Methods of reducing side effects associated with thyroid

Abstract

The present disclosure relates to methods of administering thyroid hormone receptor agonists. The present disclosure provides methods wherein the methods maintain the activity of a given thyroid receptor agonist in ameliorating or curing obesity, hyperlipidemia, hypercholesterolemia, diabetes, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, atherosclerosis, cardiovascular disease, hypothyroidism, and related conditions, meanwhile, thyroid-related and thyroid axis-related side effects are reduced or eliminated.

Description

BACKGROUND

[0001] Field of the invention

[0002] The compounds and methods described herein relate generally to the field of treatment of thyroid-mediated disorders, and in particular to mechanisms for reducing side effects from administration of thyroid hormone receptor agonists.

[0003] Prior art description

[0004] Thyroid hormones (THs) play a critical role in growth, development, metabolism, and homeostasis. They are produced by the thyroid gland as thyroxine (T4) and 3,5,3'-triiodo-L-thyronine (T3). T4 is the primary secreted form in humans and is enzymatically deiodinated to the more active form, T3, in peripheral tissues by deiodinases. THs exert their effects by interacting with the thyroid hormone receptor (TR), which belongs to the nuclear hormone receptor superfamily, and modulate transcription of target genes. THs form part of the thyroid axis, also known as the hypothalamic-pituitary-thyroid, or HPT axis, which comprises complex endocrine and paracrine feedback loops connecting tissues of the brain and endocrine system to exert global control over overall issues such as overall metabolic rate, lipid secretion, heart function, muscle and bone growth, etc. (see, e.g.,, Robins and Cotran: Pathologic Basis of Disease Robins and Cotran: Pathologic Basis of Disease , Kumar, V. et al., eds. (2005), p. 1165, which is incorporated by reference herein in its entirety).

[0005] TRs are expressed in most tissues and exist in two isoforms (TRa and TRP). Tissue distribution studies, mouse knockout studies, and evaluation of patients with resistance to thyroid hormone (RTH) syndrome have established that TRa is the dominant isoform in the heart and modulates most cardiac functions, while the TRP isoform is dominant in the liver and pituitary and modulates cholesterol metabolism and thyroid-stimulating hormone (TSH) production, respectively. Recognizing the potential benefits associated with TR modulation, many approaches have been taken to identify suitable TR agonists to lower plasma cholesterol levels. However, these benefits are offset by deleterious cardiovascular side effects such as tachycardia, arrhythmia, elevated blood pressure, and heart failure, as well as effects on the thyroid hormone axis, muscle metabolism, and bone loss.

[0006] The TR-mediated pathway is involved in the regulation of serum lipid levels, including cholesterol, triglycerides, and associated lipoproteins. See Pearce, E.N., Curr. Cardiol. Rep. 6:451-6 (2004) and Duntas, L.H., Thyroid 12:287-93 (2002), both of which are incorporated by reference in their entireties. Elevated serum lipid levels are associated with the development of atherosclerosis and the worsening of coronary artery disease. See Grundy, S.M., et al., Circulation 110:227-39 (2004), incorporated by reference in its entirety. While medications such as statins and PCSK-9 inhibitors, as well as dietary and lifestyle interventions, can help treat hyperlipidemia in some patients, many patients fail to significantly reduce their serum cholesterol levels, and many patients cannot tolerate high doses of statins. See Pearson, T. et al., Arch Intern Med. 160:459-467 (2000), incorporated by reference in its entirety. Thus, there is an unmet medical need for additional orally administered lipid-modulating therapies. Figure 1 Figure 2 , Kumar, V. et al., eds., (2005), pp. 523, 572-77, which is incorporated by reference in its entirety). Clinical trials have shown that lowering low-density lipoprotein / serum cholesterol levels reduces morbidity and mortality associated with cardiovascular disease. See Grundy, S.M., et al., Circulation 110:227-39 (2004), incorporated by reference in its entirety. While medications such as statins and PCSK-9 inhibitors, as well as dietary and lifestyle interventions, can help treat hyperlipidemia in some patients, many patients fail to significantly reduce their serum cholesterol levels, and many patients cannot tolerate high doses of statins. See Pearson, T. et al., Arch Intern Med. 160:459-467 (2000), incorporated by reference in its entirety. Thus, there is an unmet medical need for additional orally administered lipid-modulating therapies.

[0007] Similarly, nonalcoholic fatty liver disease (NAFLD), a condition associated with a cluster of metabolic irregularities known as metabolic syndrome, is defined by the accumulation of excess fat in the liver in the form of triglycerides (steatosis). This condition can also include liver cell damage and inflammation, leading to nonalcoholic steatohepatitis (NASH). NASH is often consistent with patients who have type 2 diabetes, hypercholesterolemia, hypertriglyceridemia, and obesity. Patients with NASH are at risk for cirrhosis, liver failure, and hepatocellular carcinoma. Treatment of NASH is currently limited to lifestyle interventions. However, the role of thyroid hormone in modulating LDL-C and triglyceride levels makes the TR-mediated pathway a promising target for treating NASH and NAFLD. For example, thyroid hormone mimetics have been shown to significantly reduce liver fat content in animals.

[0008] Selective TRβ agonists are being developed as a means to suppress the cardiac side effects of non-specific TR agonists while retaining the potential beneficial effects of TRβ activation, such as lowering cholesterol and serum lipid levels, and reduction of obesity due to increased cellular metabolism. See Fujitaki, J. M., et al., Drug Metab. Disp. 36(11) 2393-403 (2008), which is incorporated by reference in its entirety. However, even targeted TRβ agonists have been shown to cause suppression of the thyroid hormone axis (see Erion, M. D., PNAS USA 104(39): 15490-5 (2007), which is incorporated by reference in its entirety), which can result in side effects ranging from depression and fatigue to muscle wasting and bone loss. Thus, there is a need for compositions and methods that achieve TRβ activation while reducing HPT axis suppression and its associated side effects. SUMMARY

[0009] The present disclosure provides methods of treating conditions such as obesity, hyperlipidemia, hypercholesterolemia, diabetes, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, atherosclerosis, cardiovascular disease, hypothyroidism, and thyroid cancer; in an individual in need thereof, by administering a therapeutically effective amount of one or more compounds such as: Formula I:

[0010] wherein: G is selected from the group consisting of -0-, -S-, -S(=0)-, -S(=0)2-, -Se-, -CH2-, -CF2-, -CHF-, -C(O)-, -CH(OH)-, -CH(Ci-C4alkyl)-, -CH(Ci-C4alkoxy)-, -C(=CH2)-, -NH-, and -N(Ci-C4alkyl)-; T is selected from the group consisting of -(CR a 2)k -, -CR b =CR b -(CR a 2) n -, -(CR a 2) n -CR b =CR b -, -(CR a 2)-CR b =CR b -(CR a 2)-, -O(CR b 2)(CR a 2) n -, -S(CR b2) (CR a 2) n-, N(R c )(CR b 2) (CR a 2) n -, N(R b )C(O)(CR a 2) n , -C(O)(CR a 2) m -, -(CR a 2) m C(O)-, -(CR a 2)C(O)(CR a 2) n , -(CR a 2) n C(O)(CR a 2)- and -C(O)NH(CR b 2)(CR a 2) p -; k is an integer from 1 to 4; m is an integer from 0 to 3; n is an integer from 0 to 2; p is an integer from 0 to 1; each R a is independently selected from the group consisting of hydrogen, optionally substituted -C1-C4alkyl, halogen, -OH, optionally substituted -O-C1-C4alkyl, -OCF3, optionally substituted -S-C1-C4alkyl, -NR b R c , optionally substituted -C2-C4alkenyl, and optionally substituted -C2-C4alkynyl; provided that when one R a is attached to C via an O, S, or N atom, then the other R a is hydrogen, or attached via a carbon atom; each R b is independently selected from the group consisting of hydrogen and optionally substituted -C1-C4alkyl; each R c is independently selected from the group consisting of hydrogen and optionally substituted -C1-C4alkyl, optionally substituted -C(O)-C1-C4alkyl, and -C(O)H; R 1 and R 2 are each independently selected from the group consisting of halogen, optionally substituted -C1-C4alkyl, optionally substituted -S-C1-C3alkyl, optionally substituted -C2-C4alkenyl, optionally substituted -C2-C4alkynyl, -CF3, -OCF3, optionally substituted -O-C1-C3alkyl, and cyano; R 6 , R7 R 8 and R 9 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted -C1-C4alkyl, optionally substituted -S-C1-C3alkyl, optionally substituted -C2-C4alkenyl, optionally substituted -C2-C4alkynyl, -CF3, -OCF3, optionally substituted -O-C1-C3alkyl, and cyano; or R 6 and T, together with the carbon to which they are attached, form a ring of 5 to 6 atoms including 0 to 2 heteroatoms independently selected from -NR i -, -O-, and -S-; provided that when there are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen, then the two heteroatoms must be separated by at least one carbon atom; and X is attached to the ring by a direct bond to a ring carbon, or by -(CR a 2)- or -C(O)- bonded to a ring carbon or a ring nitrogen; R i is selected from the group consisting of hydrogen, -C(O)C1-C4alkyl, -C1-C4alkyl, and -C1-C4aryl; R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted -C1-C 12 alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, -SR d , -S(=O)R e , -S(=O)2R e , -S(=O)2NR f R g , -C(O)OR h , -C(O)R e , -N(R b )C(O)NR f R g , -N(R b )S(=O)2R e , -N(R b )S(=O)2NR f R g , and -NR f R g ; each R d is selected from the group consisting of optionally substituted -C1-C 12 alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -(CR b 2) naryl, optionally substituted -(CR b 2) n cycloalkyl, optionally substituted -(CR b 2) n Heterocyclic alkyl groups and -C(O)NR f R g ; Each R e Selected from the optional substitution -C1-C 12 Alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -(CR) a 2) n aryl, optionally substituted -(CR a 2) n cycloalkyl and optionally substituted -(CR a 2) n Heterocyclic alkyl groups; R f and R g Each is independently selected from hydrogen, with optional substitution of -C1-C. 12 Alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -(CR) b 2) n aryl, optionally substituted -(CR b 2) n cycloalkyl and optionally substituted -(CR b 2) n Heterocyclic alkyl, or R f and R g They can together form optionally substituted heterocycles, which may contain elements selected from O and NR. C The second heterogroup of S, wherein the optionally substituted heterocycle may be 0-4 selected from optionally substituted -C1-C4 alkyl, -OR b Oxygenated, cyano, -CF3, optionally substituted phenyl groups and -C(O)OR h Substituents of the substituents; Each R h Selected from the optional substitution -C1-C 12 Alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -(CR) b 2) n aryl, optionally substituted -(CR b 2) n cycloalkyl and optionally substituted -(CR b 2)n heterocycloalkyl; R 5 selected from -OH, optionally substituted -OC1-C6alkyl, OC(O)R e , -OC(O)OR h , -F, -NHC(O)R e , -NHS(=O)R e , -NHS(=O)2R e , -NHC(=S)NH(R h ) and -NHC(O)NH(R h ); X is P(O)YR 11 Y' R 11 ; Y and Y' are each independently selected from -O- and -NR v -; when Y and Y' are -O-, R 11 attached to the -O- is independently selected from -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted CH2-heterocycloalkyl, optionally substituted -alkylaryl, -C(R z )2OC(O)NR z 2, -NR z -C(O)-R y , -C(R z )2-OC(O)R y , -C(R z )2-O-C(O)OR y , -C(R z )2OC(O)SR y , -alkyl-S-C(O)R y , -alkyl-S-S-alkylhydroxy and -alkyl-S-S-S-alkylhydroxy; when Y and Y' are -NR v -, then R v attached to the -NR 11 - is independently selected from -H, -[C(R z )2] q -COOR y , -C(R x )2COOR Y , -[C(R z )2] q -C(O)SR y and -cycloalkylidene-COOR y ; when Y is -O- and Y' is NR v , then R 11independently selected from -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, -C(R z )2OC(O)NR z 2, -NR z -C(O)-R y , -C(R z )2-OC(O)R y , -C(R z )2-O-C(O)OR y , -C(R z )2OC(O)SR y , -alkyl-S-C(O)R y , -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; and R v attached to -NR 11 is independently selected from H, -[C(R z )2] q -COOR y , -C(R x )2COOR y , -[C(R z )2] q -C(O)SR y , and -cycloalkylidene-COOR y ; or when Y and Y' are independently selected from -O- and NR v , then R 11 and R 11 together are -alkyl-S-S-alkyl- to form a cyclic group, or R 11 and R 11 together are the group:

[0011] wherein: V, W and W' are independently selected from hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-alkynyl; or V and Z together are linked via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms, and the remaining atoms are carbon, which cyclic group containing 5-7 atoms is substituted with a hydroxyl, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy group attached to a carbon atom three atoms removed from both Y groups attached to phosphorus; or V and Z together are linked via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, which cyclic group is fused to the aryl group at the beta and gamma positions of Y attached to phosphorus; or V and W together are linked via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy attached to one of the carbon atoms three atoms removed from Y attached to phosphorus; or Z and W together are linked via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or W and W' together are linked via an additional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHR z OH, -CHR z OC(O)R y , -CHR z OC(S)R y , -CHR z OC(S)OR y , -CHR z OC(O)SR y , -CHR z OCO2R y , -OR z , -SR z , -CHR z N3, -CH2aryl, -CH(aryl)OH, -CH(CH=CR z 2)OH, -CH(C≡CR z )OH, -R z , -NR z 2, -OCOR y , -OCO2R y , -SCOR y , -SCO2R y , -NHCOR z , -NHCO2R y , -CH2NHaryl, -(CH2)q-OR z , and -(CH2)q-SR z ; q is an integer of 2 or 3; each R z is selected from the group consisting of R y and -H; each R y is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; each R x is independently selected from the group consisting of -H and alkyl, or R x and R x together form a cycloalkyl group; each R v is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; and pharmaceutically acceptable salts and prodrugs thereof; and pharmaceutically acceptable salts of the prodrugs of the foregoing.

[0012] In some embodiments, the compound of Formula I has the following provisos: a) when G is -O-, T is -CH2-, R 1 and R 2 are each bromo, R 3 is isopropyl, R 4 is hydrogen, and R 5 is -OH, then X is not P(O)(OH)2or P(O)(OCH2CH3)2; b) V, Z, W, W' are not all -H; and c) when Z is -R z , then at least one of V, W, and W' is not -H, alkyl, aralkyl, or heterocycloalkyl; d) when G is -O-, T is -(CH2) 1-4 -, R 1 and R 2 are each independently halo, alkyl, and cycloalkyl, R 3 is alkyl, R 4 is hydrogen, and R 5 is -OH, then X is not -P(O)(OH)2or -P(O)(O-lower alkyl)2; and e) when G is -O-, R 5 is -NHC(O)R e , -NHS(=O) 1-2 R e , -NHC(S)NH(R b ), or -NHC(O)NH(R h ), T is -(CH2) m -, -CH=CH-, -O(CH2) 1-2 -, or -NH(CH2) 1-2 -, then X is not -P(O)(OH)2or -P(O)(OH)NH2; Preferably, the composition to be administered comprises one or more of: (Compound 1) and Compound 2 (Compound 3), or Compound 4 or a pharmaceutically acceptable salt thereof.

[0013] The methods described herein can be effective to reduce or eliminate thyroid-related side effects and side effects associated with suppression of the hypothalamic-thyroid-pituitary axis (HPT axis) while maintaining the effectiveness of the compound at the same or similar levels as a standard daily dosing regimen. The methods described herein include the use of strategically placed dosing holidays that surprisingly maintain the beneficial effects of the administered compound while reducing suppression of the HPT axis. Such holidays can occur every other day during the dosing schedule, or more or less frequently. In some embodiments, daily dosing is performed for 1 to 30 days followed by a dosing holiday of 1 to 30 days.

[0014] In some embodiments, the serum level of the drug substance is allowed to drop to a subtherapeutic level before the next dose is administered. In some other embodiments, the serum level of the drug substance is maintained within a therapeutic window between doses. In some other embodiments, daily dosing is performed while monitoring components of the HPT axis. In some additional embodiments, a dosing holiday occurs whenever direct observation of suppression of the HPT axis. BRIEF DESCRIPTION OF DRAWINGS

[0015] Figure 3 Effect of once daily oral administration of Compound 2 on total plasma cholesterol (TPC) levels in beagle dogs (n = 4 per group) over 14 days is shown.

[0016] Figure 4 Effect of once daily oral administration of Compound 2 for 14 days followed by Compound 2 every other day for 14 days on total plasma cholesterol (TPC) levels in beagle dogs (n = 4 per group) is shown.

[0017] Figure 5 Total T4 / thyroxine (tT4) levels in serum following once daily oral administration of Compound 2 to beagle dogs (n = 4 / group) are shown (mean ± SEM).

[0018] Figure 6 Free T4 / thyroxine (fT4) levels in serum following once daily oral administration of Compound 2 to beagle dogs (n = 4 / group) are shown (mean ± SEM).

[0019] Figure 7Total triiodothyronine / T3 (tT3) levels in serum (mean ± SEM) following once daily oral administration of Compound 2 to beagle dogs (n = 4 / group) are shown.

[0020] Figure 8 Free triiodothyronine / T3 (fT3) levels in serum (mean ± SEM) following once daily oral administration of Compound 2 to beagle dogs (n = 4 / group) are shown.

[0021] Figure 9 Thyroid stimulating hormone (TSH) levels in serum (mean ± SEM) following once daily oral administration of Compound 2 to beagle dogs (n = 4 / group) are shown.

[0022] Definitions The effect of once daily oral administration of Compound 2 for 14 days followed by Compound 2 every other day for 14 days on total T4 (tT4) levels in serum of beagle dogs (Cycle 2 + Extension; n = 2 / group) is shown.

[0023] Figure 1 The effect of once daily oral administration of Compound 2 for 14 days followed by Compound 2 every other day for 14 days on free T4 (fT4) levels in serum of beagle dogs (Cycle 2 + Extension; n = 2 / group) is shown.

[0024] Detailed Description

[0025] The present disclosure provides methods of treating nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, hyperlipidemia, dyslipidemia, hypertriglyceridemia, and other conditions associated with misregulation of the TRβ pathway by administering a TRβ agonist. The methods of the present disclosure are further designed to prevent suppression of the HPT axis and potential side effects associated with such suppression.

[0026] Figure 1

[0027] The term "mammal" is used in its ordinary biological sense. Thus, it specifically includes humans and non-human mammals, such as dogs, cats, horses, donkeys, mules, cows, domestic water buffalo, camels, llamas, alpacas, bison, yaks, goats, sheep, pigs, elks, deer, domestic antelopes, and non-human primates, among many other species.

[0028] As used herein, "individual" refers to a human or non-human mammal, including but not limited to a dog, cat, horse, donkey, mule, cow, domestic water buffalo, camel, llama, alpaca, bison, yak, goat, sheep, pig, elk, deer, domestic antelope, or non-human primate selected for treatment or therapy.

[0029] "An individual suspected of having the disease" means an individual exhibiting one or more clinical indicators of a disease or condition. In some embodiments, the disease or condition is obesity. In some embodiments, the disease or condition is hyperlipidemia. In some embodiments, the disease or condition is hypercholesterolemia. In some embodiments, the disease or condition is diabetes. In some embodiments, the disease or condition is non-alcoholic fatty liver disease. In some embodiments, the disease or condition is non-alcoholic steatohepatitis. In some embodiments, the disease or condition is atherosclerosis. In some embodiments, the disease or condition is cardiovascular disease. In some embodiments, the disease or condition is hypothyroidism. In some embodiments, the disease or condition is thyroid cancer.

[0030] "Individuals in need" refers to individuals identified as requiring therapy or treatment.

[0031] Therapeutic effects alleviate one or more symptoms of a disease or condition to a certain extent, and include curing a disease or condition. "Cure" means the elimination of symptoms of an active disease. However, even after a cure, some long-term or permanent effects of the disease may remain (e.g., extensive tissue damage).

[0032] As used herein, “treat,” “treatment,” or “treating” refers to the administration of a pharmaceutical composition for preventive and / or therapeutic purposes. The term “preventive treatment” refers to treating a patient who does not yet have a related disease or condition but is susceptible to or at risk of developing a specific disease or condition, thereby reducing the likelihood of that patient developing the disease or condition. The term “therapeutic treatment” refers to administering treatment to a patient who already has a disease or condition.

[0033] "Preventing" or "prevention" refers to delaying or preventing the onset, development, or progression of a condition or disease for a period of time, including weeks, months, or years.

[0034] "Improvement" means reducing the severity of at least one indicator of a condition or disease. In some embodiments, improvement includes delaying or slowing the progression of one or more indicators of a condition or disease. The severity of an indicator can be determined by subjective or objective measurements known to those skilled in the art.

[0035] "Modulate" means perturbation of a function or activity. In certain embodiments, modulate means an increase in gene expression. In certain embodiments, modulate means a decrease in gene expression. In certain embodiments, modulate means an increase or decrease in total serum levels of a specific protein. In certain embodiments, modulate means an increase or decrease in free serum levels of a specific protein. In certain embodiments, modulate means an increase or decrease in total serum levels of a specific non-proteinaceous factor. In certain embodiments, modulate means an increase or decrease in free serum levels of a specific non-proteinaceous factor. In certain embodiments, modulate means an increase or decrease in total bioavailability of a specific protein. In certain embodiments, modulate means an increase or decrease in total bioavailability of a specific non-proteinaceous factor.

[0036] "Administering" means providing a pharmaceutical agent or composition to an individual and includes, but is not limited to, administration by a medical professional and self-administration.

[0037] Administration of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, can be via any acceptable mode of administration for an agent serving a similar purpose, including, but not limited to, oral, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular. Oral and parenteral administration are common for treating indications of subjects as preferred embodiments.

[0038] "Parenteral administration" means administration by injection or infusion. Parenteral administration includes, but is not limited to, subcutaneous administration, intravenous administration, intramuscular administration, intra-arterial administration, and intracranial administration.

[0039] "Subcutaneous administration" means administration just under the skin.

[0040] "Intravenous administration" means administration into a vein.

[0041] "Intra-arterial administration" means administration into an artery.

[0042] The term "agent" includes any substance, molecule, element, compound, entity, or combination thereof. It includes, but is not limited to, for example, a protein, polypeptide, peptide, or mimetic, a small organic molecule, a polysaccharide, a polynucleotide, and the like. It can be a natural product, a synthetic compound, or a chemical compound, or a combination of two or more substances.

[0043] "Agent" means a substance that provides a therapeutic effect when administered to an individual.

[0044] "Pharmaceutical composition" means a mixture of substances comprising an agent that is suitable for administration to an individual. For example, a pharmaceutical composition can comprise a modified oligonucleotide and a sterile aqueous solution.

[0045] "Active pharmaceutical ingredient" means a substance in a pharmaceutical composition that provides a desired effect.

[0046] The term "pharmaceutically acceptable salt" refers to salts of a compound that retain its biological effectiveness and properties and that are not biologically or otherwise undesirable. In many cases, the compounds disclosed herein are capable of forming acid and / or base salts by virtue of the presence of phenol and / or phosphonate groups or groups similar thereto. One of ordinary skill in the art will recognize that the protonation state of any or all of these compounds can vary with the pH and ionic character of the surrounding solution, and thus the present disclosure contemplates multiple charge states for each compound. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids as well as organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic as well as organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, particularly for example isopropylamine, trimethylamine, diethylamine, triethylamine, propylamine, and ethanolamine. Many such salts are known and described in, for example, WO 87 / 05297 to Johnston et al., published September 11, 1987 (hereby incorporated by reference in its entirety).

