norethindrone, the substrate of the enzyme, to fructose 6-phosphate. FBPase norethindrone acetate, norethynodrel, norgestimate, norg inhibition can be determined directly at the enzyme level by estomet, norgestrel, oxogestone phenpropionate, progester those skilled in the art according to standard methodology one, quingestanol acetate, quingestrone, and tigestol; and (e.g., Gidh-Jain M, ZhangY. van Poele PD et al., J Biol Chem. bone resorption inhibiting polyphosphonates including poly 1994, 269(44): 27732-8). Alternatively, FBPase inhibition phosphonates such as of the type disclosed in U.S. Pat. No. can be assessed according to standard methodology by mea 3.683,080, the disclosure of which is incorporated herein by US 2009/011 8236 A1 May 7, 2009 74 reference. Examples of polyphosphonates include geminal (4"-fluorophenyl)-6-hydroxy-1.2.3, diphosphonates (also referred to as bis-phosphonates), tiludr -4-tetrahydroisoquinoline, cis-6-(4-hydroxyphenyl)-5-(4-(2- onate disodium, ibandronic acid, alendronate, resindronate piperidin-1-yl-ethoxy)-phenyl)-5,6,-7,8-tetrahydro-naphtha Zoledronic acid, 6-amino-1-hydroxy-hexylidene-bisphos lene-2-ol: 1-(4-pyrrolidinolethoxyphenyl)-2-phenyl-6-hy phonic acid and 1-hydroxy-3 (methylpentylamino)-propy droxy-1,2,3,4-tetrahyd-roisoquinoline, 2-phenyl-3-aroyl lidene-bisphosphonic acid. Salts, co-crystals and esters of the benzoth-iophene and 2-phenyl-3-aroylbenzothiophene-1- polyphosphonates are likewise included. Specific examples oxide. include ethane-1-hydroxy 1,1-diphosphonic acid, methane 1067. Other anti-osteoporosis agents, which can be used diphosphonic acid, pentane-1-hydroxy-1,1-diphosphonic as the second agent in combination with a compound of the acid, methane dichloro diphosphonic acid, methane hydroxy present invention, include, for example, the following: par diphosphonic acid, ethane-1-amino-1,1-diphosphonic acid, athyroid hormone (PTH) (abone anabolic agent); parathyroid ethane-2-amino-1,1-diphosphonic acid, propane-3-amino-1- hormone (PTH) secretagogues (see, e.g., U.S. Pat. No. 6,132, hydroxy-1,1-diphosphonic acid, propane-N,N-dimethyl-3- 774), particularly calcium receptor antagonists; calcitonin; amino-1-hydroxy-1,1-diphosphonic acid, propane-3,3-dim and vitamin D and Vitamin Danalogs. Further anti-osteoporo ethyl-3-amino-1-hydroxy-1,1-diphosphonic acid, phenyl sis agents includes a selective androgen receptor modulator amino methane diphosphonic acid, N,N-dimethylamino (SARM). Examples of suitable SARMs include compounds methane diphosphonic acid, N(2-hydroxyethyl)amino meth Such as cyproterone acetate, chlormadinone, flutamide, ane diphosphonic acid, butane-4-amino-1-hydroxy-11 hydroxyflutamide, bicalutamide, nilutamide, Spironolactone, diphosphonic acid, pentane-5-amino-1-hydroxy-1,1-diphos 4-(trifluoromethyl)-2(1H)-pyrrolidino3.2-gquinoline phonic acid, and hexane-6-amino-1-hydroxy-11 derivatives, 1,2-dihydropyridino.5,6-glquinoline derivatives diphosphonic acid. and piperidino3.2-gquinolinone derivatives. Other 1066 Estrogen agonist/antagonist include 3-(4-(12 examples include cypterone, also known as (1b.2b)-6-chloro diphenyl-but-1-e nyl)-phenyl)-acrylic acidr, tamoxifen: 1,2-dihydro-17-hydroxy-3'-H-cyclopropa 1.2pregna-1,4,6- (ethanamine, 2-(4-(1,2-diphenyl-1-butenyl)phenoxy)-N,N- triene-3,20-dione is disclosed in U.S. Pat. No. 3,234,093. dimethyl, (Z)-2-, 2-hydroxy-1,2,3-propanetricarboxylate(1: Chlormadinone, also known as 17-(acetyloxy)-6-chloropre 1)) and related compounds which are disclosed in U.S. Pat. gna-4,6-diene-320-dione, in its acetate form, acts as an anti No. 4,536,516, the disclosure of which is incorporated herein androgen and is disclosed in U.S. Pat. No. 3,485,852. Niluta by reference, 4-hydroxy tamoxifen, which is disclosed in mide, also known as 5,5-dimethyl-3-4-nito-3- U.S. Pat. No. 4,623,660, the disclosure of which is incorpo (trifluoromethyl)phenyl-2,4-imidazolidinedione and by the rated herein by reference, raloxifene: (methanone, (6-hy trade name Nilandron(R) is disclosed in U.S. Pat. No. 4,097, droxy-2-(4-hydroxyphenyl)benzob thien-3-yl)(4-(2-(1-pip 578. Flutamide, also known as 2-methyl-N-4-nitro-3-(trif eridinyl)eth-oxy)phenyl)-hydrochloride) which is disclosed luoromethyl-1)phenylpropanamide and the trade name in U.S. Pat. No. 4,418,068, the disclosure of which is incor Eulexin R is disclosed in U.S. Pat. No. 3,847,988. Bicaluta porated herein by reference, toremifene: (ethanamine, 2-(4- mide, also known as 4-cyano-a'a'a'-trifluo-ro-3-(4-fluo (4-chloro-1,2-diphenyl-1-butenyl)phenoxy)-N,N-dimethyl-, rophenylsulfonyl)-2-hydroxy-2-methylpropiono-m-toluid (Z)-, 2-hydroxy-1,2,3-propanetricarboxylate (1:1) which is ide and the trade name Casodex(R) is disclosed in EP-100172. disclosed in U.S. Pat. No. 4,996,225, the disclosure of which The enantiomers of biclutamide are discussed by Tucker and is incorporated herein by reference, centchroman: 1-(2-((4-(- Chesterton, J. Med. Chem. 1988, 31, 885-887. Hydroxyfluta methoxy-2.2, dimethyl-3-phenyl-chrornan-4-yl)-phenoxy)- mide, a known androgen receptor antagonist in most tissues, ethyl)-p-pyrrolidine, which is disclosed in U.S. Pat. No. has been suggested to function as a SARM for effects on IL-6 3,822.287, the disclosure of which is incorporated herein by production by osteoblasts as disclosed in Hofbauer et al. J. reference, levormeloxifene, idoxifene: (E)-1-2-(4-(1-(4- Bone Miner. Res. 1999, 14, 1330-1337. Additional SARMs iodo-phenyl)-2-phenyl-but-1-enyl)-phenoxy)-ethyl)-pyrro have been disclosed in U.S. Pat. No. 6,017,924; WO lidinone, which is disclosed in U.S. Pat. No. 4,839,155, the 01/16108, WO 01/16133, WO 01/16139, WO 02/00617, WO disclosure of which is incorporated herein by reference, 2-(4- 02/16310, U.S. Patent Application Publication No. US 2002/ methoxy-phenyl)-3-4-(2-piperidin-1-yl-ethoxy)-phenoxy 0099096, U.S. Patent Application Publication No. US 2003/ benzobthio-phen-6-ol which is disclosed in U.S. Pat. No. 0022868, WO 03/011302 and WO 03/011824. All of the 5.488,058, the disclosure of which is incorporated herein by above references are hereby incorporated by reference herein. reference, 6-(4-hydroxy-phenyl)-5-(4-(2-piperidin-1-yl 1068 Formulations ethoxy)-benzyl)-naphthalen-2-ol, which is disclosed in U.S. 1069 Unit dose amounts and dose scheduling for the phar Pat. No. 5,484,795, the disclosure of which is incorporated maceutical compositions of the present invention can be herein by reference, (4-(2-(2-aza-bicyclo[2.2.1]hept-2-yl)- determined using methods well known in the art. In one ethoxy)-phenyl)-(6-hydroxy-2-(4-hyd-roxy-phenyl)-benzo aspect, the compounds of the invention are administered bithiophen-3-yl)-methanone which is disclosed, along with orally in a total daily dose of about 0.375ug/kg/day to about methods of preparation, in PCT publication no. WO95/10513 3.75 mg/kg/day. In another aspect the total daily dose is from assigned to Pfizer Inc, TSE-424 (Wyeth-Ayerst Laboratories) about 3.75ug/kg/day to about 0.375 mg/kg/day. In another and araZOXifene, cis-6-(4-fluoro-phenyl)-5-(4-(2-piperidin aspect the total daily dose is from about 3.75 ug/kg/day to 1-yl-ethoxy)-phenyl)-5,6,-7,8-tetrahydro-naphthalene-2-ol; about 37.5 g/kg/day. In another aspect the total daily dose is (-)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5, from about 3.75 g/kg/day to about 60 ug/kg/day. In a further 6,7,8-te-trahydro-naphthalene-2-ol (also known as lasofox aspect the dose range is from 30 g/kg/day to 3.0 mg/kg/day. ifene); cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phe In one aspect, the compounds of the invention are adminis nyl)-5,6,7,8-tetrah-ydro-naphthalene-2-ol; cis-1-(6'- tered orally