[0047] "Solvate" refers to a compound formed by the interaction of a solvent and an EPI, metabolite, or salt thereof. Suitable solvates are pharmaceutically acceptable solvates, including hydrates.

[0048] Useful compounds as described above can be formulated into pharmaceutical compositions for treating these conditions. Standard pharmaceutical formulation techniques are used, for example, those disclosed in Remington's The Science and Practice of Pharmacy, 21stEd., Lippincott Williams and Wilkins (2005), which is hereby incorporated by reference in its entirety. Accordingly, some embodiments include pharmaceutical compositions comprising: (a) a safe and therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

[0049] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, diluents, emulsifiers, binding agents, buffers, dispersion

[0050] Some examples of substances which can serve as pharmaceutically acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acids and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0051] The choice of a pharmaceutically acceptable carrier to be used in conjunction with the subject compounds is basically determined by the way the compound is to be administered.

[0052] It is preferred to present the compositions described herein in unit dosage form. As used herein, "unit dosage form" is a composition containing an amount of a compound that is suitable for administration to a subject in a single dose, according to good medical practice. However, the preparation of a single dose or unit dose form does not imply that the dose form is administered once a day or once per course of therapy. A unit dose form can contain a single daily single dose or a fractional sub-dose where several unit dose forms will be administered during the course of a day to complete the daily dose. A unit dose form can be given more or less than once a day, and can be administered more than once during the course of a therapy, according to the present disclosure. These dose forms can be administered in any manner that is consistent with their formulation, including orally, parenterally, and can be administered as an infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours). While single single doses are specifically contemplated, the compositions administered according to the methods described herein can also be administered as a continuous infusion or by an implantable infusion pump.

[0053] The methods described herein can use any of a variety of suitable forms for various routes of administration, such as oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular, or other parenteral routes of administration. The skilled artisan will appreciate that oral and nasal compositions include compositions that are administered by inhalation and prepared using available methodologies. Depending on the particular route of administration required, a variety of pharmaceutically acceptable carriers can be used, as is well known in the art. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, auxiliaries, surface-active and encapsulating substances. Optional pharmaceutically active materials can be included that do not substantially interfere with the activity of the compounds. The amount of carrier that is used in conjunction with the compound is sufficient to provide practical amounts of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references, all incorporated herein by reference: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker and Rhodes, Eds., 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).

[0054] Various oral dosage forms can be used, including solid forms such as tablets, capsules, granules and bulk powders. Tablets can be compressed, imprinted, enteric-coated, sugar-coated, film-coated, or multiple compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.

[0055] Pharmaceutically acceptable carriers suitable for the preparation of unit dosage forms for oral administration are well known in the art. Tablets typically comprise a conventional pharmaceutical binding agent as an inert diluent, e.g., calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; a binder, e.g., starch, gelatin and sucrose; a disintegrating agent, e.g., starch, alginic acid and cross-linked carboxymethylcellulose; a lubricant, e.g., magnesium stearate, stearic acid, microcrystalline cellulose, carboxymethylcellulose and talc. Tablets can also comprise a solubilizing or emulsifying agent, e.g., poloxamer, hydrogenated castor oil / Kolliphor® / Lutrol®, methylcellulose, hydroxypropyl methylcellulose or other known in the art. Glidants such as silicon dioxide can be used to improve flow characteristics of powder mixtures. Coloring agents, e.g., FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, e.g., aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically comprise one or more of the solid diluents disclosed above. Selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not important, and can be readily made by a person skilled in the art.

[0056] Oral (PO) compositions also include liquid solutions, emulsions, suspensions, and the like. Pharmaceutically acceptable carriers suitable for the preparation of such compositions are well known in the art. Typical carrier components for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For suspensions, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; typical preservatives include methyl paraben and sodium benzoate. Oral liquid compositions can also contain one or more components such as the sweetening agents, flavoring agents and coloring agents disclosed above.

[0057] Such compositions can also be coated by conventional methods, usually with pH dependent coatings or time dependent coatings, so that the subject compound is released in the gastrointestinal tract near the desired local application or at different times to prolong the desired effect. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, Eudragit coatings, waxes, and shellac.

[0058] The compositions described herein can optionally comprise other pharmaceutically active substances.

[0059] Other compositions for achieving systemic delivery of the subject compounds include sublingual, buccal, and nasal dosage forms. Such compositions typically include one or more soluble filler substances, such as sucrose, sorbitol, and mannitol; and binders, such as acacia, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropyl methylcellulose. Glidants, lubricants, sweeteners, colorants, antioxidants, and flavorants disclosed above can also be included.

[0060] Liquid compositions formulated for topical ophthalmic use are formulated so that they are topically applicable to the eye. While formulation considerations (e.g., drug stability) can sometimes require less than optimal comfort, comfort can be maximized as much as possible. Where comfort cannot be maximized, the liquid can be formulated so that the liquid is tolerable to the patient in need of topical ophthalmic use. Additionally, ophthalmically acceptable liquids can be packaged for single use, or contain a preservative to prevent contamination upon multiple uses.

[0061] For ophthalmic applications, solutions or drugs are typically prepared using a physiological saline solution as the primary vehicle. Ophthalmic solutions can preferably be maintained at a comfortable pH with an appropriate buffer system. The formulation can also contain conventional pharmaceutically acceptable preservatives, stabilizers, and surfactants.

[0062] Preservatives that can be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thiomersal, phenylmercuric acetate, and phenylmercuric nitrate. A useful surfactant is, for example, Tween 80. Likewise, various useful vehicles can be used in the ophthalmic formulations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamer, carboxymethylcellulose, hydroxyethylcellulose, and purified water.

[0063] Tension adjusting agents can be added as needed or if convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol, and glycerol, or any other suitable ophthalmically acceptable tension adjusting agent.

[0064] Various buffering agents and means for adjusting pH can be used so long as the resulting formulation is ophthalmically acceptable. For many compositions, the pH is from 4 to 9. Thus, buffering agents include acetate buffers, citrate buffers, phosphate buffers, and borate buffers. Acids or bases can be used to adjust the pH of these formulations as needed.

[0065] Ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0066] Other excipient components that can be included in ophthalmic formulations are chelating agents. A useful chelating agent is edetate disodium, although other chelating agents can be used or in conjunction therewith.

[0067] For topical application, including for transdermal administration, creams, ointments, gels, solutions or suspensions containing the compounds disclosed herein are used. Topical formulations can generally include a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.

[0068] For intravenous administration, the compounds and compositions described herein can be dissolved or dispersed in a pharmaceutically acceptable diluent, such as saline or dextrose solution. Suitable excipients can be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HC1, and citric acid. In various embodiments, the pH of the final composition is from 2 to 8, or preferably from 4 to 7. Antioxidant excipients can include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in final intravenous compositions can include sodium or potassium phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Additional acceptable excipients are described in Powell, et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are incorporated by reference herein in their entirety. Antimicrobial agents can also be included to obtain a bacteriostatic or fungistatic solution, including but not limited to phenylmercuric nitrate, thiomersal, benzethonium chloride, benzalkonium chloride, phenol, m-cresol, and chlorobutanol.

[0069] Compositions for intravenous administration can be presented in one or more solid forms which are reconstituted with a suitable diluent, such as sterile water, saline, or dextrose aqueous solution, shortly before administration. In other embodiments, the compositions are provided in solution ready for parenteral administration. In other embodiments, the compositions are provided in solution which is further diluted prior to administration. In embodiments comprising administration of a compound described herein in combination with another agent, the combination can be provided to the caregiver as a mixture, or the caregiver can mix the two agents prior to administration, or the two agents can be administered separately.

[0070] Actual unit dosages of the active compounds described herein depend on the particular compound and the condition to be treated. In some embodiments, the dosage can be from about 0.01 mg / kg to about 120 mg / kg body weight or more, from about 0.05 mg / kg or less to about 70 mg / kg, from about 0.1 mg / kg to about 50 mg / kg body weight, from about 1.0 mg / kg to about 10 mg / kg body weight, from about 5.0 mg / kg to about 10 mg / kg body weight, or from about 10.0 mg / kg to about 20.0 mg / kg body weight. In some embodiments, the dosage can be less than 100 mg / kg, 90 mg / kg, 80 mg / kg, 70 mg / kg, 60 mg / kg, 50 mg / kg, 40 mg / kg, 30 mg / kg, 25 mg / kg, 20 mg / kg, 10 mg / kg, 7.5 mg / kg, 6 mg / kg, 5 mg / kg, 4 mg / kg, 3 mg / kg, 2.5 mg / kg, 1 mg / kg, 0.5 mg / kg, 0.1 mg / kg, 0.05 mg / kg, or 0.005 mg / kg body weight. In some embodiments, the actual unit dosage is 0.05, 0.07, 0.1, 0.3, 1.0, 3.0, 5.0, 10.0, or 25.0 mg / kg body weight. Thus, for administration to a 70 kg human, the dosage range is from about 0.1 mg to 70 mg, from about 1 mg to about 50 mg, from about 0.5 mg to about 10 mg, from about 1 mg to about 10 mg, from about 2.5 mg to about 30 mg, from about 35 mg or less to about 700 mg or more, from about 7 mg to about 600 mg, from about 10 mg to about 500 mg, from about 20 mg to about 300 mg, or from about 200 mg to about 2000 mg. In some embodiments, the actual unit dosage is 5 mg. In some embodiments, the actual unit dosage is 10 mg. In some embodiments, the actual unit dosage is 25 mg. In some embodiments, the actual unit dosage is 250 mg or less. In some embodiments, the actual unit dosage is 100 mg or less. In some embodiments, the actual unit dosage is 70 mg or less. In some embodiments, the actual unit dosage is 5 mg.

[0071] As used herein, “loading dose” refers to an initial dose of a compound that is higher than subsequent doses of the compound.

[0072] As used herein, a “maintenance dose” refers to a subsequent dose that occurs after a loading dose and whose timing is later than the loading dose. One of ordinary skill in the art will appreciate that the dosage form or mode of administration for the maintenance dose can be different from the dosage form or mode of administration used for the loading dose. In any of the embodiments disclosed herein, the maintenance dose can comprise administration of a unit dosage form in any of the dosing regimens contemplated herein, including but not limited to once a month or multiple times a month, once every two weeks or multiple times every two weeks, once a week or multiple times a week, once a day or multiple times a day. Dosing holidays can be incorporated into the dosing period of the maintenance dose in the present disclosure. Such dosing holidays can occur immediately after administration of the loading dose, or at any time during the administration of the maintenance dose. As used herein, the timing of administration of the maintenance dose can be referred to as the “maintenance period” of the treatment period.

[0073] As used herein, “mode of administration” refers to the manner in which a compound is administered to an individual. As used herein, “mode of administration” includes the dosage form (e.g., tablet, powder, dissolved liquid, suspension, emulsion, aerosol, etc.) and the mechanism by which the dosage form is applied to the individual (e.g., by injection, such as subcutaneous, intramuscular, intraperitoneal, intravenous, or intraarterial; topically, such as by a cream, lotion, or patch; orally, such as by a pill, dissolved liquid, oral suspension, buccal film, or mouthwash; nasally, such as by a nasal aerosol, powder, or spray; or ocularly, such as by an eye drop). As used herein, “mode of administration” also includes the dose, amount dosed, and dosing regimen by which the compound is administered to the individual.

[0074] In some embodiments, the mode of administration comprises administering a loading dose followed by a maintenance dose. In some embodiments, the loading dose is 300 mg or less; 250 mg or less, 200 mg or less, 150 mg or less, or 100 mg or less. In some embodiments, the maintenance dose is 300 mg or less; 200 mg or less, 100 mg or less, 50 mg or less, 40 mg or less, 25 mg or less, 10 mg or less, 5 mg or less, or 1 mg or less.

[0075] In some embodiments, the loading dose is administered over a period of one day. In some embodiments, the loading dose is administered over a period of 2 days. In some embodiments, the loading dose is administered over a period of 3 days. In some embodiments, the loading dose is administered over a period of 4 days. In some embodiments, the loading dose is administered over a period of 5 days, 6 days, or 7 days. In some embodiments, the loading dose is administered over a period of 8-14 days or less. In some embodiments, the loading dose is administered over a period of 14 days.

[0076] As used herein, "treatment duration" refers to the time beginning with the administration of the first dose and ending with the administration of the final dose, such length of time being determined by one of ordinary skill in the art treating a disease involving TRβ, including but not limited to hyperlipidemia, hypercholesterolemia, NASH, and NAFLD involving the symptoms and health of the individual being treated.

[0077] As used herein, "dosing holiday" refers to a 24 hour or longer period during which no dose is administered to an individual, or a reduced dose is administered to an individual. As used herein, "reduced dose" refers to a dose that is less than the total daily dose to be administered to an individual.

[0078] As used herein, "hypothalamic-pituitary-thyroid axis" or "HPT axis" refers to a group of neuroendocrine pathways, signals, and molecules responsible for regulating metabolism. As used herein, "HPT axis" also refers to any molecule involved in regulating, modifying, or responding to thyroid hormones. Representative components of the HPT axis include triiodothyronine (T3), thyroxine (T4), iodothyronine, thyrotropin-releasing hormone (TRH), and thyroid-stimulating hormone (TSH).

[0079] The term "alkyl" refers to straight-chain or branched-chain or cyclic hydrocarbon groups having only single carbon-carbon bonds. Representative examples include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, and cyclohexyl, all of which can be optionally substituted. Alkyl is C1-C 12 .

[0080] The term "aryl" refers to aromatic groups having 5-14 ring atoms and at least one ring having a conjugated pi-electron system, and includes carbocyclic aryl, heterocyclic aryl, and biaryl groups, all of which can be optionally substituted.

[0081] Carbocyclic aryl is a group having 6-14 ring atoms in which the ring atoms on the aromatic ring are carbon atoms. Carbocyclic aryl includes monocyclic carbocyclic aryl and polycyclic or fused compounds, such as optionally substituted naphthyl.

[0082] Heterocyclic aryl or heteroaryl is a group having 5-14 ring atoms in which 1 to 4 heteroatoms are ring atoms in the aromatic ring, the remaining ring atoms being carbon atoms. Suitable heteroatoms include oxygen, sulfur, nitrogen, and selenium. Suitable heteroaryls include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolyl, pyridyl-N-oxide, pyrimidinyl, pyrazinyl, imidazolyl, and the like, all of which are optionally substituted.

[0083] The term "biaryl" denotes an aryl group having 5-14 atoms comprising more than one aromatic ring, including fused ring systems and aryl groups substituted with other aryl groups. These groups can be optionally substituted. Suitable biaryls include naphthyl and biphenyl.

[0084] The term "optionally substituted" or "substituted" includes groups substituted with one to six substituents independently selected from lower alkyl, lower aryl, lower aralkyl, lower cycloalkyl, lower heterocycloalkyl, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkoxy, lower heteroaryl, lower heteroaryloxy, lower heteroarylalkyl, lower heteroaralkoxy, azido, amino, halogen, lower alkylthio, oxo, lower acylalkyl, lower carboxylate, carboxy, -carboxamido, nitro, lower acyloxy, lower aminoalkyl, lower alkylaminoaryl, lower alkylaryl, lower alkylaminoalkyl, lower alkoxyaryl, lower arylamino, lower aralkylamino, sulfonyl, lower carboxamidoalkylaryl, lower carboxamidoaryl, lower hydroxyalkyl, lower haloalkyl, lower alkylaminoalkylcarboxy-, lower carbamidoalkyl-, cyano, lower alkoxyalkyl, lower perhaloalkyl, and lower arylalkoxyalkyl.

[0085] "Substituted aryl" and "substituted heteroaryl" mean aryl and heteroaryl groups substituted with 1-3 substituents. These substituents are selected from lower alkyl, lower alkoxy, lower perhaloalkyl, halogen, hydroxy, and amino.

[0086] The term "-arylalkyl" means an alkyl group substituted with an aryl group. Suitable aralkyl groups include benzyl, pyridylmethyl, and the like, and can be optionally substituted. "Heteroarylalkyl" means an alkyl group substituted with a heteroaryl group.

[0087] The term "alkylaryl-" means an aryl group substituted with an alkyl group. "Lower alkylaryl-" means such a group where the alkyl group is lower alkyl.

[0088] The term "lower" in connection with an organic group or compound is defined herein as, for example, up to and including 10, in one aspect up to and including 6, and in another aspect, up to and including four carbon atoms. The groups can be straight-chained, branched, or cyclic.

[0089] The term "cyclic alkyl" or "cycloalkyl" means a cyclic alkyl group having 3 to 10 carbon atoms, and in one aspect 3 to 6 carbon atoms. Suitable cyclic groups include norbornyl and cyclopropyl. The groups can be substituted.

[0090] The terms "heterocycle," "heterocyclic alkyl," or "heterocycloalkyl" mean a cyclic group of 3 to 10 atoms (in one aspect, 3 to 6 atoms) containing at least one heteroatom (in another aspect, 1 to 3 heteroatoms). Suitable heteroatoms include oxygen, sulfur, and nitrogen. Heterocyclic groups can be attached by a nitrogen or by a carbon atom in the ring. Heterocycloalkyl groups include unsaturated rings, fused rings, and spiro rings. Suitable heterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl, and pyridyl.

[0091] The terms "aryl amino" (a) and "aralkyl amino" (b) mean the group -NRR', where (a) R is aryl and R' is hydrogen, alkyl, aralkyl, heterocycloalkyl, or aryl, respectively, and (b) R is aralkyl and R' is hydrogen, aralkyl, aryl, alkyl, or heterocycloalkyl, respectively.

[0092] The term "acyl" means -C(O)R, where R is alkyl, heterocycloalkyl, or aryl.

[0093] The term "carboxyl ester" means -C(O)OR, where R is alkyl, aryl, aralkyl, cycloalkyl, or heterocycloalkyl, all of which are optionally substituted.

[0094] The term "carboxyl" means -C(O)OH.

[0095] The term "oxo" means =O in an alkyl or heterocycloalkyl group.

[0096] The term "amino" means -NRR', where R and R' are independently selected from hydrogen, alkyl, aryl, aralkyl, and heterocycloalkyl, all of which except H are optionally substituted; and R and R' can form a ring system.

[0097] The term "-carboxylamido" means -CONR2, where each R is independently hydrogen or alkyl.

[0098] The term "-sulphonylamido" or "-sulfonylamido" means -S(=O)2NR2, where each R is independently hydrogen or alkyl.

[0099] The term "halogen" or "halo" means -F, -Cl, -Br, and -I.

[0100] The term "alkylaminoalkylcarboxyl" means the group alkyl-NR-alk-C(O)-O-, where "alk" is alkylene and R is H or lower alkyl.

[0101] The term "sulphonyl" or "sulfonyl" means -SO2R, where R is H, alkyl, aryl, aralkyl, or heterocycloalkyl.

[0102] The term "sulphonate" or "sulfonate" means -SO2OR, where R is -H, alkyl, aryl, aralkyl, or heterocycloalkyl.

[0103] The term "alkenyl" means an unsaturated group having from 2 to 12 atoms and containing at least one carbon-carbon double bond, and includes straight chain, branched chain, and cyclic groups. The alkenyl group can be optionally substituted. Suitable alkenyl groups include allyl. A "1-alkenyl" group means an alkenyl group in which the double bond is between the first and second carbon atom. If the 1-alkenyl group is attached to another group, e.g., it is a W substituent attached to a cyclic phosphonate, it is attached on the first carbon.

[0104] The term "alkynyl" means an unsaturated group having from 2 to 12 atoms and containing at least one carbon-carbon triple bond, and includes straight chain, branched chain, and cyclic groups. The alkynyl group can be optionally substituted. Suitable alkynyl groups include ethynyl. A "1-alkynyl" group means an alkynyl group in which the triple bond is between the first and second carbon atom. If the 1-alkynyl group is attached to another group, e.g., it is a W substituent attached to a cyclic phosphonate, it is attached on the first carbon.

[0105] The term "alkylene" means a divalent straight chain, branched chain, or cyclic saturated aliphatic radical. In one aspect, the alkylene contains up to 10 atoms and includes 10 atoms. In another aspect, the alkylene chain contains up to 6 atoms and includes 6 atoms. In another aspect, the alkylene contains up to 4 atoms and includes 4 atoms. The alkylene can be straight chain, branched chain, or cyclic.

[0106] The term "acyloxy" means an ester group -O-C(O)R, where R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, or heterocycloalkyl.

[0107] The term "aminoalkyl-" means the group NR2-alk- where "alk" is an alkylene and R is selected from -H, alkyl, aryl, aralkyl, and heterocycloalkyl.

[0108] The term "alkylaminoalkyl-" means the group alkyl-NR-alk- where each "alk" is an independently selected alkylene and R is H or lower alkyl. "Lower alkylaminoalkyl-" means the group where the alkyl and alkylene are lower alkyl and alkylene, respectively.

[0109] The term "arylaminylalkyl-" refers to the group aryl-NR-alk- where "alk" is alkylene and R is -H, alkyl, aryl, aralkyl or heterocycloalkyl. In "lower arylaminylalkyl-", alkylene is lower alkylene.

[0110] The term "alkylaminylaryl-" refers to the group alkyl-NR-aryl- where "aryl" is a divalent group and R is -H, alkyl, aralkyl or heterocycloalkyl. In "lower alkylaminylaryl-", alkyl is lower alkyl.

[0111] The term "alkoxyaryl-" refers to aryl substituted with alkoxy. In "lower alkoxyaryl-", alkyl is lower alkyl.

[0112] The term "aryloxyalkyl-" refers to alkyl substituted with aryloxy.

[0113] The term "aralkyloxyalkyl-" refers to the group aryl-alk-O-alk- where "alk-" is alkylene. "Lower aralkyloxyalkyl-" refers to such groups where alkylene is lower alkylene.

[0114] The term "alkoxy-" or "alkyloxy-" refers to the group alkyl-O-.

[0115] The term "alkoxyalkyl-" or "alkyloxyalkyl-" refers to the group alkyl-O-alk- where "alk" is alkylene. In "lower alkoxyalkyl-", each alkyl and alkylene is lower alkyl and alkylene, respectively.

[0116] The terms "alkylthio-" and "alkylsulfanyl-" refer to the group alkyl-S-.

[0117] The term "alkylthioalkyl-" refers to the group alkyl-S-alk- where "alk" is alkylene. In "lower alkylthioalkyl-", each alkyl and alkylene is lower alkyl and alkylene, respectively.

[0118] The term "alkoxycarbonyloxy-" refers to alkyl-O-C(O)-O-.

[0119] The term "aryloxycarbonyloxy-" refers to aryl-O-C(O)-O-.

[0120] The term "alkylthiocarbonyloxy-" refers to alkyl-S-C(O)-O-.

[0121] The term "amido" refers to the groups NR2-C(O)-, RC(O)-NR 1 , NR2-S(=O)2- and RS(=O)2-NR 1-acyl or sulfonyl adjacent to an NR2group, where R and R' include -H, alkyl, aryl, aralkyl, and heterocycloalkyl.

[0122] The term "carboxamido" means NR2-C(O)- and RC(O)-NR 1 -acyl or sulfonyl adjacent to an NR2group, where R and R' include -H, alkyl, aryl, aralkyl, and heterocycloalkyl. The term does not include urea, -NR-C(O)-NR-.

[0123] The term "sulphonamido" or "sulfonamido" means NR2-S(=O)2- and RS(=O)2-NR 1 -acyl or sulfonyl adjacent to an NR2group, where R and R' include -H, alkyl, aryl, aralkyl, and heterocycloalkyl. The term does not include urea, -NR-C(O)-NR-.

[0124] The terms "carboxamidoalkylaryl" and "carboxamidoaryl" mean aryl-alk-NR 1 -C(O) and ar-NR 1 -C(O)-alk-, where "ar" is aryl, "alk" is alkylene, R 1 and R include H, alkyl, aryl, aralkyl, and heterocycloalkyl.

[0125] The terms "sulphonamidoalkylaryl" and "sulphonamidoaryl" mean aryl-alk-NR 1 -S(=O)2- and ar-NR 1 -S(-O)2-, where "ar" is aryl, "alk" is alkylene, R 1 and R include H, alkyl, aryl, aralkyl, and heterocycloalkyl.

[0126] The term "hydroxyalkyl" means an alkyl group substituted with one -OH.

[0127] The term "haloalkyl" means an alkyl group substituted with one halogen.

[0128] The term "cyano" means -C≡N.

[0129] The term "nitro" means -NO2.

[0130] The term "acylalkyl" means alkyl-C(O)-alk-, where "alk" is alkylene.

[0131] The term "carbamoylaminoalkyl-" means the group NR2-C(O)-N(R)-alk-, where R is alkyl or H, and "alk" is alkylene. "Lower carbamoylaminoalkyl-" means such a group where "alk" is lower alkylene.

[0132] The term "heteroarylalkyl" refers to an alkylene group substituted with a heteroaryl group.

[0133] The term "perhalo" refers to a group in which every C-H bond in an aliphatic group or aryl group has been replaced with a C-halogen bond. Suitable perhaloalkyl groups include -CF3and -CFCl2.

[0134] The term "carboxylic acid moiety" refers to a compound having a carboxylic acid group (-COOH) and its salts, carboxylate esters, or carboxylic acid surrogates. Suitable carboxylic acid surrogates include tetrazole groups, hydroxamic acid groups, thiazolidinedione groups, acyl sulfonamide groups, and 6-azauracil; and prodrugs thereof. Phosphonic acids and prodrugs thereof are not within the scope of carboxylic acid surrogates.

[0135] Table 1

[0136] Table 1 provides definitions of common abbreviations used in the art that are used in the embodiments and examples described herein.

[0137] As used herein, "inhibition of the HPT axis" refers to a decrease in circulating levels of any element of the HPT axis, particularly triiodothyronine (T3), thyroxine (T4), iodothyronine, thyrotropin releasing hormone (TRH), and thyroid stimulating hormone (TSH), whether alone, in any combination, or in aggregate. In some embodiments, inhibition of the HPT axis includes a decrease in circulating serum levels of triiodothyronine (T3), thyroxine (T4), iodothyronine, thyrotropin releasing hormone (TRH), or thyroid stimulating hormone (TSH) by at least 5%. In some embodiments, inhibition of the HPT axis includes a decrease in circulating serum levels of triiodothyronine (T3), thyroxine (T4), iodothyronine, thyrotropin releasing hormone (TRH), or thyroid stimulating hormone (TSH) by at least 10%. In some embodiments, inhibition of the HPT axis includes a decrease in circulating serum levels of triiodothyronine (T3), thyroxine (T4), iodothyronine, thyrotropin releasing hormone (TRH), or thyroid stimulating hormone (TSH) by at least 20%. In some embodiments, inhibition of the HPT axis includes a decrease in circulating serum levels of triiodothyronine (T3), thyroxine (T4), iodothyronine, thyrotropin releasing hormone (TRH), or thyroid stimulating hormone (TSH) by at least 30%, 40%, 50%, or 60%. In some embodiments, inhibition of the HPT axis includes a decrease in circulating serum levels of triiodothyronine (T3), thyroxine (T4), iodothyronine, thyrotropin releasing hormone (TRH), or thyroid stimulating hormone (TSH) by more than 60%.

[0138] In some embodiments, the suppression of the HPT axis comprises a decrease in free triiodothyronine (fT3) or free thyroxine (fT4) levels of at least 5%. In some embodiments, the suppression of the HPT axis comprises a decrease in free triiodothyronine (fT3) or free thyroxine (fT4) levels of at least 10%. In some embodiments, the suppression of the HPT axis comprises a decrease in free triiodothyronine (fT3) or free thyroxine (fT4) levels of at least 20%. In some embodiments, the suppression of the HPT axis comprises a decrease in free triiodothyronine (fT3) or free thyroxine (fT4) levels of at least 30%, 40%, 50%, or 60%. In some embodiments, the suppression of the HPT axis comprises a decrease in free triiodothyronine (fT3) or free thyroxine (fT4) levels of more than 60%.

[0139] In some embodiments, the suppression of the HPT axis comprises a decrease in total triiodothyronine (tT3) or total thyroxine (tT4) levels of at least 5%. In some embodiments, the suppression of the HPT axis comprises a decrease in total triiodothyronine (tT3) or total thyroxine (tT4) levels of at least 10%. In some embodiments, the suppression of the HPT axis comprises a decrease in total triiodothyronine (tT3) or total thyroxine (tT4) levels of at least 20%. In some embodiments, the suppression of the HPT axis comprises a decrease in total triiodothyronine (tT3) or total thyroxine (tT4) levels of at least 30%, 40%, 50%, or 60%. In some embodiments, the suppression of the HPT axis comprises a decrease in total triiodothyronine (tT3) or total thyroxine (tT4) levels of more than 60%.

[0140] As contemplated herein, the mitigation of thyroid-related side effects comprises the effect of the method of treatment wherein the level of suppression of the HPT axis is lower than the level of suppression seen in daily dosing of about 10 to about 40 mg / day per individual. In some embodiments, the mitigation of thyroid-related side effects comprises the effect of the method of treatment wherein the level of suppression of the HPT axis is lower than the level of suppression seen in daily dosing of 40 mg / day, 30 mg / day, 20 mg / day, 15 mg / day, 10 mg / day, 5 mg / day, or 2.5 mg / day per individual. In some embodiments, the mitigation of thyroid-related side effects comprises the effect of the method of treatment wherein the level of suppression of the HPT axis is lower than the level of suppression seen in daily dosing of 2.5-35 mg / day, 2.5-10 mg / day, 5-15 mg / day, 5 mg / day, or 10 mg / day per individual.

[0141] The present disclosure provides methods of administering a composition comprising one or more compounds of Formula I:

[0142] wherein: G is selected from the group consisting of -0-, -S-, -S(=0)-, -S(=0)2-, -Se-, -CH2-, -CF2-, -CHF-, -C(O)-, -CH(OH)-, -CH(Ci-C4alkyl)-, -CH(Ci-C4alkoxy)-, -C(=CH2)-, -NH-, and -N(Ci-C4alkyl)-; T is selected from the group consisting of -(CR a 2)k -(CR b =CR b -(CR a 2) n -(CR a 2) n -CR b =CR b -(CR a 2)-CR b =CR b -(CR a 2)-, -0(CR b 2)(CR a 2) n -, -S(CR b 2)(CR a 2)n-, N(R c )(CR b 2)(CR a 2) n -, N(R b )C(O)(CR a 2) n , -C(O)(CR a 2) m -, -(CR a 2) m C(O)-, -(CR a 2)C(O)(CR a 2) n -, -(CR a 2) n C(O)(CR a 2)-, and -C(O)NH(CR b 2)(CR a 2) p -; k is an integer from 1 to 4; m is an integer from 0 to 3; n is an integer from 0 to 2; p is an integer from 0 to 1; each Ra independently selected from the group consisting of hydrogen, optionally substituted -C1-C4alkyl, halogen, -OH, optionally substituted -O-C1-C4alkyl, -OCF3, optionally substituted -S-C1-C4alkyl, -NR b R c , optionally substituted -C2-C4alkenyl, and optionally substituted -C2-C4alkynyl; provided that when one R a is -OH, then the other R a is hydrogen, or attached via a carbon atom; each R b is independently selected from the group consisting of hydrogen and optionally substituted -C1-C4alkyl; each R c is independently selected from the group consisting of hydrogen and optionally substituted -C1-C4alkyl, optionally substituted -C(O)-C1-C4alkyl, and -C(O)H; R 1 and R 2 are each independently selected from the group consisting of halogen, optionally substituted -C1-C4alkyl, optionally substituted -S-C1-C3alkyl, optionally substituted -C2-C4alkenyl, optionally substituted -C2-C4alkynyl, -CF3, -OCF3, optionally substituted -O-C1-C3alkyl, and cyano; R 6 , R 7 , R 8 , and R 9 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted -C1-C4alkyl, optionally substituted -S-C1-C3alkyl, optionally substituted -C2-C4alkenyl, optionally substituted -C2-C4alkynyl, -CF3, -OCF3, optionally substituted -O-C1-C3alkyl, and cyano; or R 6 and T together with the carbon to which they are attached form a ring of 5 to 6 atoms including 0 to 2 heteroatoms independently selected from the group consisting of -NR i -, -O-, and -S-; provided that when there are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen, then the two heteroatoms must be separated by at least one carbon atom; and X is attached to the ring by a direct bond to a ring carbon, or by -(CR a 2)- or -C(O)- bonding to a ring carbon or ring nitrogen; R i is selected from the group consisting of hydrogen, -C(O)C1-C4alkyl, -C1-C4alkyl, and -C1-C4aryl; R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted -C1-C 12 alkyl, optionally substituted -C2-C12 alkenyl, optionally substituted -C2-C 12 alkynyl, -SR d , -S(=0)R e , -S(=0)2R e , -S(=0)2NR f R g , -C(O)OR h , -C(O)R e , -N(R b )C(O)NR f R g , -N(R b )S(=0)2R e , -N(R b )S(=0)2NR f R g and -NR f R g ; each R d is selected from optionally substituted -Ci-C 12 alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -(CR b 2) n aryl, optionally substituted -(CR b 2) n cycloalkyl, optionally substituted -(CR b 2) n heterocycloalkyl and -C(O)NR f R g ; each R e is selected from optionally substituted -Ci-C 12 alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -(CR a 2) n aryl, optionally substituted -(CR a 2) n cycloalkyl and optionally substituted -(CR a 2) n heterocycloalkyl; R f and R g are each independently selected from hydrogen, optionally substituted -Ci-C 12 alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -(CRb 2) n aryl, optionally substituted -(CR b 2) n cycloalkyl and optionally substituted -(CR b 2) n heterocycloalkyl, or R f and R g may together form an optionally substituted heterocyclic ring which can contain a second heteroatom selected from O, NR C and S, wherein said optionally substituted heterocyclic ring can be substituted with 0-4 substituents selected from optionally substituted -C1-C4alkyl, -OR b , oxo, cyano, -CF3, optionally substituted phenyl and -C(O)OR h ; each R h is selected from optionally substituted -C1-C 12 alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -(CR b 2) n aryl, optionally substituted -(CR b 2) n cycloalkyl and optionally substituted -(CR b 2) n heterocycloalkyl; R 5 is selected from -OH, optionally substituted -OC1-C6alkyl, OC(O)R e , -OC(O)OR h , -F, -NHC(O)R e , -NHS(=O)R e , -NHS(=O)2R e , -NHC(=S)NH(R h ) and -NHC(O)NH(R h ); X is P(O)YR 11 Y' R 11 ; Y and Y' are each independently selected from -O- and -NR v -; when Y and Y' are -O-, the R 11 attached to the -O- are independently selected from -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, -C(R z )2OC(O)NR z 2, -NR z -C(O)-Ry , -C(R z )2-OC(O)R y , -C(R z )2-O-C(O)OR y , -C(R z )2OC(O)SR y , -alkyl-S-C(O)R y , -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; when Y and Y' are -NR v -, then R v attached to -NR 11 is independently selected from the group consisting of -H, -[C(R z )2] q -COOR y , -C(R x )2COOR Y , -[C(R z )2] q -C(O)SR y , and -cycloalkylidene-COOR y ; when Y is -O- and Y' is NR v , then R 11 attached to -O- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, -C(R z )2OC(O)NR z 2, -NR z -C(O)-R y , -C(R z )2-OC(O)R y , -C(R z )2-O-C(O)OR y , -C(R z )2OC(O)SR y , -alkyl-S-C(O)R y , -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; and R v attached to -NR 11 is independently selected from the group consisting of -H, -[C(R z )2] q -COOR y , -C(R x )2COOR y , -[C(R z )2] q -C(O)SRy and -cycloalkylene-COOR y ; or when Y and Y' are independently selected from -O- and NR v , then R 11 and R 11 together are -alkyl-S-S-alkyl- to form a cyclic group, or R 11 and R 11 together are the group:

[0143] wherein: V, W and W' are independently selected from hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl and optionally substituted 1-alkynyl; or V and Z together are linked via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, of which 0-1 atoms are heteroatoms and the remainder are carbon, which cyclic group containing 5-7 atoms is substituted with a hydroxyl, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy group attached to a carbon atom three atoms removed from the two Y groups attached to phosphorus; or or V and Z together are linked via an additional 3-5 atoms to form a cyclic group, of which 0-1 atoms are heteroatoms and the remainder are carbon, which cyclic group is fused to an aryl group at the beta and gamma positions of Y attached to phosphorus; or V and W together are linked via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from hydroxyl, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy and aryloxycarbonyloxy attached to one of the carbon atoms three atoms removed from Y attached to phosphorus; or Z and W together are linked via an additional 3-5 atoms to form a cyclic group, of which 0-1 atoms are heteroatoms and the remainder are carbon, and V must be an aryl, substituted aryl, heteroaryl or substituted heteroaryl group; or W and W' together are linked via an additional 2-5 atoms to form a cyclic group, of which 0-2 atoms are heteroatoms and the remainder are carbon, and V must be an aryl, substituted aryl, heteroaryl or substituted heteroaryl group; Z is selected from -CHR z OH, -CHR z OC(O)R y , -CHR z OC(S)R y , -CHR z OC(S)OR y , -CHRz OC(O)SR y -CHR z OCO2R y -OR z -SR z -CHR z N3, -CH2aryl, -CH(aryl)OH, -CH(CH=CR) z 2) OH, -CH(C≡CR z )OH、-R z -NR z 2. -OCOR y -OCO2R y -SCOR y -SCO2R y -NHCOR z -NHCO2R y -CH2NH aryl, -(CH2)q-OR z and -(CH2)q-SR z ; q is an integer of 2 or 3; Each R z Selected from R y and -H; Each R y Selected from alkyl, aryl, heterocyclic alkyl, and aralkyl groups; Each R x Independently selected from -H and alkyl, or R x and R x Together they form cycloalkyl groups; Each R v Selected from -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl and lower acyl groups; And its pharmaceutically acceptable salts and prodrugs; and pharmaceutically acceptable salts of said prodrugs.

[0144] In some embodiments, the compound of formula I has the following additional conditions: a) When G is -O-, T is -CH2-, R 1 and R 2 Each is bromine, R 3 It is isopropyl, R 4 It is hydrogen, and R 5 When the OH group is -OH, then X is neither P(O)(OH)2 nor P(O)(OCH2CH3)2; b) Not all of V, Z, W, and W' are -H; and c) When Z is -R z In this case, at least one of V, W, and W' is not -H, alkyl, aralkyl, or heterocyclic alkyl; d) when G is -O-, T is -(CH2) 1-4 -, R 1 and R 2 are independently halogen, alkyl and cycloalkyl, R 3 is alkyl, R 4 is hydrogen, and R 5 is -OH, then X is not -P(O)(OH)2or -P(O)(O-lower alkyl)2; and e) when G is -O-, R 5 is -NHC(O)R e , -NHS(=O) 1-2 R e , -NHC(S)NH(R b ) or -NHC(O)NH(R h ), T is -(CH2) m -, -CH=CH-, -O(CH2) 1-2 - or -NH(CH2) 1-2 -, then X is not -P(O)(OH)2or -P(O)(OH)NH2; In some embodiments of formula I: G is selected from -O-, -S-, -S(=O)-, -S(=O)2-, -CH2-, -CF2-, -CHF-, -C(O)-, -CH(OH)-, -NH-, and -N(C1-C4alkyl)-; T is selected from -(CR a 2) k -, CR b =CR b -, -(CR a 2) n -, -(CR a 2) n -CR b =CR b -, -(CR a 2)-CR b =R b (CR a 2), -O(CR b 2)(CR a 2) n -, -S(CR a 2)(CR a 2) n -, -N(R b )(CR b 2)(CR a 2) n -, -N(R b )C(O)(CRa 2) n -, -(CR a 2) n CH(NR b R c )-, -C(O)(CR a 2) m -, -(CR a 2) m C(O)-, -(CR a 2)C(O)(CR a 2) n -, -(CR a 2) n C(O)(CR a 2)- and -C(O)NH(CR b 2)(CR a 2)pr; k is an integer from 0 to 4; m is an integer from 0 to 3; n is an integer from 0 to 2; p is an integer from 0 to 1; each R a is independently selected from the group consisting of hydrogen, optionally substituted -C1-C4alkyl, halogen, -OH, optionally substituted -O-C1-C4alkyl, -OCF3, optionally substituted -S-C1-C4alkyl, -NR b R c , optionally substituted -C2-C4alkenyl, and optionally substituted -C2-C4alkynyl; provided that when one R a is attached through O, S or N, then the other R a attached to the same C is hydrogen, or is attached through a carbon atom; each R b is independently selected from the group consisting of hydrogen, optionally substituted -C1-C4alkyl; each R c is independently selected from the group consisting of hydrogen and optionally substituted -C1-C4alkyl, optionally substituted -C(O)-C1-C4alkyl, and -C(O)H; R 1 and R 2 are each independently selected from the group consisting of halogen, optionally substituted -C1-C4alkyl, optionally substituted -S-C1-C3alkyl, optionally substituted -C2-C4alkenyl, optionally substituted -C2-C4alkynyl, -CF3, -OCF3, optionally substituted -O-C1-C3alkyl, and cyano; R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted -C1-C 12 alkyl, optionally substituted -C2-C12 alkenyl, optionally substituted -(CR2)2-C2-C6alkenyl, 12 alkynyl, optionally substituted -(CR2)2-C2-C6alkynyl, a 2) m aryl, optionally substituted -(CR2)1-C6aryl, a 2) m cycloalkyl, optionally substituted -(CR2)1-C3-C6cycloalkyl, a 2) m heterocycloalkyl, -OR d , -SR d , -S(=0)R e , -S(=0)2R e , -S(=0)2NR f R g , -C(O)NR e R g , -(O)OR h , -C(O)R e , -N(R)C(O)R e , -N(R)C(O)NR e R g , -N(R b )S(=0)2R e , -N(R b )S(=0)2NR f R g , and -NR f R g ; each R d is selected from the group consisting of optionally substituted -Ci-C6alkyl, optionally substituted -C2-C6alkenyl, optionally substituted -C2-C6alkynyl, optionally substituted -(CR2)1-C6aryl, optionally substituted -(CR2)1-C3-C6cycloalkyl, and -C(O)NR 12 alkenyl, optionally substituted -(CR2)2-C2-C6alkenyl, 12 alkynyl, optionally substituted -(CR2)2-C2-C6alkynyl, 12 2) b aryl, optionally substituted -(CR2)1-C6aryl, n 2) b cycloalkyl, optionally substituted -(CR2)1-C3-C6cycloalkyl, n 2) b heterocycloalkyl, and -C(O)NR n R f ; each R g is selected from the group consisting of optionally substituted -Ci-C6alkyl, optionally substituted -C2-C6alkenyl, optionally substituted -C2-C6alkynyl, optionally substituted -(CR2)1-C6aryl, optionally substituted -(CR2)1-C3-C6cycloalkyl, and -C(O)NR e alkenyl, optionally substituted -(CR2)2-C2-C6alkenyl, 12 alkynyl, optionally substituted -(CR2)2-C2-C6alkynyl, 12 2) 12 aryl, optionally substituted -(CR2)1-C6aryl, a 2) n cycloalkyl, optionally substituted -(CR2)1-C3-C6cycloalkyl, a 2) ncycloalkyl and optionally substituted -(CR a 2) n heterocycloalkyl; R f and R g are each independently selected from the group consisting of hydrogen, optionally substituted -C1-C 12 alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -(CR b 2) n aryl, optionally substituted -(CR b 2) n cycloalkyl and optionally substituted -(CR b 2) n heterocycloalkyl, or R f and R g may together form an optionally substituted heterocyclic ring which can contain a second hetero group selected from O, NR C and S, wherein said optionally substituted heterocyclic ring can be substituted with 0-4 substituents selected from the group consisting of optionally substituted -C1-C4 alkyl, -OR b , oxo, cyano, -CF3, optionally substituted phenyl and -C(O)OR h ; each R h is selected from the group consisting of optionally substituted -C1-C 12 alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -(CR b 2) n aryl, optionally substituted -(CR b 2) n cycloalkyl and optionally substituted -(CR b 2) n heterocycloalkyl; R 5 is selected from the group consisting of -OH, optionally substituted -OC1-C6 alkyl, OC(O)R e , -OC(O)OR h , -F, -NHC(O)R e , -NHS(=O)R e , -NHS(=O)2R e , -NHC(=S)NH(R h ) and -NHC(O)NH(R h ); X is P(O)YR 11 Y' R 11 ; Y and Y' are each independently selected from the group consisting of -O- and -NR v -; when Y and Y' are -O-, R 11 is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, -C(R z )2OC(O)NR z 2, -NR z -C(O)-R y , -C(R z )2-OC(O)R y , -C(R z )2-O-C(O)OR y , -C(R z )2OC(O)SR y , -alkyl-S-C(O)R y , -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; when Y and Y' are -NR v -, then R v attached to -NR 11 is independently selected from the group consisting of -H, -[C(R z )2] q -COOR y , -C(R x )2COOR Y , -[C(R z )2] q -C(O)SR y , and -cycloalkylidene-COOR y ; when Y is -O- and Y' is NR v , then R 11 attached to -O- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, -C(R z )2OC(O)NR z 2, -NR z -C(O)-R y , -C(R z )2-OC(O)R y , -C(R z )2-O-C(O)OR y , -C(R z )2OC(O)SR y , -alkyl-S-C(O)R y, -alkyl-S-S-alkylhydroxy and -alkyl-S-S-S-alkylhydroxy; and -NR v -attached R 11 is independently selected from H, -[C(R z )2] q -COOR y , -C(R x )2COOR y , -[C(R z )2] q -C(O)SR y and -cycloalkylene-COOR y ; or when Y and Y' are independently selected from -O- and NR v , then R 11 and R 11 together are -alkyl-S-S-alkyl- to form a cyclic group, or R 11 and R 11 together are the group:

[0145] wherein: V, W and W' are independently selected from hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl and optionally substituted 1-alkynyl; or V and Z together are linked via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, of which 0-1 atoms are heteroatoms, the remaining atoms being carbon, which cyclic group containing 5-7 atoms is substituted with a hydroxyl, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy group attached to a carbon atom three atoms removed from the two Y groups attached to the phosphorus; or or V and Z together are linked via an additional 3-5 atoms to form a cyclic group, of which 0-1 atoms are heteroatoms, the remaining atoms being carbon, which cyclic group is fused to an aryl group at the beta and gamma positions of Y attached to the phosphorus; or V and W together are linked via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from hydroxyl, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy and aryloxycarbonyloxy attached to one of the carbon atoms three atoms removed from the Y attached to the phosphorus; or Z and W together are linked via an additional 3-5 atoms to form a cyclic group, of which 0-1 atoms are heteroatoms, the remaining atoms being carbon, and V must be an aryl, substituted aryl, heteroaryl or substituted heteroaryl group; Alternatively, W and W' can be linked together by another 2-5 atoms to form a cyclic group, where 0-2 atoms are heteroatoms, the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl. Z is selected from -CHR z OH, -CHR z OC(O)R y -CHR z OC(S)R y -CHR z OC(S)OR y -CHR z OC(O)SR y -CR z OCO2R y -OR z -SR z -CHR z N3, -CH2aryl, -CH(aryl)OH, -CH(CH=CR) z 2) OH, -CH(C≡CR z )OH、-R z -NR z 2. -OCOR y -OCO2R y -SCOR y -SCO2R y -NHCOR z -NHCO2R y -CH2NH aryl, -(CH2)q-OR z and -(CH2)q-SR z ; q is an integer of 2 or 3; Each R z Selected from R y and -H; Each R y Selected from alkyl, aryl, heterocyclic alkyl, and aralkyl groups; Each R x Independently selected from -H and alkyl, or R x and R x Together they form cycloalkyl groups; Each R y Selected from -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl and lower acyl groups; The conditions are: a) When G is -O-, T is -CH2-, R 1 and R 2 Each is bromine, R 3 It is isopropyl, R 4is hydrogen, and R 5 when X is -P(O)(OH)2or -P(O)(OCH2CH3)2, then R b) V, Z, W, W' are not all -H; and c) when Z is -R z then at least one of V, W and W' is not -H, alkyl, aralkyl or heterocycloalkyl.