in a unit dose of about 0.375 g/kg to about 3.75 pyrrolodinoethoxy-3-pyridyl)-2-phenyl-6-hydroxy-1,2,3,4- mg/kg. In another aspect the unit dose is from about 3.75 tetrahydronaphthalene: 1-(4'-pyrrolidinoethoxyphenyl)-2- ug/kg to about 0.375 mg/kg. In another aspect the unit dose is US 2009/011 8236 A1 May 7, 2009 from about 3.75ug/kg to about 37.5ug/kg. In another aspect carbonate, lactose, calcium or Sodium phosphate; granulating the unit dose is from about 3.75ug/kg to about 60 g/kg. In and disintegrating agents, such as maize starch, or alginic one aspect, the compounds of the invention are administered acid; binding agents, such as starch, gelatin or acacia; and orally in a unit dose of about 0.188 ug/kg to about 1.88 mg/kg. lubricating agents, such as magnesium Stearate, Stearic acid In another aspect the unit dose is from about 1.88 ug/kg to or talc. Tablets and pellets may be uncoated or may be coated about 0.188 mg/kg. In another aspect the unit dose is from by known techniques including microencapsulation to delay about 1.88 g/kg to about 18.8 ug/kg. In another aspect the disintegration and adsorption in the gastrointestinal tract and unit dose is from about 1.88 ug/kg to about 30 ug/kg. In one thereby provide a Sustained action over a longer period. For aspect, the compounds of the invention are administered example, a time delay material Such as glyceryl monostearate orally in a unit dose of about 0.125ug/kg to about 1.25 mg/kg. or glyceryl distearate alone or with a wax may be employed. In another aspect the unit dose is from about 1.25 ug/kg to 1074 Formulations for oral use may be also presented as about 0.125 mg/kg. In another aspect the unit dose is from hard gelatin capsules where the active ingredient is mixed about 1.25 g/kg to about 12.5ug/kg. In another aspect the with an inert Solid diluent, for example calcium phosphate or unit dose is from about 1.25 ug/kg to about 20 ug/kg. In one kaolin, or as Soft gelatin capsules wherein the active ingredi embodiment the unit dose is administered once a day. In ent is mixed with water or an oil medium, Such as peanut oil, another embodiment the unit dose is administered twice a liquid paraffin or olive oil. day. In another embodiment the unit dose is administered 1075 Aqueous suspensions of the invention contain the three times a day. In another embodiment the unit dose is active materials in admixture with excipients suitable for the administered four times a day. manufacture of aqueous Suspensions. Such excipients 1070 Dose refers to the equivalent of the free acid. The include a Suspending agent, such as Sodium carboxymethyl use of controlled-release preparations to control the rate of cellulose, methylcellulose, hydroxypropyl methylcellulose, release of the active ingredient may be preferred. The daily Sodium alginate, polyvinylpyrrolidone, gum tragacanth and dose may be administered in multiple divided doses over the gum acacia, and dispersing or wetting agents such as a natu period of a day. Doses and dosing schedules may be adjusted rally occurring phosphatide (e.g., lecithin), a condensation to the form of the drug or form of delivery used. For example, product of an alkylene oxide with a fatty acid (e.g., polyoxy different dosages and scheduling of doses may be used when ethylene Stearate), a condensation product of ethylene oxide the form of the drug is in a controlled release form or intra with a long chain aliphatic alcohol (e.g., heptadecaethyl venous delivery is used with a liquid form. eneoxycetanol), a condensation product of ethylene oxide 1071 Compounds of this invention when used in combi with a partial ester derived from a fatty acid and a hexitol nation with other compounds or agents may be administered anhydride (e.g., polyoxyethylene Sorbitan monooleate). The as a daily dose or an appropriate fraction of the daily dose aqueous Suspension may also contain one or more preserva (e.g., bid). Administration of compounds of this invention tives Such as ethyl or n-propyl p-hydroxy-benzoate, one or may occurator near the time in which the other compound or more coloring agents, one or more flavoring agents and one or agent is administered orata different time. When compounds more Sweetening agents, such as Sucrose or saccharin. of this invention are used in combination with other com 1076 Oil suspensions may be formulated by suspending pounds or agents, the other compound or agent (e.g., atorV the active ingredient in a vegetable oil, such as arachis oil, astatin) may be administered at the approved dose or a lower olive oil, sesame oil or coconut oil, or in a mineral oil Such as dose. liquid paraffin. The oral Suspensions may contain a thicken 1072 For the purposes of this invention, the compounds ing agent, such as beeswax, hard paraffin or cetyl alcohol. may be administered by a variety of means including orally, Sweetening agents, such as those set forth above, and flavor parenterally, by inhalation including but not limited to nasal ing agents may be added to provide a palatable oral prepara spray, topically, implantables or rectally informulations con tion. These compositions may be preserved by the addition of taining pharmaceutically acceptable carriers, adjuvants and an antioxidant such as ascorbic acid. vehicles. The term parenteral as used here includes subcuta 1077 Dispersible powders, pellets, and granules of the neous, intravenous, intramuscular, and intra-arterial injec invention Suitable for preparation of an aqueous Suspension tions with a variety of infusion techniques. Intra-arterial and by the addition of water provide the active ingredient in intravenous injection as used herein includes administration admixture with a dispersing or wetting agent, a Suspending through catheters. Oral administration is generally preferred. agent, and one or more preservatives. Suitable dispersing or 1073 Pharmaceutical compositions containing the active wetting agents and Suspending agents are exemplified by ingredient may be in any form suitable for the intended those disclosed above. Additional excipients, for example method of administration. When used for oral use for Sweetening, flavoring and coloring agents, may also be example, tablets, pellets, troches, lozenges, aqueous or oil present. Suspensions, dispersible powders or granules, emulsions, 1078. The pharmaceutical compositions may also be in the hard or soft capsules, syrups or elixirs may be prepared. form of oil-in-water emulsions. The oily phase may be a Compositions intended for oral use may be prepared accord Vegetable oil. Such as olive oil or arachis oil, a mineral oil, ing to any method known to the art for the manufacture of Such as liquid paraffin, or a mixture of these. Suitable emul pharmaceutical compositions and Such compositions may Sifying agents include naturally-occurring gums, such as gum contain one or more agents including Sweetening agents, acacia and gum tragacanth, naturally occurring phosphatides, flavoring agents, coloring agents and preserving agents, in Such as Soybean lecithin, esters or partial esters derived from order to provide a palatable preparation. Tablets and pellets fatty acids and hexitol anhydrides, such as Sorbitan containing the active ingredient in admixture with non-toxic monooleate, and condensation products of these partial esters pharmaceutically acceptable excipient which are Suitable for with ethylene oxide, Such as polyoxyethylene Sorbitan manufacture of tablets are acceptable. These excipients may monooleate. The emulsion may also contain Sweetening and be, for example, inert diluents, such as calcium or sodium flavoring agents. US 2009/011 8236 A1 May 7, 2009 76