[0146] In other embodiments of Formula I: G is selected from -0-, -S-, -S(=0)-, -S(=0)2-, -CH2-, -CF2-, -CHF-, -C(O)-, -CH(OH)-, -NH-, and -N(Ci-C4alkyl)-; T is selected from -(CR a 2) k , -CR b =CR b -(CR a 2) n -, -(CR a 2) n -CR b =CR b -, -(CR a 2)-CR b =CR b -(CR a 2)-, -(CR, -(CR b 2)(CR a 2) n -, -S(CR b 2)(CR a 2) n -, N(R c )(CR b 2)(CR a 2) n -, N(R)C(O)(CR a 2)-, -(CR a 2) n CH(NR b R c )-, -C(O)(CR a 2) m -, -(CR a 2) m C(O), -(CR a 2)C(O)(CR a 2) m -(CR a 2) n C(O)(CR a2) - and -C(O)NH(CR b 2) (CR a 2) p -; k is an integer from 0 to 4; m is an integer from 0 to 3; n is an integer from 0 to 2; p is an integer from 0 to 1; each R a is independently selected from the group consisting of hydrogen, optionally substituted -C1-C4alkyl, halogen, -OH, optionally substituted -O-C1-C4alkyl, -OCF3, optionally substituted -S-C1-C4alkyl, -NR b R c , optionally substituted -C2-C4alkenyl, and optionally substituted -C2-C4alkynyl; provided that when one R a is connected to C via an O, S, or N atom, then the other R a connected to the same C is hydrogen, or connected via a carbon atom; each R b is independently selected from the group consisting of hydrogen, optionally substituted -C1-C4alkyl; each R c is independently selected from the group consisting of hydrogen, and optionally substituted -C1-C4alkyl, optionally substituted -C(O)-C1-C4alkyl, and -C(O)H; R 1 and R 2 are each independently selected from the group consisting of halogen, optionally substituted -C1-C4alkyl, optionally substituted -S-C1-C3alkyl, optionally substituted -C2-C4alkenyl, optionally substituted -C2-C4alkynyl, -CF3, -OCF3, optionally substituted -O-C1-C3alkyl, and cyano; R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted -C1-C 12 alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -(CR a 2) m aryl, optionally substituted -(CR a 2) m cycloalkyl, optionally substituted -(CR a 2) m heterocycloalkyl, -OR d , -SR d , -S(=O)R e , -S(=O)2R e , -S(=O)2NRf R g , -C(O)OR f R g , -C(O)R h , -N(R)C(O)R e , -N(R)C(O)NR e R f , -N(R)S(=O)2R g , -N(R e )S(=O)2NR b R f , -NR g R f R g ; each R d is selected from the group consisting of optionally substituted -Ci-C 12 alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -(CR b 2) n aryl, optionally substituted -(CR b 2) n cycloalkyl, optionally substituted -(CR b 2) n heterocycloalkyl, and -C(O)NR f R g ; each R e is selected from the group consisting of optionally substituted -Ci-C 12 alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -(CR a 2) n aryl, optionally substituted -(CR a 2) n cycloalkyl, and optionally substituted -(CR a 2) heterocycloalkyl; R f and R g are each independently selected from the group consisting of hydrogen, optionally substituted -Ci-C 12 alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -(CR b 2) n aryl, optionally substituted -(CR b 2) n cycloalkyl, and optionally substituted -(CR b 2)n heterocycloalkyl, or R f and R g may together form an optionally substituted heterocyclic ring which can contain a second hetero group selected from O, NR C and S, wherein said optionally substituted heterocyclic ring can be substituted with 0-4 substituents selected from optionally substituted -C1-C4alkyl, -OR b , oxo, cyano, -CF3, optionally substituted phenyl, and -C(O)OR h ; each R h is selected from optionally substituted -C1-C 12 alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -(CR b 2) n aryl, optionally substituted -(CR b 2) n cycloalkyl, and optionally substituted -(CR b 2) n heterocycloalkyl; R 5 is selected from -OH, optionally substituted -OC1-C6alkyl, OC(O)R e , -OC(O)OR h , -F, -NHC(O)R e , -NHS(=O)R e , -NHS(=O)2R e , -NHC(=S)NH(R h ), and -NHC(O)NH(R h ); X is P(O)YR 11 Y' R 11 ; Y and Y' are each independently selected from -O- and -NR v -; when Y and Y' are -O-, the R 11 attached to the -O- is independently selected from -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic portion contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, -C(R z )2OC(O)NR z 2, -NR z -C(O)-R y , -C(R z )2-OC(O)R y , -C(R z )2-O-C(O)OR y ;-C(R) z )2OC(O)SR y ,-alkyl-SC(O)R y -alkyl-SS-alkylhydroxyl and -alkyl-SSS-alkylhydroxyl; When Y and Y' are -NR v - when, then with -NR v -Connected R 11 Independently selected from -H, -[C(R) z )2] q -COOR y -C(R) x )2COOR Y -[C(R) z )2] q -C(O)SR y and -cycloalkylene-COOR y ; When Y is -O- and Y' is NR v When, R connected to -O- 11 Independently selected from -H, alkyl, optionally substituted aryl, optionally substituted heterocyclic alkyl, optionally substituted CH2-heterocyclic alkyl wherein the cyclic moiety contains carbonate or thiocarbonate, optionally substituted -alkylaryl, -C(R z )2OC(O)NR z 2. -NR z -C(O)-R y -C(R) z )2-OC(O)R y -C(R) z )2-OC(O)OR y -C(R) z )2OC(O)SR y ,-alkyl-SC(O)R y -alkyl-SS-alkylhydroxyl and -alkyl-SSS-alkylhydroxyl; and with -NR v -Connected R 11 Independently selected from H, -[C(R) z )2] q -COOR y -C(R) x )2COOR y -[C(R) z )2] q -C(O)SR y and -cycloalkylene-COOR y ; Or, when Y and Y′ are independently selected from -O- and NRv, then R 11 and R11 Together they are -alkyl-SS-alkyl- to form cyclic groups, or R 11 and R 11 Together is a group:

[0147] in: V, W, and W' are independently selected from hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocyclic alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-ynyl. Alternatively, V and Z can be linked together by another 3-5 atoms to form a cyclic group containing 5-7 atoms, where 0-1 atoms are heteroatoms and the remaining atoms are carbon atoms. This cyclic group containing 5-7 atoms is substituted with a hydroxyl, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy group linked to the carbon atom. The carbon atom is three atoms away from the two Y groups linked to the same phosphorus group. Alternatively, V and Z can be linked together by another 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and the cyclic group is fused with aryl groups at the β and γ positions of Y connected to phosphorus. Alternatively, V and W can be linked together via three additional carbon atoms to form an optionally substituted cyclic group containing six carbon atoms, and the carbon atom is replaced by a substituent selected from hydroxyl, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy linked to one of the carbon atoms, which is three atoms away from the Y linked to the same phosphorus. Alternatively, Z and W can be linked together by another 3-5 atoms to form a cyclic group, where 0-1 atoms are heteroatoms, the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl. Alternatively, W and W' can be linked together by another 2-5 atoms to form a cyclic group, where 0-2 atoms are heteroatoms, the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl. Z is selected from -CHR z OH, -CHR z OC(O)R y -CHR z OC(S)R y -CHR z OC(S)OR y -CHR z OC(O)SR y -CHR z OCO2R y -OR z -SRz -CHR z N3, -CH2aryl, -CH(aryl)OH, -CH(CH=CR z 2)OH, -CH(C≡CR z )OH, -R z , -NR z 2, -OCOR y , -OCO2R y , -SCOR y , -SCO2R y , -NHCOR z , -NHCO2R y , -CH2NHaryl, -(CH2)q-OR z , and -(CH2)q-SR z ; q is an integer of 2 or 3; each R z is selected from the group consisting of R y and -H; each R y is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; each R x is independently selected from the group consisting of -H and alkyl, or R x and R x together form a cycloalkyl group; each R v is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; with the proviso that when G is -O-, T is -CH2-, R 1 and R 2 are each bromo, R 3 is isopropyl, R 4 is hydrogen, and R 5 is -OH, then X is other than P(O)(OH)2or P(O)(OCH2CH3)2; and the pharmaceutically acceptable salts and prodrugs thereof; and the pharmaceutically acceptable salts of the prodrugs of the foregoing.

[0148] In various other embodiments of Formula I: G is selected from the group consisting of -O-, -S-, -S(=O)-, -S(=O)2-, -CH2-, -CF2-, -CHF-, -C(O)-, -CH(OH)-, -NH-, and -N(C1-C4alkyl)-; T is selected from the group consisting of -(CR a 2) k -, -CR b =CR b -(CR a 2)n -(CR a 2) n -CR b =CR b -(CR a 2)-CR b =CR b -(CR a 2)-, -O(CR b 2)(CR a 2) n -, -S(CR b 2)(CR a 2) n -, -N(R c )-(CR b 2)(CR a 2)-, -N(R b )C(O)(CR a 2) n -(CR a 2) n CH(NR b R c )-, C(O)(CR a 2) m -(CR a 2) m C(O)-, -(CR a 2)C(O)(CR a 2) n -(CR a 2) n C(O)(CR a 2)- and -C(O)NH(CR b 2)(CR a 2) p -; k is an integer from 0 to 4; m is an integer from 0 to 3; n is an integer from 0 to 2; p is an integer from 0 to 1; each R a is independently selected from the group consisting of hydrogen, optionally substituted -C1-C4alkyl, halogen, -OH, optionally substituted -O-C1-C4alkyl, -OCF3, optionally substituted -S-C1-C4alkyl, -NR b R c , optionally substituted -C2-C4alkenyl, and optionally substituted -C2-C4alkynyl; provided that when one R a is attached to C via an O, S, or N atom, then the other R a attached to the same C is hydrogen, or is attached via a carbon atom; Each R b Independently selected from hydrogen and optionally substituted -C1-C4 alkyl groups; Each R c Independently selected from hydrogen, optionally substituted -C1-C4 alkyl, optionally substituted -C(O)-C1-C4 alkyl and -C(O)H; R 1 and R 2 Each is independently selected from halogens, optionally substituted -C1-C4 alkyl, optionally substituted -S-C1-C3 alkyl, optionally substituted -C2-C4 alkenyl, optionally substituted -C2-C4 ynyl, -CF3, -OCF3, optionally substituted -O-C1-C3 alkyl and cyano; R 3 and R 4 Each is independently selected from hydrogen, halogen, -CF3, -OCF3, cyano, or optionally substituted -C1-C. 12 Alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -(CR) a 2) m aryl, optionally substituted -(CR a 2) m cycloalkyl, optionally substituted -(CR a 2) m Heterocyclic alkyl, -OR d -SR d -S(=O)R e -S(=O)2R e -S(=O)2R f R g -C(O)NR f R g -C(O)OR h -C(O)R e -N(R)C(O)R e -N(R)C(O)NR f R g -N(R) b )S(=O)2R e -N(R) b )S(=O)2NR f R g and -NR f R g ; Each R d Selected from the optional substitution -C1-C 12 Alkyl, optionally substituted -C2-C 12alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C b 2) n aryl, optionally substituted -(CR b 2) n cycloalkyl, optionally substituted -(CR b 2) n heterocycloalkyl, and -C(O)NR f R g ; each R e is selected from the group consisting of optionally substituted -C1-C 12 alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -(CR b 2) n aryl, optionally substituted -(CR b 2) n cycloalkyl, and optionally substituted -(CR b 2) n heterocycloalkyl; R f and R g are each independently selected from the group consisting of hydrogen, optionally substituted -C1-C 12 alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -(CR b 2) n aryl, optionally substituted -(CR b 2) n cycloalkyl, and optionally substituted -(CR b 2) n heterocycloalkyl, or R f and R g may together form an optionally substituted heterocyclic ring which can contain a second hetero group selected from O, NR C , and S, wherein said optionally substituted heterocyclic ring can be substituted with 0-4 substituents selected from the group consisting of optionally substituted -C1-C4alkyl, -OR b , oxo, cyano, -CF3, optionally substituted phenyl, and -C(O)OR h ; each R h is selected from the group consisting of optionally substituted -C1-C 12 alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -(CR b 2) naryl, optionally substituted -(CR b 2) n cycloalkyl and optionally substituted -(CR b 2) n heterocycloalkyl; R 5 is selected from -OH, optionally substituted -OC1-C6alkyl, OC(O)R e , -OC(O)OR h , -F, -NHC(O)R e , -NHS(=O)R e , -NHS(=O)2R e , -NHC(=S)NH(R h ) and -NHC(O)NH(R); X is P(O)YR 11 Y' R 11 ; Y and Y' are each independently selected from -O- and -NR v -; when Y and Y' are -O-, R 11 attached to the -O- is independently selected from -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, -C(R z )2OC(O)NR z 2, -NR z -C(O)-R y , -C(R z )2-OC(O)R y , -C(R z )2-O-C(O)OR y , -C(R z )2OC(O)SR y , -alkyl-S-C(O)R y , -alkyl-S-S-alkylhydroxy and -alkyl-S-S-S-alkylhydroxy; when Y and Y' are -NR v -, then R v attached to the -NR 11 is independently selected from -H, -[C(R z )2] q -COOR y , -C(R x )2COOR Y , -[C(R z )2] q -C(O)SR y and -cycloalkylidene-COOR y ; When Y is -O- and Y' is NR v When, R connected to -O- 11 Independently selected from -H, alkyl, optionally substituted aryl, optionally substituted heterocyclic alkyl, optionally substituted CH2-heterocyclic alkyl wherein the cyclic moiety contains carbonate or thiocarbonate, optionally substituted -alkylaryl, -C(R z )2OC(O)NR e 2. -NR z -C(O)-R y -C(R) z )2-OC(O)R y -C(R) z )2-OC(O)OR y -C(R) z )2OC(O)SR y ,-alkyl-SC(O)R y -alkyl-SS-alkylhydroxyl and -alkyl-SSS-alkylhydroxyl; and with -NR v -Connected R 11 Independently selected from H, -[C(R) z )2] q -COOR y -C(R) x )2COOR y -[C(R) z )2] q -C(O)SR y and -cycloalkylene-COOR y ; Or when Y and Y′ are independently selected from -O- and NR v When, then R 11 and R 11 Together they are -alkyl-SS-alkyl- to form cyclic groups, or R 11 and R 11 Together is a group:

[0149] in: V, W, and W' are independently selected from hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocyclic alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-ynyl. or V and Z together are linked via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, where 0-1 atoms are heteroatoms, the remaining atoms are carbon, which cyclic group is substituted with a substituent selected from the group consisting of hydroxyl, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy, at a carbon atom three atoms removed from the Y group attached to the phosphorus; or or V and Z together are linked via an additional 3-5 atoms to form a cyclic group, where 0-1 atoms are heteroatoms, the remaining atoms are carbon, which cyclic moiety is fused to an aryl group at the beta and gamma positions of Y attached to the phosphorus; or V and W together are linked via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxyl, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of the carbon atoms three atoms removed from the Y group attached to the phosphorus; or Z and W together are linked via an additional 3-5 atoms to form a cyclic group, where 0-1 atoms are heteroatoms, the remaining atoms are carbon, and V must be an aryl, substituted aryl, heteroaryl, or substituted heteroaryl group; or W and W' together are linked via an additional 2-5 atoms to form a cyclic group, where 0-2 atoms are heteroatoms, the remaining atoms are carbon, and V must be an aryl, substituted aryl, heteroaryl, or substituted heteroaryl group; Z is selected from the group consisting of -CHR z OH, -CHR z OC(O)R y , -CHR z OC(S)R y , -CHR z OC(S)OR y , -CHR z OC(O)SR y , -CHR z OCO2R y , -OR z , -SR z , -CHR z N3, -CH2aryl, -CH(aryl)OH, -CH(CH=CR z 2)OH, -CH(C≡CR z )OH, -R z , -NR z 2, -OCOR y , -OCO2R y , -SCOR y , -SCO2R y , -NHCOR z-NHCO2R y -CH2NHaryl, -(CH2)q-OR z and -(CH2)q-SR z ; q is an integer of 2 or 3; each R z is selected from the group consisting of R y and -H; each R y is selected from the group consisting of alkyl, aryl, heterocycloalkyl and aralkyl; each R x is independently selected from the group consisting of -H and alkyl, or R x and R x together form a cycloalkyl group; each R v is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl and lower acyl; with the provisos that: a) when G is -O-, T is -(CH2) 0-4 -, R 1 and R 2 are independently halo, alkyl of 1 to 3 carbons and cycloalkyl of 3 to 5 carbons, R 3 is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 7 carbons, R 4 is hydrogen, and R 5 is -OH, then X is not -P(O)(OH)2or -P(O)(O-lower alkyl)2; b) when G is -O-, R 5 is -NHC(O)R e , -NHS(=O) 1-2 R e , -NHC(S)NH(R h ) or -NHC(O)NH(R h ), T is -(CH2) m -, -CH=CH-, -O(CH2) 1-2 - or -NH(CH2) 1-2 -, then X is not -P(O)(OH)2or -P(O)(OH)NH2; and pharmaceutically acceptable salts and prodrugs thereof; and pharmaceutically acceptable salts of said prodrugs.

[0150] In one aspect, G is -0-. In another aspect, G is -CH2-. In another aspect, G is selected from -0- and -CH2-. In another aspect, G is -S-. In another aspect, G is -S(=0)-. In another aspect, G is -S(=0)2-. In another aspect, G is -CH2-. In another aspect, G is -CF2-. In another aspect, G is -CHF-. In another aspect, G is -CH(OH)-. In another aspect, G is -CH(OH)-. In another aspect, G is -NH-.

[0151] In another aspect, G is -N(Ci-C4alkyl)-. In another aspect, G is selected from -0-, -S-, and -CH2-.

[0152] In one aspect, T is -CH2-. In another aspect, T is -(CH2) 0-4 -. In another aspect, T is selected from -(CH2) m -, -CH=CH-, -0(CH2) 1-2 -, and -NH(CH2) 1-2 -. In another aspect, T is selected from (CR a 2) n , -0(CR b 2)(CR a 2) p -, -N(CR b 2)(CR a 2) p -, -S(CR b 2)(CR a 2) p -, -NR b (CO)-, and -CH2CH(NR c R b )-. In another aspect, T is -CH2CH(NH2)-. In another aspect, T is -N(H)C(O)-. In another aspect, T is -OCH2-. In another aspect, T is -CH2CH2-. In another aspect, T is -CH2CH(NH2)-. In another aspect, T is -N(H)C(O)-.

[0153] In another aspect, T is -(CR a 2) k -. In another aspect, T is -CR b CR b -(CR a 2) n -. In another aspect, T is -(CR a 2) n -CR b =CR b -. In another aspect, T is -(CRa 2)-CR b =CR b -(CR a 2)-. On the other hand, T is -O(CR) b 2)(CR a 2) n -. On the other hand, T is -S(CR b 2)(CR a 2) n -. On the other hand, T is -N(CR b 2)(CR a 2) n -. On the other hand, T is -N(R b )C(O)(CR a 2) n -. On the other hand, T is -(CR e 2) n CH(NR b R c On the other hand, T is -C(O)(CR) a 2) m -. On the other hand, T is -(CR a 2) m C(O)-. On the other hand, T is -(CR)-. a 2)C(O)(CR a 2) n -. On the other hand, T is -(CR a 2) n C(O)(CR a 2)-. On the other hand, T is -C(O)NH(CR) b 2)(CR a 2) p -

[0154] In one aspect, k is 0. In another aspect, k is 1. In another aspect, k is 2. In another aspect, k is 3. In another aspect, k is 4. In one aspect, m is 0. In another aspect, m is 1. In another aspect, m is 2. In another aspect, m is 3. In one aspect, n is 0. In another aspect, n is 1. In another aspect, n is 2. In one aspect, p is 0. In another aspect, p is 1.

[0155] In one respect, each R a It is hydrogen, provided that an R a When C is connected via O, S, or N atoms, other R atoms connected to the same C atom... a It is hydrogen, or linked through carbon atoms. On the other hand, each R... ais optionally substituted -C1-C4alkyl, provided that when one R a when attached to the same C through an O, S, or N atom, the other R a is hydrogen, or attached through a carbon atom. In a further aspect, each R a is halogen, provided that when one R a when attached to the same C through an O, S, or N atom, the other R a is hydrogen, or attached through a carbon atom. In a further aspect, each R a is -OH, provided that when one R a when attached to the same C through an O, S, or N atom, the other R a is hydrogen, or attached through a carbon atom. In a further aspect, each R a is optionally substituted -O-C1-C4alkyl, provided that when one R a when attached to the same C through an O, S, or N atom, the other R a is hydrogen, or attached through a carbon atom. In a further aspect, each R a is -OCF3, provided that when one R a when attached to the same C through an O, S, or N atom, the other R a is hydrogen, or attached through a carbon atom. In a further aspect, each R a is optionally substituted -S-C1-C4alkyl, provided that when one R a when attached to the same C through an O, S, or N atom, the other R a is hydrogen, or attached through a carbon atom. In a further aspect, each R a is -NR b R c , provided that when one R a when attached to the same C through an O, S, or N atom, the other R a is hydrogen, or attached through a carbon atom. In a further aspect, each R a is optionally substituted -C2-C4alkenyl, provided that when one R a when attached to the same C through an O, S, or N atom, the other R a is hydrogen, or attached through a carbon atom. In a further aspect, each R a is optionally substituted -C2-C4alkynyl, provided that when one R a when attached to the same C through an O, S, or N atom, the other R a is hydrogen, or attached through a carbon atom.