1079 Syrups and elixirs may be formulated with Sweet maceutical products have a common goal of improving drug ening agents, such as glycerol, Sorbitol or Sucrose. Such for therapy over that achieved by their non-controlled release mulations may also contain a demulcent, a preservative, a counterparts. Ideally, the use of an optimally designed con flavoring or a coloring agent. trolled-release preparation in medical treatment is character 1080. In another aspect the pharmaceutical compositions ized by a minimum of drug Substance being employed to treat may be in the form of a sterile injectable preparation, Such as or control the condition in a minimum amount of time. a sterile injectable aqueous or oleaginous Suspension. This Advantages of controlled-release formulations include: 1) Suspension may be formulated according to the known art extended activity of the drug; 2) reduced dosage frequency; 3) using those Suitable dispersing or wetting agents and Sus increased patient compliance; 4) usage of less total drug; 5) pending agents which have been mentioned above. The sterile reduction in local or systemic side effects; 6) minimization of injectable preparation may also be a sterile injectable solution drug accumulation; 7) reduction in blood level fluctuations: or Suspension in a non-toxic parenterally acceptable diluent 8) improvement in efficacy of treatment; 9) reduction of or solvent, such as a solution in 1,3-butane-diolor prepared as potentiation or loss of drug activity; and 10) improvement in a lyophilized powder. Among the acceptable vehicles and speed of control of diseases or conditions. (Kim, Chering-ju, Solvents that may be employed are water, Ringer's Solution Controlled Release Dosage Form Design, 2 Technomic Pub and isotonic sodium chloride solution. In addition, sterile lishing, Lancaster, Pa...: 2000). fixed oils may conventionally be employed as a solvent or 1085 Conventional dosage forms generally provide rapid Suspending medium. For this purpose any bland fixed oil may or immediate drug release from the formulation. Depending be employed including synthetic mono- or diglycerides. In on the pharmacology and pharmacokinetics of the drug, use addition, fatty acids such as oleic acid may likewise be used in of conventional dosage forms can lead to wide fluctuations in the preparation of injectables. the concentrations of the drug in a patient's blood and other 1081. The amount of active ingredient that may be com tissues. These fluctuations can impact a number of param bined with the carrier material to produce a single dosage eters, such as dose frequency, onset of action, duration of form will vary depending upon the host treated and the par efficacy, maintenance of therapeutic blood levels, toxicity, ticular mode of administration. For example, a time-release side effects, and the like. Advantageously, controlled-release formulation intended for oral administration to humans may formulations can be used to control a drug's onset of action, contain 0.2 to 2000 umol (approximately 0.1 to 1000 mg) of duration of action, plasma levels within the therapeutic win active material compounded with an appropriate and conve dow, and peak blood levels. In particular, controlled- or nient amount of carrier material which may vary from about extended-release dosage forms or formulations can be used to 5 to about 99.9% of the total compositions. It is preferred that ensure that the maximum effectiveness of a drug is achieved the pharmaceutical composition be prepared which provides while minimizing potential adverse effects and safety con easily measurable amounts for administration. For example, cerns, which can occur both from under dosing a drug (i.e., an aqueous Solution intended for intravenous infusion should going below the minimum therapeutic levels) as well as contain from about 0.05 to about 500 umol (approximately exceeding the toxicity level for the drug. 0.025 to 250 mg) of the active ingredient per milliliter of 1086 Most controlled-release formulations are designed solution in order that infusion of a suitable volume at a rate of to initially release an amount of drug (active ingredient) that about 30 mL/h can occur. promptly produces the desired therapeutic effect, and gradu 1082. As noted above, formulations suitable for oral ally and continually release otheramounts of drug to maintain administration may be presented as discrete units such as this level of therapeutic or prophylactic effect over an capsules, cachets, pellets, or tablets each containing a prede extended period of time. In order to maintain this constant termined amount of the active ingredient, as a powder or level of drug in the body, the drug must be released from the granules; as a solution or a Suspension in an aqueous or dosage form at a rate that will replace the amount of drug non-aqueous liquid; or as an oil-in-water liquid emulsion or a being metabolized and excreted from the body. Controlled water-in-oil liquid emulsion. The active ingredient may also release of an active ingredient can be stimulated by various be administered as a bolus, electuary or paste. conditions including, but not limited to, pH, ionic strength, 1083. A tablet may be made by compression or molding, osmotic pressure, temperature, enzymes, water, and other optionally with one or more accessory ingredients. Com physiological conditions or compounds. pressed tablets may be prepared by compressing in a Suitable 1087. A variety of known controlled- or extended-release machine the active ingredient in a free flowing form such as a dosage forms, formulations, and devices can be adapted for powder or granules, optionally mixed with a binder (e.g., use with the compositions of the invention. Examples poVidone, gelatin, hydroxypropylmethyl cellulose), lubri include, but are not limited to, those described in U.S. Pat. cant, inert diluent, preservative, disintegrant (e.g., sodium Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; 4,008,719; starch glycolate, cross-linked povidone, cross-linked sodium 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543: carboxymethyl cellulose) Surface active or dispersing agent. 5,639,476; 5,354,556; 5,733,566; and 6,365,185 B1; each of Molded tablets may be made by molding in a suitable which is incorporated herein by reference. These dosage machine a mixture of the powdered compound moistened forms can be used to provide slow or controlled-release of one with an inert liquid diluent. Tablets may optionally be pro or more active ingredients using, for example, hydroxypro vided with an enteric coating, to provide release in parts of the pylmethyl cellulose, other polymer matrices, gels, permeable gut other than the stomach. This is particularly advantageous membranes, osmotic systems (such as OROSR (Alza Corpo with the compounds of the present invention when Such com ration, Mountain View, Calif. USA)), multilayer coatings, pounds are Susceptible to acid hydrolysis. microparticles, liposomes, or microspheres or a combination 1084 Pharmaceutical compositions comprising the com thereof to provide the desired release profile in varying pro pounds of the present invention can be administered by con portions. Additionally, ion exchange materials can be used to trolled- or delayed-release means. Controlled-release phar prepare immobilized forms of compositions of the invention US 2009/011 8236 A1 May 7, 2009 77 and thus effect controlled delivery of the drug. Examples of formed or formable therein and at least a portion of the wall specific anion exchangers include, but are not limited to, being semipermeable; an expandable layer located within the DUOLITE A568 and DUOLITE AP143 (Rohm & Haas, cavity remote from the exit orifice and in fluid communica Spring House, Pa. USA). tion with the semipermeable portion of the wall; a drug layer 1088 One embodiment of the invention encompasses a located within the cavity adjacent the exit orifice and in direct unit dosage form which comprises a compound of the present or indirect contacting relationship with the expandable layer; invention or a pharmaceutically acceptable salt, or a poly the drug layer comprising a liquid, active agent formulation morph, Solvate, hydrate, dehydrate, co-crystal, anhydrous, or absorbed in porous particles, the porous particles being amorphous form thereof, and one or more pharmaceutically adapted to resist compaction forces Sufficient to form a com acceptable excipients or diluents, wherein the pharmaceutical pacted drug layer without significant exudation of the liquid, composition or dosage form is formulated for controlled active agent formulation, the dosage form optionally having a release. Specific dosage forms utilize an osmotic drug deliv ery system. placebo layer between the exit orifice and the drug layer, 1089. A particular and well-known osmotic drug delivery wherein the active agent formulation comprises a compound system is referred to as OROS (Alza Corporation, Mountain of the present invention, including a polymorph, Solvate, View, Calif. USA). This technology can readily be adapted hydrate, dehydrate, co-rystal, anhydrous, or amorphous form for the delivery of compounds and compositions of the inven thereof. See U.S. Pat. No. 6,342.249, the entirety of which is tion. Various aspects of the technology are disclosed in U.S. incorporated herein by reference. Pat. Nos. 6,375,978 B1; 6,368,626 B1; 6,342,249 B1; 6,333, 1093 Transdermal Delivery System: The controlled 050 B2: 6,287,295 B1; 6,283,953 B1; 6,270,787 B1; 6,245, release formulations of the present invention may be formu 357 B1; and 6,132,420; each of which is incorporated herein lated as a transdermal delivery system, such as transdermal by reference. Specific adaptations of OROS that can be used patches. In certain embodiments of the present invention, a to administer compounds and compositions of the invention transdermal patch comprises a compound of the present include, but are not limited to, the OROS Push-Pull, Delayed invention contained in a reservoir or a matrix, and an adhesive Push-Pull, Multi-Layer Push-Pull, and Push-Stick Systems, which allows the transdermal device to adhere to the skin, all of which are well known. Additional OROS systems that allowing the passage of the active agent from the transdermal can be used for the controlled oral delivery of compounds and device through the skin of the patient. Once the compound has compositions of the invention include OROS-CT and penetrated the skin layer, the drug is absorbed into the blood L-OROS. Id.; see also, Delivery Times, vol. II, issue II (Alza stream where it exerts desired pharmaceutical effects. The Corporation). transdermal patch releases the compound of the present 1090 Conventional OROS oral dosage forms are made by compressing a drug powder (e.g., a T3 mimetic composition invention in a controlled-release manner, such that the blood of the present invention) into a hard tablet, coating the tablet levels of the a compound of the present invention is main with cellulose derivatives to form a semi-permeable mem tained at a therapeutically effective level through out the brane, and then drilling an orifice in the coating (e.g., with a dosing period, and the blood levels of the a compound of the laser). (Kim, Cherng-ju, Controlled Release Dosage Form present invention is maintained at a concentration that is Design, 231-238 Technomic Publishing, Lancaster, Pa. sufficient to reduce side effects associated with immediate 2000). The advantage of such dosage forms is that the deliv release dosage forms but not sufficient to negate the thera ery rate of the drug is not influenced by physiological or peutic effectiveness of the compound. experimental conditions. Even a drug with a pH-dependent 1094 Transdermal refers to the delivery of a compound by solubility can be delivered at a constant rate regardless of the passage through the skin or mucosal tissue and into the blood pH of the delivery medium. But because these advantages are stream. There are four main types of transdermal patches provided by a build-up of osmotic pressure within the dosage listed below. form after administration, conventional OROS drug delivery 1095 1. Single-layer Drug-in-Adhesive: The adhesive systems cannot be used to effectively deliver drugs with low layer of this system also contains the drug. In this type of water solubility. patch the adhesive layer not only serves to adhere the 1091. A specific dosage form of the invention comprises: various layers together, along with the entire system to a wall defining a cavity, the wall having an exit orifice formed the skin, but is also responsible for the releasing of the or formable therein and at least a portion of the wall being drug. The adhesive layer is Surrounded by a temporary semipermeable; an expandable layer located within the cavity liner and a backing. remote from the exit orifice and in fluid communication with 1096 2. Multi-layer Drug-in-Adhesive: The multi the semipermeable portion of the wall; a dry or substantially layer drug-in adhesive patch is similar to the single-layer dry state drug layer located within the cavity adjacent to the system in that both adhesive layers are also responsible exit orifice and in direct or indirect contacting relationship for the releasing of the drug. The multi-layer system is with the expandable layer; and a flow-promoting layer inter different however that it adds another layer of drug-in posed between the inner surface of the wall and at least the adhesive, usually separated by a membrane (but not in external surface of the drug layer located within the cavity, all cases). This patch also has a temporary liner-layer wherein the drug layer comprises a compound of the present and a permanent backing. invention, including a polymorph, Solvate, hydrate, dehy 1097 3. Reservoir: Unlike the Single-layer and Multi drate, co-crystal, anhydrous, or amorphous form thereof. See layer Drug-in-adhesive systems the resevoir transdermal U.S. Pat. No. 6,368.626, the entirety of which is incorporated system has a separate drug layer. The drug layer is a herein by reference. liquid compartment containing a drug solution or Sus 1092 Another specific dosage form of the invention com pension separated by the adhesive layer. This patch is prises: a wall defining a cavity, the wall having an exit orifice also backed by the backing layer. US 2009/011 8236 A1 May 7, 2009 78