[0156] In one aspect, R bis hydrogen. In another aspect, R b is optionally substituted -C1-C4alkyl.

[0157] In one aspect, R c is hydrogen. In another aspect, R c is optionally substituted -C1-C4alkyl. In other aspects, R c is optionally substituted -C(O)-C1-C4alkyl. In another aspect, R c is -C(O)H.

[0158] In one aspect, R 1 and R 2 are each bromine. In another aspect, R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, alkyl of 1 to 3 carbons, and cycloalkyl of 3 to 5 carbons. In another aspect, R 1 and R 2 are independently halogen, alkyl of 1 to 3 carbons, and cycloalkyl of 3 to 5 carbons. In another aspect, R 1 and R 2 are the same and selected from the group consisting of halogen, -C1-C4alkyl, -CF3, and cyano. In another aspect, R 1 and R 2 are different and selected from the group consisting of halogen, -C1-C4alkyl, -CF3, and cyano. In one aspect, R 1 and R 2 are each independently selected from the group consisting of halogen, -C1-C4alkyl, -CF3, and cyano. In another aspect, R 1 and R 2 are each independently selected from the group consisting of iodine, bromine, chlorine, methyl, and cyano. In another aspect, R 1 and R 2 are each iodine. In one aspect, R 1 and R 2 are each methyl. In another aspect, R 1 and R 2 are each chlorine. In another aspect, R 1 and R 2 are each independently selected from the group consisting of iodine, bromine, chlorine, and methyl.

[0159] In another aspect, R 1 and R 2 are each halogen. In another aspect, R 1 and R 2 are each optionally substituted -C1-C4alkyl. In other aspects, R 1 and R 2 are each optionally substituted -S-C1-C3alkyl. In another aspect, R 1 and R 2Each is an optionally substituted -C2-C4 alkenyl group. On the other hand, R 1 and R 2 Each is an optionally substituted -C2-C4 ynyl group. On the other hand, R 1 and R 2 Each is -CF3. On the other hand, R 1 and R 2 Each is -OCF3. On the other hand, R 1 and R 2 Each is an optionally substituted -O-C1-C3 alkyl group. On the other hand, R... 1 and R 2 Each is a cyano group.

[0160] On the other hand, R 3 and R 4 Each is hydrogen. On the other hand, R 3 and R 4 Each is a halogen. On the other hand, R 3 and R 4 Each is -CF3. On the other hand, R 3 and R 4 Each is -OCF3. On the other hand, R 3 and R 4 Each is a cyano group. On the other hand, R 3 and R 4 Each is an optional replacement for -C1-C 12 Alkyl group. On the other hand, R 3 and R 4 Each is an optional replacement for -C2-C 12 Alkenyl. On the other hand, R 3 and R 4 Each is an optional replacement for -C2-C 12 Alkyne group. In other respects, R 3 and R 4 Each is an optional replacement -(CR) a 2) m Aryl. On the other hand, R 3 and R 4 Each is an optional replacement -(CR) a 2) m Cycloalkyl. In other respects, R 3 and R 4 Each is an optional replacement -(CR) a 2) n Heterocyclic alkyl groups. On the other hand, R 3 and R 4 Each is -OR d On the other hand, R 3 and R4 Each is -SR d In other respects, R 3 and R 4 Each is -S(=O)R e On the other hand, R 3 and R 4 Each is -S(=O)2R e In other respects, R 3 and R 4 Each is -S(=O)2NR f R g On the other hand, R 3 and R 4 Each is -C(O)NR 9 In other respects, R 3 and R 4 Each is -C(O)OR h On the other hand, R 3 and R 4 Each is -C(O)R e In other respects, R 3 and R 4 Each is -N(R) b )C(O)R e On the other hand, R 3 and R 4 Each is -N(R)C(O)NR f R g In other respects, R 3 and R 4 Each is -N(R)S(=O)2R e On the other hand, R 3 and R 4 Each is -N(R) b )S(=O)2NR f R g In other respects, R 1 and R 4 Each is -NR f R g .

[0161] In one respect, R 4 Selected from hydrogen, halogens, -C1-C4 alkyl groups, cyano groups, and CF3. On the other hand, R... 4 It's not hydrogen. In other respects, R... 4 Selected from hydrogen and halogens. On the other hand, R 4 Selected from hydrogen and iodine. In other respects, R... 4 It is hydrogen.

[0162] On the other hand, each R dIt is an optional substitution of -C1-C 12 Alkyl groups. In other respects, each R d It is an optional substitution of -C2-C 12 Alkenyl. On the other hand, each R d It is an optional substitution of -C2-C 12 Alkyne group. In other respects, each R d It is an optional substitution -(CR) b 2) n Aryl. On the other hand, each R d It is an optional substitution -(CR) b 2) n Cycloalkyl. In other respects, each R d It is an optional substitution -(CR) b 2) n Heterocyclic alkyl groups. On the other hand, each R d It is -C(O)NR f R g .

[0163] In another respect, R e It is an optional substitution of -C1-C 12 Alkyl group. On the other hand, R e It is an optional substitution of -C2-C 12 Alkenyl. In other respects, R a It is an optional substitution of -C2-C 12 Alkynyl group. On the other hand, R e It is an optional substitution -(CR) a 2) n Aryl. In other respects, R e It is an optional substitution -(CR) b 2) n Cycloalkyl. On the other hand, R e It is an optional substitution -(CR) a 2) n Heterocyclic alkyl groups.

[0164] In one respect, R f and R g Each is hydrogen. In another aspect, R... f and R g Each is an optional replacement for -C1-C 12 Alkyl group. On the other hand, R f and R g Each is an optional replacement for -C2-C 12 Alkenyl. In another respect, R f and R g Each is an optional replacement for -C2-C 12 Alkyne group. In other respects, Rf and R g each is optionally substituted -(CR b 2) n aryl. In another aspect, R f and R g each is optionally substituted -(CR b 2) n cycloalkyl. In another aspect, R f and R g each is optionally substituted -(CR b 2) n heterocycloalkyl.

[0165] In another aspect, R f and R g may together form an optionally substituted heterocyclic ring which can contain a second hetero group which is O. In another aspect, R f and R g may together form an optionally substituted heterocyclic ring which can contain a second hetero group which is NR c . In another aspect, R f and R g may together form an optionally substituted heterocyclic ring which can contain a second hetero group which is S. In one aspect, R f and R g may together form an unsubstituted heterocyclic ring which can contain a second hetero group. In another aspect, the optionally substituted heterocyclic ring can be substituted with 1 substituent selected from the group consisting of optionally substituted -C1-C4alkyl, -OR b , oxo, cyano, -CF3, optionally substituted phenyl, and -C(O)OR h . In other aspects, the optionally substituted heterocyclic ring can be substituted with 2 substituents selected from the group consisting of optionally substituted -C1-C4alkyl, -OR h , oxo, cyano, -CF3, optionally substituted phenyl, and -C(O)OR h . In another aspect, the optionally substituted heterocyclic ring can be substituted with 3 substituents selected from the group consisting of optionally substituted -C1-C4alkyl, -OR b , oxo, cyano, -CF3, optionally substituted phenyl, and -C(O)OR h . In other aspects, the optionally substituted heterocyclic ring can be substituted with 4 substituents selected from the group consisting of optionally substituted -C1-C4alkyl, -OR b , oxo, cyano, -CF3, optionally substituted phenyl, and -C(O)OR h .

[0166] In other aspects, R h is optionally substituted -C1-C 12alkyl. In another aspect, R h is optionally substituted -C2-C 12 alkenyl. In other aspects, R h is optionally substituted -C2-C 12 alkynyl. In another aspect, R h is optionally substituted -(CR b 2) n aryl. In other aspects, R h is optionally substituted -(CR b 2) n cycloalkyl. In another aspect, R h is optionally substituted -(CR b 2) n heterocycloalkyl.

[0167] In one aspect, R 5 is -OH. In another aspect, R 5 is selected from -OH, -OC(O)R e , -OC(O)OR h , -F, and -NHC(O)R e . In another aspect, R 5 is selected from -OH and -OC(O)R e . In a further aspect, R 5 is optionally substituted -OCi-C6alkyl. In another aspect, R 5 is -OC(O)R e . In another aspect, R 5 is -OC(O)OR h . In another aspect, R 5 is -F. In another aspect, R 5 is -NHC(O)R e . In another aspect, R 5 is -NHS(=O)R e . In another aspect, R 5 is -NHS(=O)2R e . In another aspect, R 5 is -NHC(=S)NH(R h ). In another aspect, R 5 is -NHC(O)NH(OH).

[0168] In one aspect, R 3 is selected from halogen, optionally substituted -Ci-C6alkyl, -CF3, cyano, -C(O)NR f R g , optionally substituted (CR a 2) n aryl, -SO2NR fR g and -SO2R e . In another aspect, R 3 is isopropyl. In another aspect, R 3 is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 7 carbons. In another aspect, R 3 is selected from halogen, optionally substituted -C1-C6alkyl, optionally substituted -CH2aryl, optionally substituted -CH(OH)aryl, -C(O)-amido, -S(=O)2-amido (wherein amido is selected from phenethylamino, piperidinyl, 4-methylpiperazinyl, morpholinyl, cyclohexylamino, anilino, and indolinyl), and -SO2R a wherein R e is selected from phenyl, 4-chlorophenyl, 4-fluorophenyl, and 4-pyridyl. In another aspect, R 3 is iodo. In another aspect, R 3 is selected from iodo, bromo, optionally substituted -C1-C6alkyl, optionally substituted -CH2aryl, optionally substituted -CH(OH)aryl, -(O)-amido, -S(=O)2-amido (wherein amido is selected from phenethylamino, piperidinyl, 4-methylpiperazinyl, morpholinyl, cyclohexylamino, anilino, and indolinyl), and -SO2R e wherein R e is selected from phenyl, 4-chlorophenyl, 4-fluorophenyl, and 4-pyridyl. In one aspect, R 3 is -CH(OH)(4-fluorophenyl).

[0169] In one aspect, X is -P(O)YR 11 Y' R 11 .

[0170] In one aspect, X is selected from -PO3H2, -P(O)[-OCR z 2OC(O)R y ]2, -P(O)[-OCR z 2OC(O)OR y ]2, -P(O)[-N(H)CR z 2C(O)OR y ]2, -P(O)[-N(H)CR z 2C(O)OR 1 ][-OR 11 ], and -P(O)[-OCH(V)CH2CH2O-], wherein V is selected from optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl. In another aspect, X is selected from -PO3H2, -P(O)[-OCR z 2OC(O)R y ]2, -P(O)[-OCR z2OC(O)OR y ]2, -P(O)[-OCH2CH2SC(O)Me]2, -P(O)[-N(H)CR z 2C(O)OR y 2. -P(O)[-N(H)CR z 2C(O)OR y ][-OR 11 X is selected from -PO3H2, -P(O)[-OCH(V)CH2CH2O-], where V is selected from optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl groups. On the other hand, X is selected from -PO3H2, -P(O)[-OCR], and -P(O)[-OCH(V)CH2CH2O-]. z 2OC(O)R y ]2、-P(O)[-OCR z 2OC(O)OR y ]2、-P(O)[-Oalk-SC(O)R y 2. -P(O)[-N(H)CR z 2C(O)OR y 2. -P(O)[-N(H)CR z 2C(O)OR][-OR 11and -P(O)[-OCH(V)CH2CH2O-], where V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl. In one aspect, X is selected from the group consisting of -PO3H2, -P(O)[-OCH2OC(O)-tert-butyl]2, -P(O)[-OCH2OC(O)O-isopropyl]2, -P(O)[-N(H)CH(CH3)C(O)OCH2CH3]2, -P(O)[-N(H)C(CH3)2C(O)OCH2CH3]2, -P(O)[-N(H)CH(CH3)C(O)OCH2CH3][3,4-methylenedioxyphenyl], -P(O)[-N(H)C(CH3)2C(O)OCH2CH3][3,4-methylenedioxyphenyl], -P(O)[-O-CH2CH2S-C(O)CH3]2, and -P(O)[-OCH(3-chlorophenyl)CH2CH2O-]. In other aspects, X is selected from the group consisting of -PO3H2, -P(O)[-OCH2OC(O)-tert-butyl]2, -P(O)[-OCH2OC(O)O-isopropyl]2, -P(O)[-N(CH(CH3)C(O)OCH2CH3]2, -P(O)[-N(H)C(CH3)2C(O)OCH2CH3]2, -P(O)[-N(H)CH(CH3)C(O)OCH2CH3][3,4-methylenedioxyphenyl], -P(O)[-N(H)C(CH3)2C(O)OCH2CH3][3,4-methylenedioxyphenyl], and -P(O)[-OCH(3-chlorophenyl)CH2CH2O-]. In another aspect, X is -PO3H2. In another aspect, X is selected from the group consisting of -P(O)[-OCH2OC(O)-tert-butyl]2and -P(O)[-OCH2OC(O)-isopropyl]2.

[0171] In one aspect, X is selected from the group consisting of -P(O)[-OCH2OC(O)O-ethyl]2and -P(O)[-OCH2OC(O)O-isopropyl]2. In another aspect, X is selected from the group consisting of -P(O)[-N(F)CH(CH3)C(O)OCH2CH3]2and -P(O)[-N(H)C(CH3)2C(O)OCH2CH3]2. In other aspects, X is -P(O)[-OCH2CH2SC(O)Me]2. In another aspect, X is selected from the group consisting of -P(O)[-N(H)CH(CH3)C(O)OCH2CH3][3,4-methylenedioxyphenyl] and -P(O)[-N(H)C(CH3)2C(O)OCH2CH3][3,4-methylenedioxyphenyl]. In other aspects, X is selected from the group consisting of -PO3H2, -P(O)[-OCR z 2OC(O)R y ]2, -P(O)[-OCRz 2OC(O)OR y ]2, -P(O)[-N(H)CR z 2C(O)OR y ]2, -P(O)[-N(H)CR z 2C(O)OR y ][-OR 11 ] and -P(O)[-OCH(V)CH2CH2O-], where V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl. In another aspect, X is selected from the group consisting of -PO3H2, -P(O)[-OCH2OC(O)-tert-butyl]2, -P(O)[-OCH2OC(O)O-isopropyl]2, -P(O)[-N(H)CH(CH3)C(O)OCH2CH3]2, -P(O)[-N(H)C(CH3)2C(O)OCH2CH3]2, -P(O)[-N(H)CH(CH3)C(O)OCH2CH3][3,4-methylenedioxyphenyl], -P(O)[-N(H)C(CH3)2C(O)OCH2CH3][3,4-methylenedioxyphenyl], and -P(O)[-OCH(3-chlorophenyl)CH2CH2O-].

[0172] In another aspect, X is -P(O)YR 11 Y'R 11 .

[0173] wherein Y and Y' are each independently selected from the group consisting of -O- and -NR-; R 11 and R 11 together are a group:

[0174] wherein

[0175] V, W, and W' are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-alkynyl; or V and Z together are linked via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms, and the remaining atoms are carbon, which cyclic group containing 5-7 atoms is substituted with a hydroxyl, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy group attached to a carbon atom three atoms removed from both Y groups attached to phosphorus; or or V and Z together are linked via an additional 3-5 atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, which is fused to the aryl group at the beta and gamma positions of Y attached to phosphorus; or V and W together are linked via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy attached to one of the carbon atoms three atoms removed from Y attached to phosphorus; or Z and W together are linked via an additional 3-5 atoms to form a cyclic group, where 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or W and W' together are linked via an additional 2-5 atoms to form a cyclic group, where 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is selected from the group consisting of -CHR z OH, -CHR z OC(O)R y , -CHR z OC(S)R y , -CHR z OC(S)OR y , -CHR 2 OC(O)SR y , -CHR z OCO2R y , -OR z , -SR z , -CHR e N3, -CH2aryl, -CH(aryl)OH, -CH(CH=CR z 2)OH, -CH(C≡CR z )OH, -R z , -NR z 2, -OCOR y , -OCO2R y , -SCOR y , -SCO2R y , -NHCOR e , -NHCO2R y , -CH2NHaryl, -(CH2) q -OR z , and -(CH2) q -SR z ; q is an integer of 2 or 3; with the proviso that: a) V, Z, W, W' are not all -H; and b) when Z is -R z then at least one of V, W and W' is not -H, alkyl, aralkyl or heterocycloalkyl; each R z is selected from R y and -H; each R y is selected from alkyl, aryl, heterocycloalkyl and aralkyl; and each R v is selected from -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl and lower acyl.

[0176] In one aspect, V is optionally substituted aryl. In another aspect, V is selected from 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 3-fluorophenyl, pyridin-4-yl, pyridin-3-yl and 3,5-dichlorophenyl.

[0177] In one aspect, the relative stereochemistry between the V-group substituent and T on the dioxaphosphorinane ring is cis. In another aspect, the cis dioxaphosphorinane ring has R stereochemistry on the carbon to which V is attached. In another aspect, the cis dioxaphosphorinane ring has S stereochemistry on the carbon to which V is attached.

[0178] In one aspect, R 11 is not hydrogen.

[0179] In other aspects, when G is -O-, T is -CH2-, R 1 and R 2 are each bromo, R 3 is isopropyl, and R 5 is -OH, then R 4 is not hydrogen. In another aspect, when G is -O-, T is -(CH2) 0-4 , R 1 and R 2 are each independently selected from halogen, alkyl of 1 to 3 carbons and cycloalkyl of 3 to 5 carbons, R 3 is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 7 carbons, and R 5 is -OH, then R 4 is not hydrogen; and wherein when G is -O-, R 5 is selected from

[0180] NHC(O)R e , -NHS(=O) 1-2 R e , -NHC(=S)NH(R h ) and -NHC(O)NH(R h), T is selected from -(CH2) m -, -CH=CH-, -O(CH2) 1-2 -, -S(CH2) 1-2 -, and -NH(CH2) 4 -; when G is -O-, T is not hydrogen. In other aspects of the compounds of Formula I, G is selected from -O- and -CH2-; T is selected from -(CR a 2) n -, -O(CR b 2)(CR a 2) p -, -N(R c )(CR b 2)(CR a 2) p -, -S(CR b 2)(CR a 2) p -, -NR b (CO)-, and -CH2CH(NR c R b )-; R 1 and R 2 are each independently selected from halogen, -C1-C4alkyl, -CF3, and cyano; R 4 is selected from hydrogen, halogen, -C1-C4alkyl, cyano, and CF3; R 5 is selected from -OH, -OC(O)R e , -OC(O)OR h , -F, and -NHC(O)R e ; R 3 is selected from halogen, optionally substituted -C1-C6alkyl, -CF3, cyano, -C(O)NR f R g , optionally substituted -(CR a 2) n aryl, -SO2NR f R g , and -SO2R e ; X is selected from -PO3H2, -P(O)[-OCR z 2OC(O)R y ]2, -P(O)[-OCR z 2OC(O)OR y ]2, -P(O)[-Oalk-SC(O)R y ]2, -P(O)[-N(H)CR z 2C(O)OR y ]2, -P(O)[-N(H)CR z 2C(O)OR y ][-OR 11and -P(O)[-OCH(V)CH2CH2O-], where V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl and optionally substituted heteroaryl.

[0181] In another aspect, G is selected from -O- and -CH2-; T is selected from the group consisting of -(CR a 2) n , -O(CR b 2)(CR a 2) p -, -N(R c )2)(CR b b 2) (CR a 2) p -, -S(CR b 2)(CR a 2) p -, -NR b (CO)- and -CH2CH(NR c R b )-; R 1 and R 2 are each independently selected from the group consisting of halogen, -C1-C4alkyl, -CF3and cyano; R 4 is selected from the group consisting of hydrogen, halogen, -C1-C4alkyl, cyano and CF3; R 1 is selected from the group consisting of -OH, -OC(O)R e , -OC(O)OR h , -F and -NHC(O)R e ; R 3 is selected from the group consisting of halogen, optionally substituted -C1-C6alkyl, -CF3, cyano, -C(O)NR f R g , optionally substituted -(CR a 2) n aryl, -SO2NR f R g and -SO2R e ; and X is selected from the group consisting of -PO3H2, -P(O)[-OCR z 2OC(O)R y ]2, -P(O)[-OCR z 2OC(O)OR y ]2, -P(O)[-N(H) c R z 2C(O)OR y ]2, -P(O)[-N(H)CR z 2C(O)OR y ][-OR 11and -P(O) [-OCH(V)CH2CH2O-], where V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl.

[0182] In another aspect, G is selected from -O- and -CH2-; T is -CH2CH(NH2)-; R 1 and R 2 are each independently selected from the group consisting of iodo, bromo, chloro, methyl, and cyano; R 4 is hydrogen; R 5 is selected from the group consisting of -OH and -OC(O)R e ; R 3 is selected from the group consisting of halogen, optionally substituted -C1-C6 alkyl, optionally substituted -CH2aryl, optionally substituted -CH(OH)aryl, -C(O)-amido (wherein amido is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperazinyl, morpholinyl, cyclohexylamino, anilino, and indolinyl), -S(=O)2-amido (wherein amido is selected from the group consisting of phenethylamino, piperidinyl, 4-methylpiperazinyl, morpholinyl, cyclohexylamino, anilino, and indolinyl), and -SO2R, wherein R is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, and 4-pyridyl, and X is selected from the group consisting of -PO3H2, -P(O) [-OCR z 2OC(O)R y ]2, -P(O) [-OCR z 2OC(O)OR y ]2, -P(O) [-N(H)CR z 2C(O)OR y ]2, -P(O) [-N(H)CR z 2C(O)OR y ][OR e ] and -P(O) [-OCR z (aryl)CH2CH2O-].

[0183] In another aspect, when G is -O-, T is -CH2-, R 1 and R 2 is bromo, R 3 is isopropyl, R 5 is -OH, and X is selected from the group consisting of -PO3H2, -P(O) [-OCR z 2OC(O)R y ]2, -P(O) [-OCR z 2OC(O)OR y ]2, -P(O) [-N(H)CR z 2C(O)OR y ]2, -P(O) [-N(H)CR e 2C(O)OR y ][ORe ] and -P(O)[-OCR z When [(aryl)CH2CH2O-] is used, then R 4 It's not hydrogen.

[0184] In one aspect of the compounds of formula I, G is -O-; T is -CH2CH(NH2)-; R 1 and R 2 Each is iodine; R 4 Selected from hydrogen and iodine; R 5 It is -OH; and R 3 It is iodine; and X is selected from -PO3H2, -P(O) [-OCR] z 2OC(O)R y ]2、-P(O)[-OCR z 2OC(O)OR y 2. -P(O)[-N(H)CR z 2C(O)OR y 2. -P(O)[-N(H)CR z 2C(O)OR y [OR] e ] and -P(O)[-OCR z (aryl)CH2CH2O-].