1098 4. Matrix: The Matrix system has a drug layer of to a functional group that can be transformed into T. Protec a semisolid matrix containing a drug solution or Suspen tion and deprotection in the Schemes may be carried out sion. The adhesive layer in this patch Surrounds the drug according to the procedures generally known in the art (e.g., layer partially overlaying it “Protecting Groups in Organic Synthesis', 3rd Edition, 1099. Other modes of transdermal delivery are known Wiley, 1999). in the art and are included in the present invention. 1105 All stereoisomers of the compounds of the instant 1100 Formulations suitable for topical administration in invention are contemplated, either in admixture or in pure or the mouth include lozenges comprising the active ingredient Substantially pure form. The compounds of the present inven in a flavored base, usually sucrose and acacia or tragacanth; tion can have stereogenic centers at the phosphorus atom and pastilles comprising the active ingredient in an inert base Such at any of the carbons including any of the R substituents. as gelatin and glycerin, or Sucrose and acacia; and mouth Consequently, compounds of Formula I can exist in enantio washes comprising the active ingredient in a Suitable liquid meric or diastereomeric forms or in mixture thereof. The carrier. processes for preparation can utilize racemates, enantiomers 1101 Formulations for rectal administration may be pre or diastereomers as starting materials. When enantiomeric or sented as a Suppository with a suitable base comprising for diastereomeric products are prepared, they can be separated example cocoa butter or a salicylate. Formulations suitable by conventional methods for example, chromatographic or for vaginal administration may be presented as pessaries, fractional crystallization. tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient Such carriers as Preparation of a Phosphonate Prodrug are known in the art to be appropriate. 1102 Formulations suitable for parenteral administration 1106 Prodrugs can be introduced at different stages of the include aqueous and non-aqueous isotonic sterile injection synthesis. Most often these prodrugs are made from the phos Solutions which may contain antioxidants, buffers, bacteri phonic acids of Formula I because of their lability. ostats and solutes which render the formulation isotonic with 1107 Phosphonic acids of Formula I can be alkylated with the blood of the intended recipient; and aqueous and non electrophiles Such as alkylhalides and alkyl Sulfonates under aqueous sterile Suspensions which may include Suspending nucleophilic Substitution conditions to give phosphonate agents and thickening agents. The formulations may be pre esters. For example, compounds of Formula I whereinYR'' is sented in unit-dose or multi-dose sealed containers, for an acyloxyalkyl group can be prepared by direct alkylation of example, ampoules and vials, and may be stored in a freeze compounds of Formula I with an appropriate acyloxyalkyl dried (Oyophilized) condition requiring only the addition of halide (e.g., Cl, Br, I; Phosphorus Sulfur 1990, 54, 143, the Sterile liquid carrier, for example water for injections, Synthesis 1988, 62) in the presence of a suitable base (e.g., immediately prior to use. Injection solutions and Suspensions pyridine, TEA, diisopropylethylamine) in suitable solvents may be prepared from Sterile powders, granules and tablets of such as DMF (J. Med Chem. 1994, 37, 1875). The carboxy the kind previously described. late component of these acyloxyalkyl halides includes but is 1103 In one aspect the unit dosage formulations are those not limited to acetate, propionate, isobutyrate, pivalate, ben containing a daily dose or unit, daily Sub-dose, or an appro Zoate, carbonate and other carboxylates. priate fraction thereof, of a drug. It will be understood, how 1108 Dimethylformamide dialkyl acetals can also be used ever, that the specific dose level for any particular patient will for the alkylation of phosphonic acids (Collect. Czech Chem. depend on a variety of factors including the activity of the Commu. 1994, 59, 1853). Compounds of Formula I wherein specific compound employed; the age, body weight, general YR' is a cyclic carbonate, a lactone or aphthalidyl group can health, sex and diet of the individual being treated; the time also be synthesized by direct alkylation of the free phospho and route of administration; the rate of excretion; other drugs nic acids with appropriate halides in the presence of a Suitable which have previously been administered; and the severity of base such as NaH or diisopropylethylamine (J. Med. Chem. the particular disease undergoing therapy, as is well under 1995, 38, 1372, J. Med. Chem. 1994, 37, 1857, J. Pharm. Sci. stood by those skilled in the art. 1987, 76, 180). Synthesis of Compounds of Formula I 1109 Alternatively, these phosphonate prodrugs can be synthesized by the reactions of the corresponding dichloro 1104) The compounds in this invention may be prepared phosphonates and an alcohol (Collect Czech Chem. Commun. by the processes described in the following Schemes, as well 1994, 59, 1853). For example, a dichlorophosphonate is as relevant published literature procedures that are used by reacted with substituted phenols and arylalkyl alcohols in the those skilled in the art. It should be understood that the fol presence of a base such as pyridine or TEA to give the com lowing schemes are provided solely for the purpose of illus pounds of Formula I wherein YR'' is an aryl group (J. Med. tration and do not limit the invention which is defined by the Chem. 1996, 39,4109, J. Med. Chem. 1995, 38, 1372, J. Med. claims. Typically the synthesis of a compound of Formula I Chem. 1994, 37, 498) or an arylalkyl group (J. Chem. Soc. includes the following general steps: (1) Preparation of a Perkin Trans. 1 1992, 38, 2345). The disulfide-containing phosphonate prodrug; (2) Deprotection of a phosphonate prodrugs (Antiviral Res. 1993, 22, 155) can be prepared from ester; (3) Introduction of a phosphonate group; (4) Construc a dichlorophosphonate and 2-hydroxyethyldisulfide under tion of the diaryl ring system; and (5) Preparation of key standard conditions. Dichlorophosphonates are also useful precursors. The order of introduction of a phosphonate group for the preparation of various phosphonamides as prodrugs. and the construction of the diaryl backbone in the synthesis of For example, treatment of a dichlorophosphonate with compounds of Formula I can be freely decided by those ammonia gives both a monophosphonamide and a diphos skilled in the art based on the structure of the substrate. In all phonamide; treatment of a dichlorophosphonate with applicable structures contained in the Schemes described in 1-amino-3-propanol gives a cyclic 1.3-propylphosphona this invention, PG refers to a protecting group and FG refers mide; treatment of a chlorophosphonate monophenyl ester US 2009/011 8236 A1 May 7, 2009 79 with an aminoacid ester in the presence of a suitable base Suitable coupling precursors to react with phosphonic acid gives a Substituted monophenyl monophosphonamidate. salts. These precursors can be made from the corresponding 1110 Such reactive dichlorophosphonates can be gener diols as described in the literature. ated from the corresponding phosphonic acids with a chlori 1117. Alternatively, cyclic phosphonate esters of substi nating agent (e.g., thionyl chloride, J. Med. Chem. 1994, tuted 1,3-propane diols can be synthesized by trans esterifi 1857; oxalyl chloride, Tetrahedron Lett. 1990, 31, 3261; cation reaction with substituted 1,3-propane diol under suit phosphorous pentachloride, Synthesis 1974, 490). Alterna able conditions. Mixed anhydrides of parent phosphonic tively, a dichlorophosphonate can be generated from its cor acids generated in situ under appropriate conditions react responding disilyl phosphonate esters (Synth. Commu. 1987, with diols to give prodrugs as in the case of carboxylic acid 17, 1071) or dialkyl phosphonate esters (Tetrahedron Lett. esters (Bull. Chem. Soc. Jpn. 52:1989 (1979)). Aryl esters of 1983, 24, 4405, Bull. Soc. Chim. 1993, 130, 485). phosphonates are also known to undergo transesterification 1111. It is envisioned that compounds of Formula I can be with alkoxy intermediates (Tetrahedron Lett. 38:2597 (1997); mixed phosphonate ester (e.g., phenyl and benzyl esters, or Synthesis 968 (1993)). phenyl and acyloxyalkyl esters) including the chemically 1118. One aspect of the present invention provides meth combined mixed esters such as phenyl and benzyl combined ods to synthesize and isolate single isomers of prodrugs of prodrugs reported in Bioorg. Med. Chem. Lett. 1997, 7, 99. phosphonic acids of Formula I. Because phosphorus is a 1112 Dichlorophosphonates are also useful for the prepa Stereogenic atom, formation of a prodrug with a racemic ration of various phosphonamides as prodrugs. For example, substituted-1,3-propane-diol will produce a mixture of iso treatment of a dichlorophosphonate with an amine (e.g. an mers. For example, formation of a prodrug with a racemic amino acid alkyl ester Such as L-alanine ethyl ester) in the 1-(V)-substituted-1,3-propane diol gives a racemic mixture presence of a suitable base (e.g. triethylamine, pyridine, etc.) of cis-prodrugs and a racemic mixture of trans-prodrugs. In gives the corresponding bisphosphonamide; treatment of a an other aspect, the use of the enantioenriched Substituted-1, dichlorophosphonate with 1-amino-3-propanol gives a cyclic 3-propane diol with the R-configuration gives enantioen 1,3-propylphosphonamide; treatment of a chlorophospho riched R-cis- and R-trans-prodrugs. These compounds can be nate monophenyl ester with an aminoacid ester in the pres separated by a combination of column chromatography and/ ence of a Suitable base gives a Substituted monophenyl mono or fractional crystallization. phosphonamidate. Direct couplings of a phosphonic acid 1119 A. Deprotection of A Phosphonate Ester with an amine (e.g. an amino acid alkyl ester Such as L-ala 1120 Compounds of Formula I wherein X is - POH nine ethyl ester) are also reported to give the corresponding may be prepared from phosphonate esters using the known bisamidates under Mukaiyama conditions (J. Am. Chem. cleavage methods. Silyl halides are generally used to cleave Soc., 1972, 94,8528). various phosphonate esters and give the desired phosphonic 1113. The SATE (S-acetylthioethyl) prodrugs can be syn acid upon mild hydrolysis of the resulting silyl phosphonate thesized by the coupling reaction of the phosphonic acids of esters. When needed, acid scavengers (for example, HMDS) Formula I and S-acyl-2-thioethanol in the presence of DCC, can be used for the acid sensitive compounds. Such silyl EDCI or PYBOP (J. Med. Chem. 1996, 39, 1981). halides include TMSC1 (J. Org. Chem. 1963, 28, 2975), 1114 Cyclic phosphonate esters of substituted 1,3-pro TMSBr (Tetrahedron Lett. 1977, 155) and TMSI (J. Chem. pane diols can be synthesized by either reactions of the cor Soc., Chem. Commu. 1978, 870). Alternatively, phosphonate responding dichlorophosphonate with a substituted 1,3-pro esters can be cleaved under strong acid conditions (Tetrahe panediol or coupling reactions using Suitable coupling dron Lett. 1992,33,4137, Synthesis-Stuttgart 1993, 10,955). reagents (e.g. DCC, EDCI, PyBOP; Synthesis 1988, 62). The Those phosphonate esters can also be cleaved via dichloro reactive dichlorophosphonate intermediates can be prepared phosphonates prepared by treating the phosphonate esters from the corresponding acids and chlorinating agents such as with halogenating agents such as PCls, SOCl and BF (J. thionyl chloride (J.Med. Chem., 1994, 1857), oxalyl chloride Chem. Soc. 1961, 238) followed by aqueous hydrolysis to (Tetrahedron Lett., 1990, 31: 3261) and phosphorus pen give the phosphonic acids. Aryl and benzyl phosphonate tachloride (Synthesis, 1974, 490). Alternatively, these dichlo esters can be cleaved under hydrogenolysis conditions (Syn rophosphonates can also be generated from disilyl esters thesis 1982, 412, J. Med. Chem. 1985, 28, 1208) or metal (Synth. Commun., 1987, 17: 1071) and dialkyl esters (Tetra reduction conditions (J. Chem. Soc. 1977,99,5118). Electro hedron Lett., 1983, 24: 4405, Bull. Soc. Chim. Fr., 1993, 130: chemical (J. Org. Chem. 1979, 44, 4508) and pyrolysis 485). (Synth. Commu. 1980, 10, 299) conditions have been used to 1115. Alternatively, these cyclic phosphonate esters of cleave various phosphonate esters. Substituted 1,3-propane diols are prepared from phosphonic acids by coupling with diols under Mitsunobu reaction con Introduction of A Phosphonate Group ditions (Synthesis 1 (1981); J. Org. Chem. 52:6331 (1992)), 1121. The introduction of a phosphonate group can gen and other acid coupling reagents including, but not limited to, erally be accomplished according to known methods. Com carbodiimides (Collect. Czech. Chem. Commun. 59:1853 pounds of Formula I wherein T is O(CR)(CR), , (1994); Bioorg. Med. Chem. Lett. 2:145 (1992); Tetrahedron —S(CR)(CR), or NM)(CR)(CR"), may be Lett. 29:1189 (1988)), and benzotriazolyloxytris-(dimethy prepared by coupling a phenol, thiophenol, or aniline with a lamino) phosphonium salts (Tetrahedron Lett. 34, 6743 phosphonate ester component such as I(CR)(CR),P(O) (1993)). (OEt), TsC(CR)(CR), P(O)(OEt), or TfG(CR)(CR) 1116 Phosphonic acids also undergo cyclic prodrug for P(O)(OEt) in the presence of a base such as NaH, KCO, mation with cyclic acetals or cyclic ortho esters of substituted KO-t-Bu or TEA (Tetrahedron Lett. 1986,27, 1477; J. Chem. propane-1,3-diols to provide prodrugs as in the case of car Soc. Perkin Tran 1 1994, 1987) as described in Scheme 1. boxylic acid esters (Helv. Chim. Acta. 48:1746 (1965)). Alter Following the procedures described as above, deprotection of natively, more reactive cyclic sulfites or Sulfates are also the phosphonate ester 2 gives the desired phosphonic acid 3. US 2009/011 8236 A1 May 7, 2009