[0185] On the other hand, G is -O-; T is -CH2CH(NH2)-; R 1 and R 2 Each is iodine; R 4 Selected from hydrogen and iodine; R 5 It is -OH; R 3 It is iodine; and X is selected from -PO3H2, -P(O)[-OCH2OC(O)-tert-butyl]2, -P(O)[-OCH2OC(O)O-isopropyl]2, -P(O)[-N(H)CH(CH3)C(O)OCH2CH3]2, -P(O)[-N(H)C(CH3)2C(O)OCH2CH3]2, -P(O)[-N(H)CH(CH3)C(O)OCH2CH3][3,4-methylenedioxyphenyl], -P(O)[-N(H)C(CH3)2C(O)OCH2CH3][3,4-methylenedioxyphenyl] and -P(O)[-OCH(3-chlorophenyl)CH2CH2O-].

[0186] In other respects of compounds of formula I, G is selected from -O- and -CH2-; T is -N(H)C(O)-; R 1 and R 2 Each is independently selected from iodine, bromine, chloride, methyl, and cyano groups; R 4Selected from hydrogen, iodine, 4-chlorophenyl, and cyclohexyl; R 5 Selected from -OH and -OC(O)R e ;R 3 Selected from hydrogen, iodine, bromine, optionally substituted -C1-C6 alkyl, optionally substituted -CH2 aryl, optionally substituted -CH(OH) aryl, -C(O)-acylamino (wherein the acylamino is selected from phenylethylamino, piperidinyl, 4-methylpiperazinyl, morpholinyl, cyclohexylamino, aniline, and indololinyl), -S(=O)2-acylamino (wherein the acylamino is selected from phenylethylamino, piperidinyl, 4-methylpiperazinyl, morpholinyl, cyclohexylamino, aniline, and indololinyl), and -SO2R (wherein R is selected from phenyl, 4-chlorophenyl, 4-fluorophenyl, and 4-pyridinyl); and X is selected from -PO3H2, -P(O)[-OCR z 2OC(O)R y ]2、-P(O)[-OCR z 2OC(O)OR y 2. -P(O)[-N(H)CR z 2C(O)OR y 2. -P(O)[-N(H)CR z 2C(O)OR y [OR] e ] and -P(O)[-OCR z (aryl)CH2CH2O-].

[0187] Another aspect is that when G is -O-; T is -N(H)C(O)-; R 1 R2 is a methyl group; R 4 It is hydrogen; R 5 It is -OH; R 3 It is -CH(OH)(4-fluorophenyl); and X is selected from -PO3H2, -P(O)[-OCR] z 2OC(O)R y 2. -P(O) [-OCR] z 2OC(O)OR y 2. -P(O)[-N(H)CR z 2C(O)OR y 2. -P(O)[-N(H)CR z 2C(O)OR y [OR] e ] and -P(O)[-OCR z (aryl)CH2CH2O-].

[0188] In another respect, G is -O-; T is -N(H)C(O)-; R 1 and R 2Each is a methyl group; R 4 It is hydrogen; R 5 It is -OH; R 3 It is -CH(OH)(4-fluorophenyl); and X is selected from -PO3H2, -P(O)[-OCH2OC(O)-tert-butyl]2, -P(O)[-OCH2OC(O)O-isopropyl]2, -P(O)[-N(H)CH(CH3)C(O)OCH2CH3]2, -P(O)[-N(H)C(CH3)2C(O)OCH2CH3]2, -P(O)[-N(H)CH(CH3)C(O)OCH2CH3][3,4-methylenedioxyphenyl], -P(O)[-N(H)C(CH3)2C(O)OCH2CH3][3,4-methylenedioxyphenyl] and -P(O)[-OCH(3-chlorophenyl)CH2CH2O-].

[0189] In other respects, G is selected from -O- and -CH2-; T is -OCH2-; R 1 and R 2 Each is independently selected from iodine, bromine, chloride, methyl, and cyano groups; R 4 Selected from hydrogen, iodine, 4-chlorophenyl, and cyclohexyl; R 5 Selected from -OH and -OC(O)R e ;R 3 The group is selected from hydrogen, iodine, bromine, optionally substituted lower alkyl groups, optionally substituted -CH2 aryl, optionally substituted -CH(OH) aryl, -C(O)-amide, wherein the amide group is selected from phenylethylamino, piperidinyl, 4-methylpiperazinyl, morpholinyl, cyclohexylamino, aniline and indololinyl, -S(=O)2-acylamino (wherein the amide group is selected from phenylethylamino, piperidinyl, 4-methylpiperazinyl, morpholinyl, cyclohexylamino, aniline and indololinyl) and -SO2R, wherein R is selected from phenyl, 4-chlorophenyl, 4-fluorophenyl and 4-pyridinyl; and X is selected from -PO3H2, -P(O)[-OCR z 2OC(O)R y ]2、-P(O)[-OCR z 2OC(O)OR y 2. -P(O)[-N(H)CR z 2C(O)OR y 2. -P(O)[-N(H)CR z 2C(O)OR y [OR] e ] and -P(O)[-OCR z (aryl)CH2CH2O-].

[0190] In another respect, G is -CH2-; T is -OCH2-; R1 and R 2 Each is a methyl group; R 4 It is hydrogen; R 5 It is -OH; R 3 It is isopropyl; and X is selected from -PO3H2, -P(O)[-OCR] z 2OC(O)R y ]2、-P(O)[-OCR a 2OC(O)OR y 2. -P(O)[-N(H)CR z 2C(O)OR y 2. -P(O)[-N(H)CR z 2C(O)OR y [OR] e ] and -P(O)[-OCR z (aryl)CH2CH2O-].

[0191] On the other hand, G is -CH2-; T is -OCH2-; R 1 and R 2 Each is a methyl group; R 4 It is hydrogen; R 5 It is -OH; R 3 It is isopropyl; and X is selected from -PO3H2, -P(O)[-OCH2OC(O)-tert-butyl]2, -P(O)[-OCH2OC(O)O-isopropyl]2, -P(O)[-N(H)CH(CH3)C(O)OCH2CH3]2, -P(O)[-N(H)C(CH3)2C(O)OCH2CH3]2, -P(O)[-N(H)CH(CH3)C(O)OCH2CH3][3,4-methylenedioxyphenyl], -P(O)[-N(H)C(CH3)2C(O)OCH2CH3][3,4-methylenedioxyphenyl] and -P(O)[-OCH(3-chlorophenyl)CH2CH2O-].

[0192] In other respects, G is selected from -O- and -CH2-; T is -CH2-; R 1 and R 2 Each is independently selected from iodine, bromine, chloride, methyl, and cyano groups; R 4 Selected from hydrogen, iodine, 4-chlorophenyl, and cyclohexyl; R 5 Selected from -OH and -OC(O)R e ;R 3The radical is selected from hydrogen, iodine, bromine, optionally substituted lower alkyl groups, optionally substituted -CH2 aryl groups, optionally substituted -CH(OH) aryl groups, -C(O)-acylamino groups (wherein the acylamino group is selected from phenylethylamino, piperidinyl, 4-methylpiperazinyl, morpholinyl, cyclohexylamino, aniline, and indololinyl), -S(=O)2-acylamino groups (wherein the acylamino group is selected from phenylethylamino, piperidinyl, 4-methylpiperazinyl, morpholinyl, cyclohexylamino, aniline, and indololinyl), and -SO2R, where R is selected from phenyl, 4-chlorophenyl, 4-fluorophenyl, and 4-pyridinyl; and X is selected from -PO3H2, -P(O)[-OCR] z 2OC(O)R y ]2、-P(O)[-OCR z 2OC(O)OR y 2. -P(O)[-N(H)CR z 2C(O)OR y 2. -P(O)[-N(H)CR z 2C(O)OR y [OR] e ] and -P(O)[-OCR z (aryl)CH2CH2O-].

[0193] In another respect, when G is -O-, T is -CH2-, R 1 and R 2 Each is bromine, R 3 It is isopropyl, R 5 It is -OH; and X is selected from -PO3H2, -P(O)[-OCR] z 2OC(O)R y ]2、-P(O)[-OCR z 2OC(O)OR y 2. -P(O)[-N(H)CR z 2C(O)OR y 2. -P(O)[-N(H)CR z 2C(O)OR y [OR] e ] and -P(O)[-OCR z When [(aryl)CH2CH2O-] is used, then R 4 It's not hydrogen.

[0194] On the other hand, G is -O-; T is -CH2-; R 1 and R 2 Each is chlorine; R 4 It is hydrogen; R 5 It is -OH; R is isopropyl; and X is selected from -PO3H2, -P(O) [-OCR] z2OC(O)R y ]2、-P(O)[-OCR z 2OC(O)OR y 2. -P(O)[-N(H)CR z 2C(O)OR y 2. -P(O) [-N(H)CR z 2C(O)OR y [OR] e ] and -P(O)[-OCR z (aryl)CH2CH2O-].

[0195] On the other hand, G is -O-; T is -CH2-; R 1 and R 2 Each is chlorine; R 4 It is hydrogen; R 5 It is -OH; R 3 It is isopropyl; and X is selected from -PO3H2, -P(O)[-OCH2OC(O)-tert-butyl]2, -P(O)[-OCH2OC(O)O-isopropyl]2, -P(O)[-N(H)CH(CH3)C(O)OCH2CH3]2, -P(O)[-N(H)C(CH3)2C(O)OCH2CH3]2, -P(O)[-N(H)CH(CH3)C(O)OCH2CH3][3,4-methylenedioxyphenyl], -P(O)[-N(H)C(CH3)2C(O)OCH2CH3][3,4-methylenedioxyphenyl] and -P(O)[-OCH(3-chlorophenyl)CH2CH2O-].

[0196] In other aspects of the compounds of formula I, G is selected from -O- and -CH2-; T is -CH2CH2-; R 1 and R 2 Each is independently selected from iodine, bromine, chloride, methyl, and cyano groups; R 4 Selected from hydrogen, iodine, 4-chlorophenyl, and cyclohexyl; R 5 Selected from -OH and -OC(O)R e ;R 3The amino group is selected from hydrogen, iodine, bromine, optionally substituted lower alkyl groups, optionally substituted -CH2 aryl, optionally substituted -CH(OH) aryl, -C(O)-amide (wherein the amide group is selected from phenylethylamino, piperidinyl, 4-methylpiperazinyl, morpholinyl, cyclohexylamino, aniline, and indololinyl), -S(=O)2-amide (wherein the amide group is selected from phenylethylamino, piperidinyl, 4-methylpiperazinyl, morpholinyl, cyclohexylamino, aniline, and indololinyl), and -SO2R, wherein R is selected from phenyl, 4-chlorophenyl, 4-fluorophenyl, and 4-pyridinyl; and X is selected from -PO3H2, -P(O)[-OCR] z 2OC(O)R y ]2、-P(O)[-OCR z 2OC(O)OR y 2. -P(O)[-N(H)CR z 2C(O)OR y 2. -P(O)[-N(H)CR z 2C(O)OR y [OR] e ] and -P(O)[-OCR z (aryl)CH2CH2O-].

[0197] In other respects, G is -O-; T is -CH2CH2-; R 1 and R 2 Each is chlorine; R 4 It is hydrogen; R 5 It is -OH; R 3 It is isopropyl; and X is selected from -PO3H2, -P(O)[-OCR] z 2OC(O)R y ]2、-P(O)[-OCR z 2OC(O)OR y 2. -P(O)[-N(H)CR z 2C(O)OR y 2. -P(O)[-N(H)CR z 2C(O)OR y [OR] e ] and -P(O)[-OCR z (aryl)CH2CH2O-].

[0198] On the other hand, G is -O-; T is -CH2CH2-; R 1 and R 2 Each is chlorine; R 4 It is hydrogen; R 5 It is -OH; R 3It is isopropyl; and X is selected from -PO3H2, -P(O)[-OCH2OC(O)-tert-butyl]2, -P(O)[-OCH2OC(O)O-isopropyl]2, -P(O)[-N(H)CH(CH3)C(O)OCH2CH3]2, -P(O)[-N(H)C(CH3)2C(O)OCH2CH3]2, -P(O)[-N(H)CH(CH3)C(O)OCH2CH3][3,4-methylenedioxyphenyl], -P(O)[-N(H)C(CH3)2C(O)OCH2CH3][3,4-methylenedioxyphenyl] and -P(O)[-OCH(3-chlorophenyl)CH2CH2O-].

[0199] In another respect, G is -CH2-; T is -OCH2-; R 1 and R 2 Each is a methyl group; R 4 It is hydrogen; R 5 It is -OH; R 3 It is isopropyl; and X is -PO3H2. In other respects, G is -CH2-; T is -OCH2-; R... 1 and R 2 Each is a methyl group; R 4 It is hydrogen; R 5 It is -OH; R 3 It is isopropyl; and X is selected from -P(O)[-OCH2OC(O)-tert-butyl]2 and -P(O)[-OCH2OC(O)-isopropyl]2. On the other hand, G is -CH2-; T is -OCH2-; R 1 and R 2 Each is a methyl group; R 4 It is hydrogen; R 5 It is -OH; R 3 It is isopropyl; and X is selected from -P(O)[-OCH2OC(O)-ethyl]2 and -P(O)[-OCH2OC(O)-isopropyl]2. In another aspect, G is -CH2-; T is -OCH2-; R 1 and R 2 Each is a methyl group; R 4 It is hydrogen; R 5 It is -OH; R 3 It is isopropyl; and X is selected from -P(O)[-N(H)CH(CH3)C(O)OCH2CH3]2 and -P(O)[-N(H)C(CH3)2C(O)OCH2CH3]2. In another respect, G is -CH2-; T is -OCH2-; R 1 and R 2 Methyl; R 4 It is hydrogen; R 5It is -OH; R 3 It is isopropyl; and X is -P(O)[-OCH2CH2SC(O)Me]2, or X is -P(O)[-N(H)C(CH3)C(O)OCH2CH3][3,4-methylenedioxyphenyl], or X is -P(O)[-N(H)C(CH3)2C(O)OCH2CH3][3,4-methylenedioxyphenyl].

[0200] In another respect, G is -O-, and T is -(CH2). 0-4 -, R 1 and R 2 Independently selected from hydrogen, halogens, alkyl groups with 1-3 carbons, and cycloalkyl groups with 3-5 carbons, R 3 It is an alkyl group with 1-4 carbons or a cycloalkyl group with 3-7 carbons, and R 5 If it is -OH, then R 4 It is not hydrogen; and where G is -O-, R 5 Selected from NHC(O)R e -NHS(=O) 1-2 R e , -NHC(S)NH(Th) and -NHC(O)NH(R) h T is selected from -(CH2). m -、-CH=CH-, -O(CH2) 1-2 - and -NH(CH2) 1-2 - When, then R 4 It's not hydrogen.

[0201] In another respect, G is -CH2-; T is -OCH2-; R 1 and R 2 Each is a methyl group; R 1 It is hydrogen; R 5 It is -OH; R 3 It is isopropyl; and X is -P(O)YR 11 Y′R 11 ; Y and Y' are each independently selected from -O- and -NR. v -;R 11 and R 11 Together is a group:

[0202] in: V, W, and W' are independently selected from hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocyclic alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-ynyl. Alternatively, V and Z can be linked together by another 3-5 atoms to form a cyclic group containing 5-7 atoms, where 0-1 atoms are heteroatoms and the remaining atoms are carbon atoms. This cyclic group containing 5-7 atoms is substituted with a hydroxyl, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy group linked to the carbon atom. The carbon atom is three atoms away from the two Y groups linked to the same phosphorus group. Alternatively, V and Z can be linked together by another 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and the cyclic group is fused with aryl groups at the β and γ positions of Y connected to phosphorus. Alternatively, V and W can be linked together via three additional carbon atoms to form an optionally substituted cyclic group containing six carbon atoms, and substituted by a substituent selected from hydroxyl, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy linked to one of the carbon atoms, wherein the carbon atom is three atoms away from the phosphorus-linked Y. Alternatively, Z and W can be linked together by another 3-5 atoms to form a cyclic group, where 0-1 atoms are heteroatoms, the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl. Alternatively, W and W' can be linked together by another 2-5 atoms to form a cyclic group, where 0-2 atoms are heteroatoms, the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl. Z is selected from -CHR z OH, -CHR z OC(O)R y -CHR z OC(S)R y -CHR z OC(S)OR y -CHR z OC(O)SR y -CHR z OCO2R y -OR z -SR z -CHR z N3, -CH2aryl, -CH(aryl)OH, -CH(CH=CR) z 2) OH, -CH(C≡CR z )OH、-R z -NR z 2. -OCOR y -OCO2R y -SCOR y -SCO2R y -NHCOR z-NHCO2R y -CH2NH aryl, -(CH2)q-OR z and -(CH2)q-SR z ; q is an integer of 2 or 3; The conditions are: a) Not all of V, Z, W, and W' are -H; and b) When Z is -R z In this case, at least one of V, W, and W' is not -H, alkyl, aralkyl, or heterocyclic alkyl; Each R z Selected from R y and -H; Each R y Selected from alkyl, aryl, heterocyclic alkyl, and aralkyl groups; Each R x Independently selected from -H and alkyl, or R x and R x Together they form cycloalkyl groups; Each R V Selected from -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl groups. In other respects, V is aryl. In other respects, Z is hydrogen, W is hydrogen, and W' is hydrogen. In other respects, V is 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 3-fluorophenyl, pyridin-4-yl, pyridin-3-yl, or 3,5-dichlorophenyl. In other respects, the relative stereochemistry between the substituents on the dioxaphosphonane ring is cis.

[0203] On another front, each R a Independently selected from hydrogen, optionally substituted -C1-C2 alkyl, halogen, -OH, optionally substituted -O-C1-C2 alkyl, -OCF3, optionally substituted -S-C1-C2 alkyl, -NR b R c Optionally substituted -C2 alkenyl and Optionally substituted -C2 ynyl; Each R b Independently selected from hydrogen, or optionally substituted -C1-C2 alkyl groups; Each R c Independently selected from hydrogen, optionally substituted -C1-C4 alkyl, optionally substituted -C(O)-C1-C2 alkyl, -C(O)H; Each R d Selected from optionally substituted -C1-C6 alkyl, optionally substituted -C2-C6 alkenyl, optionally substituted -C2-C6 ynyl, optionally substituted -(CR b 2) n Phenyl, optionally substituted -(CR) b 2)n Non-cyclic heteroaryl, optionally substituted -(CR b 2) n -C3-C6-cycloalkyl, optionally substituted -(CR b 2) n -C4-C5 heterocyclic alkyl groups and -C(O)NR f R g ; Each R e Selected from optionally substituted -C1-C6 alkyl, optionally substituted -C2-C6 alkenyl, optionally substituted -C2-C6 ynyl, optionally substituted -(CR b 2) n Phenyl, optionally substituted -(CR) b 2) n Monocyclic heteroaryl, optionally substituted -(CR b 2) n -C3-C6-cycloalkyl, optionally substituted -(CR b 2) n -C4-C5 heterocyclic alkyl groups; R f and R g Each is independently selected from hydrogen, optionally substituted -C1-C6 alkyl, optionally substituted -C2-C6 alkenyl, optionally substituted -C2-C6 ynyl, optionally substituted -(CR b 2) n Phenyl, optionally substituted -(CR) b 2) n Monocyclic heteroaryl, optionally substituted -(CR b 2) n -C3-C6-cycloalkyl, optionally substituted -(CR b 2) n -C4-C5-heterocyclic alkyl, or R f and R g They can together form optionally substituted heterocycles, which may contain elements selected from O and NR. b The second heterogroup of S, wherein the optionally substituted heterocycle may be selected from optionally substituted -C1-C2 alkyl, -OR b Oxygenated, cyano, -CF3, optionally substituted phenyl groups and -C(O)OR h 0-2 substituents; Each R h -C1-C is an optional substitute 16 Alkyl, optionally substituted -C2-C 16 alkenyl, optionally substituted -C2-C 16 alkynyl, optionally substituted -(CR) b 2) nPhenyl, optionally substituted -(CR) b 2) n Monocyclic heteroaryl, optionally substituted -(CR b 2) n -C3-C6-cycloalkyl, optionally substituted -(CR b 2) n -C4-C5-heterocyclic alkyl groups.

[0204] On the other hand, each R a Independently selected from hydrogen, methyl, fluorine, chlorine, -OH, -O-CH3, -OCF3, -SCH3, -NHCH3, -N(CH3)2; Each R b Independently selected from hydrogen and methyl; Each R c Independently selected from hydrogen, methyl, -C(O)CH3, -C(O)H; Each R d Selected from optionally substituted -C1-C4 alkyl, optionally substituted -C2-C4 alkenyl, optionally substituted -C2-C4 ynyl, optionally substituted -(CH2). n Phenyl, optionally substituted -(CH2) n Monocyclic heteroaryl, optionally substituted -(CH2) n -C3-C6-cycloalkyl, optionally substituted -(CH2) n -C4-C5-heterocyclic alkyl groups and -C(O)NR f R g ; Each R e Selected from optionally substituted -C1-C4 alkyl, optionally substituted -C2-C4 alkenyl, optionally substituted -C2-C4 ynyl, optionally substituted -(CH2). n Phenyl, optionally substituted -(CH2) n Monocyclic heteroaryl, optionally substituted -(CH2) n -C3-C6-cycloalkyl, optionally substituted -(CH2) n -C4-C5-heterocyclic alkyl; R f and R g Each is independently selected from hydrogen, optionally substituted -C1-C4 alkyl, optionally substituted -C2-C4 alkenyl, optionally substituted -C2-C4 ynyl, optionally substituted -(CH2). n (phenyl, optionally substituted -CH2) n Monocyclic heteroaryl, optionally substituted -(CH2) n -C3-C6-cycloalkyl, optionally substituted -(CH2) n -C4-C8-heterocyclic alkyl, or Rf and R g They can together form optionally substituted heterocycles, which may contain elements selected from O and NR. b and the second heterogroup of S, wherein the optionally substituted heterocycle may be selected from the optionally substituted methyl, -OR b Oxygenated, cyano, -CF3, optionally substituted phenyl groups and -C(O)OR h 0-2 substituents; Each R h It can be an optionally substituted -C1-C4 alkyl, optionally substituted -C2-C4 alkenyl, optionally substituted -C2-C4 ynyl, or optionally substituted -(CH2). n Phenyl, optionally substituted -(CH2) n Monocyclic heteroaryl, optionally substituted -(CH2) n -C3-C6-cycloalkyl, optionally substituted -(CH2)6-C4-C8-heterocyclic alkyl.

[0205] Exemplary compounds for incorporation into compositions for administration within the methods disclosed herein include, but are not limited to, those disclosed in U.S. Patent No. 7,829,552, which is incorporated herein by reference in its entirety. U.S. Patent No. 7,829,552 further discloses methods for synthesizing said compounds. These compounds include those having the following structures or pharmaceutically acceptable salts thereof:

[0206] Preferred compositions for application according to the method of this disclosure include those comprising compounds 1, 2, 3, and / or 4, respectively corresponding to the structures , , and , Or a salt acceptable for its medication.

[0207] In some embodiments, the compound applied according to the compositions and methods of this disclosure may comprise one or more of the following:

[0208] Or a drug-acceptable salt thereof, or any combination thereof.

[0209] In some other embodiments, the compound administered according to the compositions and methods of this disclosure may comprise one or more of the following or a pharmaceutically acceptable salt thereof:

[0210] Or any combination thereof.