1122 Compounds of Formula I wherein T is N(R')C (O)(CR), can be prepared by coupling an aniline 1 (MNH) with a carboxylic acid containing a phosphonate moiety (EtO)2P(O)(CR) COH in the presence of DCC or EDC according to the known methods (for example, J. Org. Chem. 1977, 42, 2019) or converting an aniline 1 (MNH) to an isocyanate with diphosgene followed by reacting with a, b or c P(OEt) (J. Org. Chem. 1956, 1661; Tetrahedron Lett. 1996, 37, 5861). Deprotection of the phosphonate ester 2 as R4 R1 described above leads to the phosphonic acid 3. 1 1123 For compounds of Formula I wherein T is —(CR) R3 R2 , the phosphonate group can be introduced by a number of O known methods. For example, the coupling reaction of a 5 | Deprotection phenyl bromide (J. Org. Chem. 1999, 64, 120), iodide (Phos R G T--OE -- phorus Sulfur 1997, 130,59) or triflate (J. Org. Chem. 2001, OEt 66, 348) with diethyl phosphonate in the presence of a Pd R4 R1 catalyst is widely used within the art (when k is 0). Other 2 methods such as Michaelis-Arbuzov reaction (Client. Rev. R3 R2 1981, 81, 415) can also be an efficient way to introduce the phosphonate group by coupling a benzyl or arylalkyl halide with triethyl phosphonate (when m is 1-3). R5 G T- – OH 1124 For compounds of Formula I wherein T is -(CR) OH CR”—CR” , the phosphonate group can be introduced R4 RI by coupling an aldehyde and tetraethyl methylenediphospho nate in the presence of a base such as NaH, NaOH or KO-t-Bu (Tetrahedron Lett. 1988, 29, 3007). For compounds of For mula I wherein T is –CR'—CR (CR), or —(CR) CR”—CR (CR) , the phosphonate group can be introduced by Michaelis-Arbuzov reaction of the cor responding olefinic halide with triethyl phosphite. 1125 For compounds of Formula I wherein T is —(CR) (CO)—, the phosphonate group can be introduced by react Construction of the Diaryl Ring ing diethyl phosphite with an acid chloride (J. Org, Chem. 1129 Compounds of Formula I wherein G is —O— can 1964,29,3862; Tetrahedron 1998,54, 12233) or an aldehyde be prepared according to known methods. As described in followed by oxidation (Tetrahedron 1996, 52, 9963). Also, this type of compounds can be transformed into the com Scheme 2, 2a is reacted with 2b at room temperature in the pounds of Formula I wherein T is —(CR), CH(NRR)— presence of Cu powder and a suitable base such as TEA, according to known procedures (Tetrahedron Lett. 1996, 37, diisopropylamine or pyridine to provide the coupling product 407). 4 (J.Med. Chem. 1995,38,695). Deprotection of the methoxy 1126 For compounds of Formula I wherein T is —(CO) group with Suitable reagents such as borontribromide, boron (CR), , the phosphonate group can be introduced by a trichloride or boron trifluoride in CHCl gives the interme number of known methods such as reacting a substituted diate 5. Introduction of the phosphonate group followed by benzoyl chloride with diethylphosphonoacetic acid (Syn deprotection of the phosphonate ester as described in Scheme thetic Commu. 2000, 30, 609) or a phosphonate copper 1 leads to the desired phosphonic acid 6. Those skilled in the reagent (Tetrahedron Lett. 1990, 31, 1833). Alternatively, art can use other known methods such as coupling of an coupling of triethyl phosphonate with a silyl enol ether (Syn arylboronic acid and a phenol in the presence of Cu(OAc), thetic Commu. 1994, 24., 629) or a C-bromobenzophenone (Tetrahedron Lett. 1998, 39,2937), nucleophilic substitution (Phosphorus Sulfur 1994, 90,47) can also introduce the phos of a fluorobenzene (Synthesis-Stuttgart 1991, 1,63) or iodo phonate group. benzene (J. Am. Chem. Soc. 1997, 119, 10539) with a phenol 1127. For compounds of Formula I wherein T is —C(O) and coupling of a bromobenzene with a phenol in the pres NH(CR 2)(CR'2). , the phosphonate group can be intro ence of Pd(dba), (Tetrahedron Lett. 1997, 38,8005) to form duced by coupling reaction of a Substituted benzoic acid and the diaryl ether system. an aminophosphonate according to the standard amide bond Scheme 2 formation methods (Tetrahedron Lett. 1990, 31, 7119. Tetra hedron Lett. 1989, 30, 6917, J. Org. Chem. 1993, 58,618). R3 BF4 R3 1128 For compounds of Formula I wherein T is —(CR) C(O)(CR), or (CR),C(O)(CR), the phosphonate -- group can be introduced by reacting a benzyl bromide with a MeO OMe functionalized phosphonate (Tetrahedron Lett. 1989, 30. 4787). Alternatively, a coupling reaction of a substituted phe R4 R4 nylacetate and methylphosphonate also yields the desired 2a product (J. Am. Chem. Soc. 1999, 121, 1990). US 2009/011 8236 A1 May 7, 2009