[0211] In previous trials, daily administration of these compounds in dogs resulted in a dose-dependent decrease in serum lipid levels and inhibition of the HPT axis with an unclear dose-dependent effect. Surprisingly, given the dose-dependent nature of the primary lipid-lowering effect, changing the dosing regimen to every other day did not reduce the efficacy in lowering plasma cholesterol, but did alleviate the inhibition of the HPT axis. Therefore, some implementation methods include administering compounds 1, 2, and related compounds in a manner that maintains their primary effect as TRβ agonists, thereby achieving relief of clinical symptoms while improving or eliminating the inhibition of the HPT axis and the accompanying side effects of such inhibition.

[0212] According to the methods disclosed herein, the HPT-inhibiting side effects associated with the administration of the aforementioned compounds can be reduced by adjusting the dosing regimen, allowing individuals to experience periodic partial or complete dose reductions over fixed time periods, followed by a resumption of the dose. In some embodiments, a daily dose is administered for one to thirty days, followed by a dosing rest period of one to thirty days. In some embodiments, no dose is administered during the dosing rest period. In some other embodiments, the compound and its metabolites are allowed to be completely eliminated from the individual's body before administering the next dose. In some other embodiments, a dose less than the usual daily dose is administered during the dosing rest period. In some other embodiments, an amount of the administered compound less than the therapeutically effective amount is allowed to remain in the individual's body during the dosing rest period. In some other embodiments, an amount of the administered compound sufficient to maintain therapeutic levels in the affected tissues is allowed to remain in the individual's body.

[0213] In some embodiments, the maximum serum concentration of the compound during the dosing regimen is less than 120 ng / ml, less than 100 ng / ml, less than 90 ng / ml, less than 80 ng / ml, less than 70 ng / ml, less than 60 ng / ml, or less than 50 ng / ml. In some embodiments, the minimum serum concentration during the dosing regimen is less than 10 ng / ml, less than 1 ng / ml, less than 0.1 ng / ml, less than 0.01 ng / ml, or less than 0.001 ng / ml. In some embodiments, the level of the compound administered during the dosing regimen may be undetectable during certain portions of the dosing rest period.

[0214] In some embodiments, the maximum serum concentration of the compound during the dosing regimen is higher during the initial phase of dosing and lower in subsequent phases. In some embodiments, the maximum serum concentration of the compound during the initial (loading) phase of administration is less than 500 ng / ml, less than 400 ng / ml, less than 300 ng / ml, less than 200 ng / ml, less than 150 ng / ml, less than 120 ng / ml, less than 100 ng / ml, less than 90 ng / ml, less than 80 ng / ml, less than 70 ng / ml, less than 60 ng / ml, or less than 50 ng / ml. In some such embodiments, the maximum serum concentration during the initial phase of administration is from 5 ng / ml to 250 ng / ml. In some embodiments, the maximum serum concentration of the compound during the subsequent (maintenance) phase of administration is less than 350 ng / ml, less than 200 ng / ml, less than 120 ng / ml, less than 100 ng / ml, less than 90 ng / ml, or less than 80 ng / ml, less than 70 ng / ml, less than 60 ng / ml, less than 50 ng / ml, less than 40 ng / ml, less than 35 ng / ml, or less than 10 ng / ml. Those skilled in the art will readily recognize the methods existing in the art for monitoring the serum concentration of pharmaceutical agents, and the ways in which the dosage of the compounds disclosed herein is adjusted to achieve desired serum concentrations. In some embodiments, the weekly dose to be administered is 600 mg or less. In some embodiments, the weekly dose to be administered is 500 mg or less, 400 mg or less, 300 mg or less, 200 mg or less, 100 mg or less, 50 mg or less, 40 mg or less, 25 mg or less, 10 mg or less, or 5 mg or less, or within the range defined by any two of the foregoing.

[0215] In some implementations, each R is applied 11 It is not a hydrogen-containing compound of formula I, and the compound is metabolized in the body to form each of the R groups. 11 It is a compound of formula I that is an anion of hydrogen or a compound. For example, in some embodiments, compound 1 is administered and metabolized in vivo to form compound 3. In some embodiments, compound 2 is administered and metabolized in vivo to form compound 4. In some such embodiments, during the initial (loading) phase of administration, each R... 11The maximum serum concentration of Formula I compounds that are hydrogen or anions of compounds (e.g., compounds 3 or 4) is 500 ng / ml or less, 450 ng / ml or less, 400 ng / ml or less, 350 ng / ml or less, 300 ng / ml or less, or 250 ng / ml or less. In some embodiments, the maximum serum concentration during the subsequent (maintenance) administration phase is 500 ng / ml or less, 450 ng / ml or less, 400 ng / ml or less, 350 ng / ml or less, 300 ng / ml or less, 250 ng / ml or less, 200 ng / ml or less, 150 ng / ml or less, or 120 ng / ml or less.

[0216] According to this disclosure, the dosing regimen can be modified to achieve the desired therapeutic effect while eliminating HPT-related side effects. In each of the following embodiments, the variation of the dosing regimen can be repeated throughout the duration of treatment. In each of the following embodiments, the first dose can be higher, lower, or equal to the dose following the first dose. In each of the following embodiments, the loading dose can be administered before the disclosed dosing regimen, and the dosing rest period can or may not be administered after the loading dose.

[0217] In some embodiments, the dose is administered every other day during the duration of treatment. In other embodiments, the dose is administered for two out of every three days during the duration of treatment. In other embodiments, the dose is administered for two out of every four days during the duration of treatment. In some embodiments, the dose is administered daily for one day, followed by a two-day rest period. In some embodiments, the dose is administered daily for one day, followed by a two-day rest period. In some embodiments, the dose is administered daily for one day, followed by a three-day rest period. In some embodiments, the dose is administered daily for one day, followed by a four-day rest period. In some embodiments, the dose is administered daily for one day, followed by a five-day rest period. In some embodiments, the dose is administered daily for one day, followed by a six-day rest period. In some embodiments, the dose is administered daily for one day, followed by a seven-day rest period. In some embodiments, the dose is administered daily for one day, followed by an eight-day rest period. In some embodiments, the dose is administered daily for one day, followed by a nine-day rest period. In some embodiments, the dose is administered daily for one day, followed by a ten-day rest period. In some embodiments, the dose is administered daily for one day, followed by an eleven-day rest period. In some implementations, the daily dose is administered for one day, followed by a twelve-day rest period. In some implementations, the daily dose is administered for one day, followed by a thirteen-day rest period. In some implementations, the daily dose is administered for one day, followed by a fourteen-day rest period.

[0218] In some embodiments, the daily dose is administered for two days, followed by a one-day rest period. In some embodiments, the daily dose is administered for two days, followed by a two-day rest period. In some embodiments, the daily dose is administered for two days, followed by a three-day rest period. In some embodiments, the daily dose is administered for two days, followed by a four-day rest period. In some embodiments, the daily dose is administered for two days, followed by a five-day rest period. In some embodiments, the daily dose is administered for two days, followed by a six-day rest period. In some embodiments, the daily dose is administered for two days, followed by a seven-day rest period. In some embodiments, the daily dose is administered for two days, followed by an eight-day rest period. In some embodiments, the daily dose is administered for two days, followed by a nine-day rest period. In some embodiments, the daily dose is administered for two days, followed by a ten-day rest period. In some embodiments, the daily dose is administered for two days, followed by an eleven-day rest period. In some embodiments, the daily dose is administered for two days, followed by a twelve-day rest period. In some embodiments, the daily dose is administered for two days, followed by a thirteen-day rest period. In some implementations, the daily dose is administered for two consecutive days, followed by a fourteen-day rest period.

[0219] In some embodiments, the daily dose is administered for three days, followed by a one-day rest period. In some embodiments, the daily dose is administered for three days, followed by a two-day rest period. In some embodiments, the daily dose is administered for three days, followed by a three-day rest period. In some embodiments, the daily dose is administered for three days, followed by a four-day rest period. In some embodiments, the daily dose is administered for three days, followed by a five-day rest period. In some embodiments, the daily dose is administered for three days, followed by a six-day rest period. In some embodiments, the daily dose is administered for three days, followed by a seven-day rest period. In some embodiments, the daily dose is administered for three days, followed by an eight-day rest period. In some embodiments, the daily dose is administered for three days, followed by a nine-day rest period. In some embodiments, the daily dose is administered for three days, followed by a ten-day rest period. In some embodiments, the daily dose is administered for three days, followed by an eleven-day rest period. In some embodiments, the daily dose is administered for three days, followed by a twelve-day rest period. In some embodiments, the daily dose is administered for three days, followed by a thirteen-day rest period. In some implementations, the daily dose is administered for three consecutive days, followed by a fourteen-day rest period.

[0220] In some embodiments, the daily dose is administered for four days, followed by a one-day rest period. In some embodiments, the daily dose is administered for four days, followed by a two-day rest period. In some embodiments, the daily dose is administered for four days, followed by a three-day rest period. In some embodiments, the daily dose is administered for four days, followed by a four-day rest period. In some embodiments, the daily dose is administered for four days, followed by a five-day rest period. In some embodiments, the daily dose is administered for four days, followed by a six-day rest period. In some embodiments, the daily dose is administered for four days, followed by a seven-day rest period. In some embodiments, the daily dose is administered for four days, followed by an eight-day rest period. In some embodiments, the daily dose is administered for four days, followed by a nine-day rest period. In some embodiments, the daily dose is administered for four days, followed by a ten-day rest period. In some embodiments, the daily dose is administered for four days, followed by an eleven-day rest period. In some embodiments, the daily dose is administered for four days, followed by a twelve-day rest period. In some implementations, the daily dose is administered for four days, followed by a thirteen-day rest period. In other implementations, the daily dose is administered for four days, followed by a fourteen-day rest period.

[0221] In some embodiments, the daily dose is administered for five days, followed by a one-day rest period. In some embodiments, the daily dose is administered for five days, followed by a two-day rest period. In some embodiments, the daily dose is administered for five days, followed by a three-day rest period. In some embodiments, the daily dose is administered for five days, followed by a four-day rest period. In some embodiments, the daily dose is administered for five days, followed by a five-day rest period. In some embodiments, the daily dose is administered for five days, followed by a six-day rest period. In some embodiments, the daily dose is administered for five days, followed by a seven-day rest period. In some embodiments, the daily dose is administered for five days, followed by an eight-day rest period. In some embodiments, the daily dose is administered for five days, followed by a nine-day rest period. In some embodiments, the daily dose is administered for five days, followed by a ten-day rest period. In some embodiments, the daily dose is administered for five days, followed by an eleven-day rest period. In some embodiments, the daily dose is administered for five days, followed by a twelve-day rest period. In some implementations, the daily dose is administered for five days, followed by a thirteen-day rest period. In other implementations, the daily dose is administered for five days, followed by a fourteen-day rest period.

[0222] In some embodiments, the daily dose is administered for six days, followed by a one-day rest period. In some embodiments, the daily dose is administered for six days, followed by a two-day rest period. In some embodiments, the daily dose is administered for six days, followed by a three-day rest period. In some embodiments, the daily dose is administered for six days, followed by a four-day rest period. In some embodiments, the daily dose is administered for six days, followed by a five-day rest period. In some embodiments, the daily dose is administered for six days, followed by a six-day rest period. In some embodiments, the daily dose is administered for six days, followed by a seven-day rest period. In some embodiments, the daily dose is administered for six days, followed by an eight-day rest period. In some embodiments, the daily dose is administered for six days, followed by a nine-day rest period. In some embodiments, the daily dose is administered for six days, followed by a ten-day rest period. In some embodiments, the daily dose is administered for six days, followed by an eleven-day rest period. In some embodiments, the daily dose is administered for six days, followed by a twelve-day rest period. In some implementations, the daily dose is administered for six days, followed by a thirteen-day rest period. In other implementations, the daily dose is administered for six days, followed by a fourteen-day rest period.

[0223] In some embodiments, the daily dose is administered for seven days, followed by a one-day rest period. In some embodiments, the daily dose is administered for seven days, followed by a two-day rest period. In some embodiments, the daily dose is administered for seven days, followed by a three-day rest period. In some embodiments, the daily dose is administered for seven days, followed by a four-day rest period. In some embodiments, the daily dose is administered for seven days, followed by a five-day rest period. In some embodiments, the daily dose is administered for seven days, followed by a six-day rest period. In some embodiments, the daily dose is administered for seven days, followed by a seven-day rest period. In some embodiments, the daily dose is administered for seven days, followed by an eight-day rest period. In some embodiments, the daily dose is administered for seven days, followed by a nine-day rest period. In some embodiments, the daily dose is administered for seven days, followed by a ten-day rest period. In some embodiments, the daily dose is administered for seven days, followed by an eleven-day rest period. In some embodiments, the daily dose is administered for seven days, followed by a twelve-day rest period. In some implementations, the daily dose is administered for seven days, followed by a thirteen-day rest period. In other implementations, the daily dose is administered for seven days, followed by a fourteen-day rest period.

[0224] In some embodiments, the daily dose is administered for eight days, followed by a one-day rest period. In some embodiments, the daily dose is administered for eight days, followed by a two-day rest period. In some embodiments, the daily dose is administered for eight days, followed by a three-day rest period. In some embodiments, the daily dose is administered for eight days, followed by a four-day rest period. In some embodiments, the daily dose is administered for eight days, followed by a five-day rest period. In some embodiments, the daily dose is administered for eight days, followed by a six-day rest period. In some embodiments, the daily dose is administered for eight days, followed by a seven-day rest period. In some embodiments, the daily dose is administered for eight days, followed by an eight-day rest period. In some embodiments, the daily dose is administered for eight days, followed by a nine-day rest period. In some embodiments, the daily dose is administered for eight days, followed by a ten-day rest period. In some embodiments, the daily dose is administered for eight days, followed by an eleven-day rest period. In some embodiments, the daily dose is administered for eight days, followed by a twelve-day rest period. In some implementations, the daily dose is administered for eight days, followed by a thirteen-day rest period. In other implementations, the daily dose is administered for eight days, followed by a fourteen-day rest period.

[0225] In some embodiments, the daily dose is administered for nine days, followed by a one-day rest period. In some embodiments, the daily dose is administered for nine days, followed by a two-day rest period. In some embodiments, the daily dose is administered for nine days, followed by a three-day rest period. In some embodiments, the daily dose is administered for nine days, followed by a four-day rest period. In some embodiments, the daily dose is administered for nine days, followed by a five-day rest period. In some embodiments, the daily dose is administered for nine days, followed by a six-day rest period. In some embodiments, the daily dose is administered for nine days, followed by a seven-day rest period. In some embodiments, the daily dose is administered for nine days, followed by an eight-day rest period. In some embodiments, the daily dose is administered for nine days, followed by a nine-day rest period. In some embodiments, the daily dose is administered for nine days, followed by a nine-day rest period. In some embodiments, the daily dose is administered for nine days, followed by a ten-day rest period. In some embodiments, the daily dose is administered for nine days, followed by an eleven-day rest period. In some embodiments, the daily dose is administered for nine days, followed by a twelve-day rest period. In some implementations, the daily dose is administered for nine days, followed by a thirteen-day rest period. In other implementations, the daily dose is administered for nine days, followed by a fourteen-day rest period.

[0226] In some embodiments, the daily dose is administered for ten days, followed by a one-day rest period. In some embodiments, the daily dose is administered for ten days, followed by a two-day rest period. In some embodiments, the daily dose is administered for ten days, followed by a three-day rest period. In some embodiments, the daily dose is administered for ten days, followed by a four-day rest period. In some embodiments, the daily dose is administered for ten days, followed by a five-day rest period. In some embodiments, the daily dose is administered for ten days, followed by a six-day rest period. In some embodiments, the daily dose is administered for ten days, followed by a seven-day rest period. In some embodiments, the daily dose is administered for ten days, followed by an eight-day rest period. In some embodiments, the daily dose is administered for ten days, followed by a nine-day rest period. In some embodiments, the daily dose is administered for ten days, followed by a ten-day rest period. In some embodiments, the daily dose is administered for ten days, followed by an eleven-day rest period. In some embodiments, the daily dose is administered for ten days, followed by a twelve-day rest period. In some implementations, the daily dose is administered for ten days, followed by a thirteen-day rest period. In other implementations, the daily dose is administered for ten days, followed by a fourteen-day rest period.

[0227] In some embodiments, the daily dose is administered for eleven days, followed by a one-day rest period. In some embodiments, the daily dose is administered for eleven days, followed by a two-day rest period. In some embodiments, the daily dose is administered for eleven days, followed by a three-day rest period. In some embodiments, the daily dose is administered for eleven days, followed by a four-day rest period. In some embodiments, the daily dose is administered for eleven days, followed by a five-day rest period. In some embodiments, the daily dose is administered for eleven days, followed by a six-day rest period. In some embodiments, the daily dose is administered for eleven days, followed by a seven-day rest period. In some embodiments, the daily dose is administered for eleven days, followed by an eight-day rest period. In some embodiments, the daily dose is administered for eleven days, followed by a nine-day rest period. In some embodiments, the daily dose is administered for eleven days, followed by a ten-day rest period. In some embodiments, the daily dose is administered for eleven days, followed by an eleven-day rest period. In some embodiments, the daily dose is administered for eleven days, followed by a twelve-day rest period. In some implementations, the daily dose is administered for eleven days, followed by a thirteen-day rest period. In other implementations, the daily dose is administered for eleven days, followed by a fourteen-day rest period.

[0228] In some embodiments, the daily dose is administered for twelve days, followed by a one-day rest period. In some embodiments, the daily dose is administered for twelve days, followed by a two-day rest period. In some embodiments, the daily dose is administered for twelve days, followed by a three-day rest period. In some embodiments, the daily dose is administered for twelve days, followed by a four-day rest period. In some embodiments, the daily dose is administered for twelve days, followed by a five-day rest period. In some embodiments, the daily dose is administered for twelve days, followed by a six-day rest period. In some embodiments, the daily dose is administered for twelve days, followed by a seven-day rest period. In some embodiments, the daily dose is administered for twelve days, followed by an eight-day rest period. In some embodiments, the daily dose is administered for twelve days, followed by a nine-day rest period. In some embodiments, the daily dose is administered for twelve days, followed by a ten-day rest period. In some embodiments, the daily dose is administered for twelve days, followed by an eleven-day rest period. In some embodiments, the daily dose is administered for twelve days, followed by a twelve-day rest period. In some implementations, the daily dose is administered for twelve days, followed by a thirteen-day rest period. In other implementations, the daily dose is administered for twelve days, followed by a fourteen-day rest period.

[0229] In some embodiments, the daily dose is administered for thirteen days, followed by a one-day rest period. In some embodiments, the daily dose is administered for thirteen days, followed by a two-day rest period. In some embodiments, the daily dose is administered for thirteen days, followed by a three-day rest period. In some embodiments, the daily dose is administered for thirteen days, followed by a four-day rest period. In some embodiments, the daily dose is administered for thirteen days, followed by a five-day rest period. In some embodiments, the daily dose is administered for thirteen days, followed by a six-day rest period. In some embodiments, the daily dose is administered for thirteen days, followed by a seven-day rest period. In some embodiments, the daily dose is administered for thirteen days, followed by an eight-day rest period. In some embodiments, the daily dose is administered for thirteen days, followed by a nine-day rest period. In some embodiments, the daily dose is administered for thirteen days, followed by a ten-day rest period. In some embodiments, the daily dose is administered for thirteen days, followed by an eleven-day rest period. In some embodiments, the daily dose is administered for thirteen days, followed by a twelve-day rest period. In some implementations, the daily dose is administered for thirteen days, followed by a thirteen-day rest period. In other implementations, the daily dose is administered for thirteen days, followed by a fourteen-day rest period.

[0230] In some embodiments, the daily dose is administered for fourteen days, followed by a one-day rest period. In some embodiments, the daily dose is administered for fourteen days, followed by a two-day rest period. In some embodiments, the daily dose is administered for fourteen days, followed by a three-day rest period. In some embodiments, the daily dose is administered for fourteen days, followed by a four-day rest period. In some embodiments, the daily dose is administered for fourteen days, followed by a five-day rest period. In some embodiments, the daily dose is administered for fourteen days, followed by a six-day rest period. In some embodiments, the daily dose is administered for fourteen days, followed by a seven-day rest period. In some embodiments, the daily dose is administered for fourteen days, followed by an eight-day rest period. In some embodiments, the daily dose is administered for fourteen days, followed by a nine-day rest period. In some embodiments, the daily dose is administered for fourteen days, followed by a ten-day rest period. In some embodiments, the daily dose is administered for fourteen days, followed by an eleven-day rest period. In some embodiments, the daily dose is administered for fourteen days, followed by a twelve-day rest period. In some implementations, the daily dose is administered for fourteen days, followed by a thirteen-day rest period.

[0231] In some embodiments, the daily dose is administered for 30 days, followed by a 30-day rest period. In some embodiments, the daily dose is administered for 30 days, followed by a 25-30 day rest period. In some embodiments, the daily dose is administered for 30 days, followed by a 20-25 day rest period. In some embodiments, the daily dose is administered for 30 days, followed by a 15-20 day rest period. In some embodiments, the daily dose is administered for 30 days, followed by a 10-15 day rest period. In some embodiments, the daily dose is administered for 30 days, followed by a 5-10 day rest period. In some embodiments, the daily dose is administered for 30 days, followed by a 1-5 day rest period.

[0232] In some embodiments, the daily dose is administered for 25-30 days, followed by a 30-day rest period. In some embodiments, the daily dose is administered for 25-30 days, followed by a 25-30-day rest period. In some embodiments, the daily dose is administered for 25-30 days, followed by a 20-25-day rest period. In some embodiments, the daily dose is administered for 25-30 days, followed by a 15-20-day rest period. In some embodiments, the daily dose is administered for 25-30 days, followed by a 10-15-day rest period. In some embodiments, the daily dose is administered for 25-30 days, followed by a 5-10-day rest period. In some embodiments, the daily dose is administered for 25-30 days, followed by a 1-5-day rest period.

[0233] In some embodiments, the daily dose is administered for 20-25 days, followed by a 30-day rest period. In some embodiments, the daily dose is administered for 20-25 days, followed by a 25-30 day rest period. In some embodiments, the daily dose is administered for 20-25 days, followed by a 20-25 day rest period. In some embodiments, the daily dose is administered for 20-25 days, followed by a 15-20 day rest period. In some embodiments, the daily dose is administered for 20-25 days, followed by a 10-15 day rest period. In some embodiments, the daily dose is administered for 20-25 days, followed by a 5-10 day rest period. In some embodiments, the daily dose is administered for 20-25 days, followed by a 1-5 day rest period.

[0234] In some embodiments, the daily dose is administered for 15-20 days, followed by a 30-day rest period. In some embodiments, the daily dose is administered for 15-20 days, followed by a 25-30 day rest period. In some embodiments, the daily dose is administered for 15-20 days, followed by a 20-25 day rest period. In some embodiments, the daily dose is administered for 15-20 days, followed by a 15-20 day rest period. In some embodiments, the daily dose is administered for 15-20 days, followed by a 10-15 day rest period. In some embodiments, the daily dose is administered for 15-20 days, followed by a 5-10 day rest period. In some embodiments, the daily dose is administered for 15-20 days, followed by a 1-5 day rest period.

[0235] In any of the foregoing embodiments, daily administration may be performed once a day or as one dose per day, or as two or more fractional doses administered multiple times a day. For example, the compounds described herein may be administered once a day, twice a day, three times a day, or four times a day.

[0236] In some implementations, an individual's T3, T4, or TSH levels are monitored so that the daily dose can be eliminated or reduced on any day in which the T3, T4, or TSH level is below a predetermined threshold. Normal daily dosing can continue if the T3, T4, or TSH level rises above the predetermined threshold during a dosing rest period.