-continued R2 Scheme 3 HO R3 Br R2 Cu Her PG -- OHC n-BuLi n R1 FG O 2b R4 RI FG 3a 3b R2 OH R2 R3 O R3 1. Hydrogenolysis Deprotection 2. Deprotection He --- PG MeO R1 FG No R1 FG R4 R4 4 7 R2 R2 R3 Scheme 1 R3 O -e- Scheme 1 He HO RI FG HO RI FG R4 R4 8 5 R2 R3 R2 O | R3 O HO R1 T- – OH R4 OH 9 HO R1 1--0 PG = protecting group FG = functional group that can be R4 OH transformed into T 6

FG = functional group that can be transformed into T 1131. For compounds of Formula I wherein G is —S , —S(=O)—or S(=O)—, the formation of the diaryl ring can be achieved according to known methods. As illustrated 1130 For compounds of Formula I wherein G is in Scheme 4, 3a can be reacted with 4a in the presence of a —CH2—, the installation of the diaryl ring can be accom catalyst such as Pd(dba) or CuBr to provide the diaryl sul plished by a number of known methods. For example, as fide 10 (Tetrahedron 2001, 57,3069, Tetrahedron Lett. 2000, described in Scheme 3, benzyl alcohol 7 is formed by treat 41, 1283). Phosphonic acid 12 is formed from 10 after ment of 3a with n-BuLi at -78° C. in THF followed by removal of the protecting groups followed by the same pro reacting with 3b (Bioorg Med. Chem. Lett. 2000, 10, 2607). cedures as described in Scheme 1. The diaryl sulfide 10 can Hydrogenolysis with Pd C or dehydroxylation of benzyl also be converted to the sulfoxide 13 according to known alcohol 7 by NaBH (Synthetic Commu. 1987, 17, 1001) and methods (Synthetic Commu. 1986, 16, 1207, J. Org. Chem. (i-Bu)A1 (Synthesis 1987, 736) followed by removal of the 1997, 62, 4253, Tetrahedron Lett. 1990, 31, 4533), which protecting group gives the diaryl intermediate 8. Phosphonic leads to the phosphonic acid 15 following the same proce acid 9 is formed from 8 according to the same procedures as dures as described in Scheme 1. Also, the biarylsulfide 10 can described in Scheme 1. Alternatively, coupling of benzyl be converted to the sulfone (Tetrahedron Lett. 1991, 32,7353, bromide with an aryl Grignard reagent (Tetrahedron Lett. J. Prakt. Chem. 1942, 160) which leads to the phosphonic 1981, 22, 2715), an arylboronic acid (Tetrahedron, Lett. 1999, acid (G is S(=O)—) following the same procedures as 40, 7599) or a zinc reagent (Chem. Lett. 1999, 11, 1241) and described above. In addition, nucleophilic substitution of reduction of a diaryl ketone (J. Org. Chem. 1986, 51, 3038) chlorobenzene and bromobenzene with a thiol is also an are all widely used methods for the construction of the diary1 efficient way to install the diaryl sulfide ring (J. Med. Chem. r1ng. 1988, 31, 254, J. Org. Chem. 1998, 63, 6338). US 2009/011 8236 A1 May 7, 2009

Scheme 4 R3 Br HS

PG

No -- Ol FG R4 4a 3a re R3 S

PG No FG R4 10 ?Deprotection \e

R3 S R3 S - C FG PG No FG R4 R4 11 13 e 1 prete O R3 S R3 S

HO T-P-OH HO FG R4 OH 12 R4 14 te 1

R3 MS

HO Ol T- – OH R4 OH 15 PG = protecting group FG = functional group that can be transformed into T

1132 For compounds of Formula I wherein G is —NH hedron Lett. 1996, 37, 6993, Org. Lett. 1999, 1, 2057) or an or —N(C-C alkyl)-, the diarylamine backbone can be aryl tosylate (J. Org. Chem. 1997, 62. 1268) in the presence of formed by a number of known methods. Among those con- a catalyst such as PdCl or Pd(dba). As illustrated in ditions, one widely used by those skilled in the art is the Scheme 5, the diarylamine intermediate 16 can be prepared coupling reaction of an aniline with an aryl bromide (J. Org. by coupling of bromide 3a and aniline 5a in the presence of Chem. 1999, 64, 5575, J. Org. Chem. 1997, 62, 6066, Tetra- Pd(dba). After removal of the protecting group, the diary US 2009/011 8236 A1 May 7, 2009 83 lamine 17 is converted to the phosphonic acid 18 following the same procedures as described in Scheme 1. Alternatively, -continued coupling of an aniline and aryl halide using other catalysts R R2 such as copper-bronze (Org. Synth. 1943, 2, 446, J. Org. R3 l Chem. 1955, 20) and Cu(OAc). (J. Med. Chem. 1986, 4,470; Synthetic Commu. 1996, 26, 3877) to construct the diary- Shin lamine backbone is also a feasible approach. HO RI FG R4 17 R3 Br R R2

-- R3 N PG No R4 HO R1 T- – OH 3a R4 OH 18 R = H, C1-C4 alkyl R2 PG = Protecting Group H FG = Functional group that can be N transformed into T R1 Pd(dba) 1133 For compounds of Formula I wherein G is —CHF or —CF, , the diaryl backbone can be established from the R FG benzyl alcohol 7. Accordingly, as described in Scheme 6, 5a benzyl alcohol 7 can be converted to the benzyl fluoride 19 by reacting with DAST in CH2Cl according to known proce dure (J. Chem. Soc. Chem. Commu. 1981, 11, 511; Tetrahe R R2 dron Lett. 1995, 36,6271; Tetrahedron 1988, 14, 2875). Also, the benzyl alcohol 7 can be easily oxidized to the benzophe R3 N none 22 according to known methods such as MnO2 oxida Deprotection tion, PCC oxidation, Swern oxidation and Dess-Martin oxi He- dation, which is subsequently converted to the benzyl PGn difluoride 23 by treatment with DAST (J. Fluorine 1993, 61, O R FG 117) or other known reagents (J. Org. Chem. 1986, 51,3508; 4 Tetrahedron 1999, 55, 1881). After removal of the protecting R groups, the benzyl fluoride 20 and difluoride 24 are converted 16 to the desired phosphonic acids following the same proce dures as described in Scheme 1.

Scheme 6 OH R2 R3

PG No RI FG R4 7 fist \to F R2 O R2 R3 R3

PG GP No R1 FG No R1 FG R4 R4 19 22 protein past US 2009/011 8236 A1 May 7, 2009 84

-continued F R2 F. F. R. R3 R3

GP HO RI No R1 FG R4 R4 2O 23 e 1 pe F R2 2 3 F F R R R3

HO RI T-P-OH HO RI FG R4 OH 21 R4 24 e 1 F F R R3

HO R1 1--0 R4 OH 25

PG = Protecting Group FG = Functional group that can be transformed into T

1134 Compounds of Formula I wherein G is —CH (OH)—or —C(O)— can be prepared from the intermediates 7 and 22. Removal of the protecting groups of 7 and 22 followed by introduction of the phosphate and deprotection as R3 R2 described in Scheme 1 provides the desired phosphonic acids of Formula I. 1) NaNO2, HCI He R5 G 2) PPA, Synthesis of Compounds of Formula II 1135 The synthesis of compounds of Formula II where A R4 RI is —NH and B is —CH or —C-alkyl- can be accom- 1 plished from the corresponding amino diaryl precursor 1 using the well-known, to those skilled in the art, Fisher indole synthesis (Scheme 6a) (Phosphorus and Sulfur, 1988, Vol. 37, pp. 41-63). Alternatively, the aryl-indole scaffold is con structed using the procedures previously described and the phosphonic acid moiety is introduced by making the anion next to the nitrogen of the indole derivative, protected at the nitrogen, with a base such as Bulli and quenching the anion with diethyl chlorophosphate. Further protecting group and R4 functional group manipulations of intermediates 2 provide compounds of Formula II. US 2009/011 8236 A1 May 7, 2009

1136 Compounds of Formula II where A is —O— and B sation of the corresponding diaryl precursor 6 with an ortho is —CH- are synthesized from the corresponding diary1 formate such as triethyl orthoformate in presence of acid to phenol precursor 3 and ring cyclization with the dimethylac give heterocycle 7 (Org. Prep. Proced. Int., 1990, 22(5), etal of bromoacetaldehyde to give benzofuran 4 (Scheme 6b) 613-618). The phosphonic acid moiety can then be intro (J. Chem. Soc., Perkin Trans. 1, 1984, 4, 729). The phospho duced by making the anion at the 2-position of the heterocycle nic acid moiety can then be introduced by making the anion 7 with a base such as Bulli and quenching the anion with next to the oxygen of the benzofuran with a base such as BuLi diethyl chlorophosphate to give phosphonate 8. Further pro and quenching the anion with diethyl chlorophosphate to tecting group and functional group manipulations of interme provide phosphonate 5. Further protecting group and func diates 8 provide compounds of Formula II. tional group manipulations of intermediate 5 provides com pounds of Formula II. Scheme 6c

Scheme 6b R3 R2 NH2 PPA, 1) CsCO3 HC(OEt) R3 R2 OMe R5 G KH —-

R5 G OH - in-l.Y OMe R4 R1 2) PPA, 6 R4 R1 3 R3 R2 N N BuLi, CIP(O)(OEt) R3 R2 R5 G K He N BuLi, CIP(O)(OEt) R5 G O -- R4 RI 7 R4 RI 4 R3 R2 N re-op NY YE --- R3 R2 P-OEt R5 G K N OEt He R5 G O R4 R1 8 Formula II R4 R1 5 K = O, NH, S Formula II

1137 Compounds of Formula II where A is NH , Synthesis of Compounds of Formula III —O— or —S— and B is —N— can be made from conden 1138

Scheme 6d R2 R3 R3 R2 F F N F HT-P(OEt) 4 R5 GH + -- R G N He R1 2N \ / R4 F R4 RI F 1 2 3 US 2009/011 8236 A1 May 7, 2009 86

-continued

R3 R2 T-P(OEt) R3 R2 T-P(OEt)

5 o HR 5 o R G \ / N —- R. G \ / N R4 RI F R4 RI R7 5 6

Formula III

1139. The general synthesis of compounds of Formula III wherein G is —O— —S or —NH utilizes the displace- -continued ment of an appropriately Substituted phenol, thiophenol or O aniline 1 with a pentasubstituted pyridine such as 3.5- dichloro-2,4,6-trifluoro-pyridine- 0 2 to provide- intermediate0 3 R3 CN R2 T-P(OEt) (Scheme 6d) (Org. Prep. Proced. Int., 2000, 32(5), 502-504). o Subsequent displacement of the 2-fluoro and 6-fluoro sub- R5 N stituents on the pyridine ring with nucleophiles 4 and HR’ \ / sequentially provide intermediates 5 and 6. Examples of Suit- 4 able nucleophiles, include but are not limited to, diethyl R R F hydroxymethyl-phosphonate and diethylaminomethyl-phos- 9 O phonate. Example of reactants HR, include but are not lim- | ited to, alkylthiol, Sodium alkoxide, alkylamine or benzy- R3 o R. T-P(OEt) lamine. Compounds of Formula III where G is —S(=O)— o and —S(=O) can be derived from intermediates 5 and 6 R5 N when G is \ / —S - via oxidation with an oxidizing agent such as mCPBA. 4 Further protecting group and functional group manipulations R R F of intermediates 5 and 6 will provide compounds of Formula 10 III. /

R2 R3 R2 T-P(OEt) R3 F F o CN N -as- R5 N -- Formula III R5 2N \ / R1 4 R4 RI F R 11 7 2

1140 Compounds of Formula III wherein G is —CH2— 3 2 or —(O)—are synthesized according to scheme 6e. Conden R CN R. F HT-P(OEt) sation of benzyl cyanide 7 with pentasubstituted pyridine 2 o 4 provide intermediate 8. Displacement of 2-fluoro with R5 —- reagent 4 gives intermediate 9. Oxidation of benzyl cyanide 9 \ M provides keto derivative 10 which after deprotection and functional group manipulation gives a compound of Formula R4 R1 F III. Alternatively, reductive deoxygenation of keto interme diate followed by deprotection and functional group manipu lation gives a compound of Formula III.