[0237] The implementation schemes of this application include, but are not limited to, the following implementation schemes.

[0238] Implementation Plan 1. A method for treating a disease or condition, comprising the following steps in sequence: Administer the first-day dose of the compound to the individual in need for the first day; Discontinue administration of the compound, or administer a second-day dose of the compound on the second day, wherein the second-day dose of the compound is less than the first-day dose; and The third dose of the compound was administered to the individual on the third day. The diseases or conditions described are selected from obesity, hyperlipidemia, hypercholesterolemia, diabetes, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, atherosclerosis, cardiovascular disease, hypothyroidism, and thyroid cancer; and The compound described above has the structure of Formula I:

[0239] in: G is selected from -O-, -S-, -S(=O)-, -S(=O)2-, -Se-, -CH2-, -CF2-, -CHF-, -C(O)-, -CH(OH)-, -CH(C1-C4 alkyl)-, -CH(C1-C4 alkoxy)-, -C(=CH2)-, -NH- and -N(C1-C4 alkyl)-; T is selected from -(CR) a 2) k -、-CR b =CR b -(CR a 2) n -、-(CR a 2) n -CR b =CR b -、-(CR a 2)-CR b =CR b -(CR a 2)-、-O(CR b 2)(CR a 2) n -、-S(CR b2)(CR a 2) n -、N(R c (CR) b 2)(CR a 2) n -、N(R b )C(O)(CR a 2) n -C(O)(CR) a 2) m -、-(CR a 2) m C(O)-、-(CR a 2)C(O)(CR a 2) n 、-(CR a 2) n C(O)(CR a 2)- and -C(O)NH(CR b 2)(CR a 2) p -; k is an integer from 1 to 4; m is an integer from 0 to 3; n is an integer from 0 to 2; p is an integer between 0 and 1; Each R a Independently selected from hydrogen, optionally substituted -C1-C4 alkyl, halogen, -OH, optionally substituted -O-C1-C4 alkyl, -OCF3, optionally substituted -S-C1-C4 alkyl, -NR b R c Optionally substituted -C2-C4 alkenyl and optionally substituted -C2-C4 ynyl; the condition being that when one R a When C is connected via O, S, or N atoms, other R atoms connected to the same C atom... a It is hydrogen, or linked via carbon atoms; Each R b Independently selected from hydrogen and optionally substituted -C1-C4 alkyl groups; Each R c Independently selected from hydrogen and optionally substituted -C1-C4 alkyl, optionally substituted -C(O)-C1-C4 alkyl and -C(O)H; R 1 and R 2 Each is independently selected from halogens, optionally substituted -C1-C4 alkyl groups, optionally substituted -S-C1-C3 alkyl groups, optionally substituted -C2-C4 alkenyl groups, optionally substituted -C2-C4 alkynyl groups, -CF3 groups, -OCF3 groups, optionally substituted -O-C1-C3 alkyl groups, and cyano groups; R6 R 7 R 8 and R 9 Each is independently selected from hydrogen, halogen, optionally substituted -C C1-C4 alkyl, optionally substituted -S-C1-C3 alkyl, optionally substituted -C2-C4 alkenyl, optionally substituted -C2-C4 ynyl, -CF3, -OCF3, optionally substituted -O-C1-C3 alkyl and cyano; or R 6 And T together with the carbons they are attached to form including independently selected from -NR i -, -O-, and -S- rings of 0 to 2 heteroatoms of 5 to 6 atoms, provided that when there are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen, the two heteroatoms must be separated by at least one carbon atom; and X is separated by a direct bond to the ring carbon, or by a -(CR) bond to the ring carbon or ring nitrogen. a 2) - or - C(O) - connected to the ring; R i Selected from hydrogen, -C(O)C1-C4 alkyl, -C1-C4 alkyl, and -C1-C4 aryl; R 3 and R 4 Independently selected from hydrogen, halogen, -CF3, -OCF3, cyano, or optionally substituted -C1-C 12 Alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl group, -SR d -S(=O)R e -S(=O)2R e -S(=O)2NR f R g -C(O)OR h -C(O)R e -N(R) b )C(O)NR f R g -N(R) b )S(=O)2R e -N(R) b )S(=O)2NR f R g and -NR f R g ; Each R d Selected from the optional substitution -C1-C 12 Alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -(CR) b 2)n aryl, optionally substituted -(CR b 2) n cycloalkyl, optionally substituted -(CR b 2) n Heterocyclic alkyl groups and -C(O)NR f R g ; Each R e Selected from the optional substitution -C1-C 12 Alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -(CR) a 2) n aryl, optionally substituted -(CR a 2) n cycloalkyl and optionally substituted -(CR a 2) n Heterocyclic alkyl groups; R f and R g Each is independently selected from hydrogen, with optional substitution of -C1-C. 12 Alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -(CR) b 2) n aryl, optionally substituted -(CR b 2) n cycloalkyl and optionally substituted -(CR b 2) n Heterocyclic alkyl, or R f and R g They can together form optionally substituted heterocycles, which may contain elements selected from O and NR. C The second heterogroup of S, wherein the optionally substituted heterocycle may be selected from optionally substituted -C1-C4 alkyl, -OR b Oxygenated, cyano, -CF3, optionally substituted phenyl groups and -C(O)OR h 0-4 substituents; Each R h Selected from the optional substitution -C1-C 12 Alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -(CR) b 2) n aryl, optionally substituted -(CR b 2) n cycloalkyl and optionally substituted -(CR b2) n Heterocyclic alkyl groups; R 5 Selected from -OH, optionally substituted -OC1-C6 alkyl groups, OC(O)R e -OC(O)OR h -F, -NHC(O)R e -NHS(=O)R e -NHS(=O)2R e -NHC(=S)NH(R) h ) and -NHC(O)NH(R h ); X is P(O)YR 11 Y′R 11 ; Y and Y' are each independently selected from -O- and -NR. v -; When Y and Y' are -O-, R connected to -O- 11 Independently selected from -H, alkyl, optionally substituted aryl, optionally substituted heterocyclic alkyl, optionally substituted CH2-heterocyclic alkyl wherein the cyclic moiety contains carbonate or thiocarbonate, optionally substituted -alkylaryl, -C(R z )2OC(O)NR z 2. -NR z -C(O)-R y -C(R) z )2-OC(O)R y -C(R) z )2-OC(O)OR y -C(R) z )2OC(O)SR y ,-alkyl-SC(O)R y -alkyl-SS-alkylhydroxyl and -alkyl-SSS-alkylhydroxyl; When Y and Y' are -NR v - when, then with -NR v -Connected R 11 Independently selected from -H, -[C(R) z )2] q -COOR y -C(R) x )2COOR Y -[C(R) z )2] q -C(O)SR y and -cycloalkylene-COOR y ; When Y is -O- and Y' is NR v When, R connected to -O- 11Independently selected from -H, alkyl, optionally substituted aryl, optionally substituted heterocyclic alkyl, optionally substituted CH2-heterocyclic alkyl wherein the cyclic moiety contains carbonate or thiocarbonate, optionally substituted -alkylaryl, -C(R z )2OC(O)NR z 2. -NR z -C(O)-R y -C(R) z )2-OC(O)R y -C(R) z )2-OC(O)OR y -C(R) z )2OC(O)SR y ,-alkyl-SC(O)R y -alkyl-SS-alkylhydroxyl and -alkyl-SSS-alkylhydroxyl; and with -NR v -Connected R 11 Independently selected from H, -[C(R) z )2] q -COOR y -C(R) x )2COOR y -[C(R) z )2] q -C(O)SR y and -cycloalkylene-COOR y ; Or when Y and Y′ are independently selected from -O- and NR v When, then R 11 and R 11 Together they are -alkyl-SS-alkyl- to form cyclic groups, or R 11 and R 11 Together is a group:

[0240] in: V, W, and W' are independently selected from hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocyclic alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-ynyl. Alternatively, V and Z can be linked together by another 3-5 atoms to form a cyclic group containing 5-7 atoms, where 0-1 atoms are heteroatoms and the remaining atoms are carbon atoms. The cyclic group containing 5-7 atoms is replaced by a hydroxyl, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy group linked to the carbon atom. The carbon atom is three atoms away from the two Y groups linked to the same phosphorus. Alternatively, V and Z can be linked together by another 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and the cyclic group is fused with aryl groups at the β and γ positions of Y connected to phosphorus. Alternatively, V and W can be linked together via three additional carbon atoms to form an optionally substituted cyclic group containing six carbon atoms, and substituted by a substituent selected from hydroxyl, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy linked to one of the carbon atoms, wherein the carbon atom is three atoms away from the phosphorus-linked Y. Alternatively, Z and W can be linked together by another 3-5 atoms to form a cyclic group, where 0-1 atoms are heteroatoms, the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl. Alternatively, W and W′ can be linked together by another 2-5 atoms to form a cyclic group, where 0-2 atoms are heteroatoms, the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl. Z is selected from -CHR z OH, -CHR z OC(O)R y -CHR z OC(S)R y -CHR z OC(S)OR y -CHR z OC(O)SR y -CHR z OCO2R y -OR z -SR z -CHR z N3, -CH2-aryl, -CH(aryl)OH, -CH(CH=CR) z 2) OH, -CH(C≡CR z )OH、-R z -NR z 2. -OCOR y -OCO2R y -SCOR y -SCO2R y -NHCOR z -NHCO2R y -CH2NH-aryl, -(CH2)q-OR z and -(CH2)q-SR z ; q is an integer of 2 or 3; Each R z Selected from R yand -H; Each R y Selected from alkyl, aryl, heterocyclic alkyl, and aralkyl groups; Each R x Independently selected from -H and alkyl, or R x and R x Together they form cycloalkyl groups; and Each R v Selected from -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl and lower acyl groups; And its pharmaceutically acceptable salts and prodrugs; and pharmaceutically acceptable salts of said prodrugs.

[0241] Implementation Scheme 2. The method of Implementation Scheme 1, wherein the compound to be applied comprises one or more compounds having a structure selected from: , , ,as well as ; Or a salt acceptable for its medication.

[0242] Implementation Scheme 3. The method as described in Implementation Scheme 1, wherein the first day dose and the third day dose are the same.

[0243] Implementation Scheme 4. The method as described in Implementation Scheme 1, wherein the third-day dose is less than the first-day dose.

[0244] Implementation Scheme 5. The method as described in Implementation Scheme 1, wherein the second-day dose and the third-day dose are the same.

[0245] Implementation Scheme 6. The method of any one of Implementation Schemes 1 to 4, wherein the third-day dose is greater than the second-day dose.

[0246] Implementation Scheme 7. The method as described in any one of Implementation Schemes 1 to 6, wherein the number of the first day and the number of the third day are the same.

[0247] Implementation Scheme 8. The method as described in any one of Implementation Schemes 1 to 7, wherein the number of the first day, the number of the second day, and the number of the third day are the same.

[0248] Implementation Scheme 9. The method of any one of Implementation Schemes 1 to 6, wherein the number of the third day is less than the number of the first day.

[0249] Implementation Scheme 10. The method of any one of Implementation Schemes 1 to 9, wherein the number of the first day, the number of the second day, and the number of the third day are independently selected from 1 to 90.

[0250] Implementation Scheme 11. The method as described in any one of Implementation Schemes 1 to 9, wherein the number of the first day, the number of the second day, and the number of the third day are independently selected from 1 to 30.

[0251] Implementation Scheme 12. The method as described in any one of Implementation Schemes 1 to 9, wherein the number of the first day, the number of the second day, and the number of the third day are independently selected from 1 to 20.

[0252] Implementation Scheme 13. The method of any one of Implementation Schemes 1 to 9, wherein the number of the first day, the number of the second day, and the number of the third day are independently selected from 1 to 10.

[0253] Implementation Scheme 14. The method as described in any one of Implementation Schemes 1 to 9, wherein the number of the first day, the number of the second day, and the number of the third day are independently selected from 1 to 5.

[0254] Implementation Scheme 15. The method of any one of Implementation Schemes 1 to 9, wherein the number of the first day and the number of the third day are 1, and the number of the second day is 1.

[0255] Implementation Scheme 16. The method of any one of Implementation Schemes 1 to 6, wherein the number of the first day and the number of the third day are 1, and the number of the second day is 2.

[0256] Implementation Scheme 17. The method of any one of Implementation Schemes 1 to 6, wherein the number of the first day and the number of the third day are 3, and the number of the second day is 4.

[0257] Implementation Scheme 18. The method of any one of Implementation Schemes 1 to 6, wherein the number of the first day and the number of the third day are 4, and the number of the second day is 3.

[0258] Implementation Scheme 19. The method of any one of Implementation Schemes 1 to 9, wherein the number of the first day and the number of the third day are 4, and the number of the second day is 4.

[0259] Implementation Scheme 20. The method of any one of Implementation Schemes 1 to 6, wherein the number of the first day and the number of the third day are 5, and the number of the second day is 4.

[0260] Implementation Scheme 21. The method of any one of Implementation Schemes 1 to 6, wherein the number of the first day and the number of the third day are 4, and the number of the second day is 5.

[0261] Implementation Scheme 22. The method of any one of Implementation Schemes 1 to 9, wherein the number of the first day and the number of the third day are 10, and the number of the second day is 10.

[0262] Implementation Scheme 23. The method of any one of Implementation Schemes 1 to 9, wherein the number of the first day and the number of the third day are 30, and the number of the second day is 30.

[0263] Implementation Scheme 24. The method of any one of Implementation Schemes 1 to 6, wherein the number of the first day and the number of the third day are 2, and the number of the second day is 1.

[0264] Implementation Scheme 25. The method as described in any one of Implementation Schemes 1 to 24, wherein the application during the first day and the third day is once daily.

[0265] Implementation Scheme 26. The method of any one of Implementation Schemes 1 to 25, including the number of days after stopping the application of the compound.

[0266] Implementation Scheme 27. The method of any one of Implementation Schemes 1 to 25, comprising administering the second daily dose of the compound on the second day.

[0267] Implementation Scheme 28. The method of any one of Implementation Schemes 1 to 27, comprising monitoring the individual's T3, T4, or TSH levels and stopping the administration of the compound, or administering a second daily dose of the compound when the T3, T4, or TSH levels are below a first threshold, and resuming administration of the compound at the first daily dose when the T3, T4, or TSH levels are above a second threshold.

[0268] Implementation Scheme 29. The method as described in Implementation Scheme 28, wherein the first threshold and the second threshold are the same.

[0269] Implementation Scheme 30. The method of any one of Implementation Schemes 1 to 29, wherein the total weekly dose of the compound during the first day period is 40 mg to 150 mg.

[0270] Implementation Scheme 31. The method of any one of Implementation Schemes 1 to 29, wherein the total weekly dose of the compound during the first day period is 50 mg to 90 mg.

[0271] Implementation Scheme 32. The method of any one of Implementation Schemes 1 to 29, wherein the total weekly dose of the compound during the first day period is 60 mg to 80 mg.

[0272] Implementation Scheme 33. The method of any one of Implementation Schemes 1 to 29, wherein the total weekly dose of the compound during the first day period is from 5 mg to 250 mg.

[0273] Implementation Scheme 34. The method of any one of Implementation Schemes 1 to 33, wherein the maximum serum concentration of the compound during the third day is 100 ng / mL or less.

[0274] Implementation Scheme 35. The method of any one of Implementation Schemes 1 to 33, wherein the maximum serum concentration of the compound is 100 ng / mL or less throughout the treatment period.

[0275] Implementation Scheme 36. The method of any one of Implementation Schemes 1 to 35, wherein the compound applied has the structure: or ; And has structure throughout the treatment: or The maximum serum concentration of the compound is 500 ng / mL or lower.

[0276] Implementation Scheme 37. The method as described in Implementation Scheme 1, wherein the applied compound has the structure of Formula I, wherein each R 11 It is not hydrogen, and has each of its R values ​​throughout the treatment period. 11 The maximum serum concentration of a compound of the hydrogen formula I or its anion is 500 ng / mL or lower.

[0277] Implementation Scheme 38. The method as described in Implementation Scheme 1, wherein the number of the first day and the number of the third day are 30, and the number of the second day is 30.

[0278] Implementation Scheme 39. The method as described in Implementation Scheme 1, comprising: Discontinue administration of the compound or administer the second day's dose of the compound for the fourth day; The compound was administered at the third-day dose on the fifth day; and Repeat the process of stopping administration or administering the second day dose for the fourth day, and administer the compound at the third day dose for the fifth day.

[0279] Example

[0280] Example 1: Alternative Dosing Study of Compound 2 in Dogs: The aim of this study was to determine the effect of oral administration of Compound 2 once daily for 14 days, followed by every other day for 14 days, on plasma cholesterol levels and thyroid function parameters in beagle dogs. Compound 2 was formulated with Lutrol F68 NF (poloxamer 188) and carboxymethyl cellulose (CMC; sodium salt / high viscosity) and administered as a suspension of 0.5% CMC / 1% Lutrol in deionized water. Twelve beagle dogs (9–15 kg) were randomly assigned to six dosing groups (one male and one female per group) and administered 0.1, 0.3, 1, 3, or 10 mg / day of the 0.5% CMC / 1% Lutrol F68 suspension of Compound 2 once daily, or by gavage, for 14 days. At the end of the treatment cycle (cycle 1), the dogs were cleaned for four weeks before starting a second 14-day treatment cycle. Cycle 2 used the same dosage pattern as Cycle 1, but the animals were randomized to Cycle 2, so that each combined dosing group from the two cycles consisted of four different animals (two males and two females). At the end of Cycle 2, dosing was continued every other day for another 14 days (Cycle 2 extension). Blood samples were collected at baseline and at appropriate time intervals thereafter, and serum levels of total plasma cholesterol, total T4 (tT4), free T4 (fT4), total T3 (tT3), free T3 (fT3), and thyroid-stimulating hormone (TSH) were analyzed.

[0281] Treatment with compound 2 for 14 days resulted in a progressive, dose-dependent decrease in total plasma cholesterol levels, with an average reduction of approximately 28 mg / dL or approximately 22% from baseline at a dose of 0.3 mg / kg / day on day 15, and a reduction of approximately 71 mg / dL or approximately 47% from baseline at the highest evaluated dose (10 mg / kg / day) (see [link to relevant documentation]). Figure 2 The lowest dose of compound 2 evaluated, 0.1 mg / kg / day, had the least effect on total plasma cholesterol levels. Figure 3 During the alternate-day dosing period of cycle 2 (cycle 2 extension), total plasma cholesterol levels in the compound 2 treatment group remained lower than those observed after once-daily dosing in the carboxyl treatment group to a degree similar to or greater than that observed after once-daily dosing (see [link to article]). Figure 4 Once-daily treatment with compound 2 resulted in a dose-dependent reduction in serum tT4 from baseline levels (approximately 20-54%, see below). Figure 6 A dose-related reduction in fT4 (approximately 8-39%, see [reference]). Figure 5 The dose-dependent reduction of fT3 (approximately 15-32%, see [reference]) and fT3 ([reference]). Figure 7In any of the compound 2 treatment groups, there were no significant changes in tT3 levels relative to baseline, exceeding those observed in the mediator treatment groups (see [link to compound 2 treatment group]). Figure 8 The effect of once-daily compound 2 treatment on serum TSH levels was variable, with complete suppression in some animals and up to a 4-fold increase in others by day 8. On day 15, in the compound 2 treatment group, TSH levels decreased from baseline by approximately 6–27% in a non-dose-dependent manner (see [link to compound 2 treatment]). Figure 9 During the extended period of cycle 2, the tT4 and fT4 levels suppressed by once-daily treatment gradually recovered to near the levels seen in the vector-treated animals (see [link to relevant documentation]). ​ , ​ Further changes in fT3 and TSH levels were observed to recover, but these did not extend to all compound 2 dose groups.

[0282] In summary, once-daily oral administration of compound 2 (0.1–10 mg / kg) for 14 days resulted in a dose-dependent decrease in mean total plasma cholesterol levels (up to 47% from baseline), accompanied by a dose-dependent decrease in serum tT4 levels, a dose-related decrease in fT4 levels, and significant fluctuations in serum TSH levels. tT3 levels were unaffected by treatment, while fT3 levels decreased in a non-dose-dependent manner. Changing from once-daily to every-other-day administration of compound 2 during extended cycle 2 did not impair the cholesterol-lowering efficacy but resulted in a gradual recovery of tT4 and fT4 levels, and in some dose groups, a gradual recovery of fT3 and TSH levels suppressed by once-daily oral administration of compound 2. Therefore, every-other-day administration is an effective alternative to once-daily administration, reducing the impact on the thyroid hormone axis.

[0283] Example 2: Primary Alternative Dosing Study of Compound 1 in Dogs: The aim of this study was to investigate the effects of alternative dosing regimens on various clinical parameters in beagle dogs. Five beagle dogs of single sex were randomly assigned to five groups. One group received only the daily dose of the medium. The test group received 1) daily dosing of the test product; 2) one day dosing followed by a one-day dosing rest period; 3) one day dosing followed by a two-day dosing rest period; 4) three consecutive days dosing followed by a four-day dosing rest period; or 5) five consecutive days dosing followed by a two-day dosing rest period. The dogs were from non-native populations. Dosing was performed by once-daily administration. The test product was administered at a dose of 10 mg / kg of Compound 1. Treatment was administered orally via intensive feeding once daily for three weeks (21 days). No recovery period was used. The medium administered was a deionized aqueous solution of 0.5% CMC / 1% Kolliphor P188, prepared weekly and refrigerated. Food consumption was not monitored, and veterinary examination was not performed unless necessary. Blood was drawn from each individual 7 days before the start of administration, 4 days before the start of administration, and on days 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 22 after dose initiation. Plasma cholesterol levels, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, and thyroid function were assessed. Total T4, total T3, free T4, free T3, and thyroid-stimulating hormone (TSH) were also assessed. Data were compiled and subjected to appropriate statistical analysis after 22 days.

[0284] Example 3: Second Alternative Dosing Study of Compound 1 in Dogs: The aim of this study was to investigate the effects of alternative dosing regimens on various clinical parameters in beagle dogs. Four, five, or six beagle dogs of single sex were randomly assigned to five groups. One group received only the daily dose of the medium. The test group received 1) daily dosing of the test product; 2) one day of dosing followed by a two-day rest period; 3) three consecutive days of dosing followed by a four-day rest period; or 4) four consecutive days of dosing followed by a three-day rest period. The dogs were from non-native populations. Treatment was administered orally via intensive feeding once daily for three weeks. No recovery period was used. The medium was a deionized aqueous solution of 0.5% CMC / 1% Lutrol F68, prepared weekly and refrigerated. Food consumption was not monitored, and veterinary examination was not performed unless necessary. Blood was drawn from each individual every two days or every 3–4 days. Plasma cholesterol levels, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, and thyroid function were assessed. Total T4, total T3, free T4, free T3, and thyroid-stimulating hormone (TSH) were assessed. Data were recompiled and appropriately statistically analyzed at 14 and 22 days.

[0285] Example 4: Alternative dosing study of compound 1 in humans. A phase 2, randomized, double-blind, placebo-controlled, multicenter study was conducted in patients with primary hypercholesterolemia and non-alcoholic fatty liver disease to evaluate the efficacy, safety, and tolerability of compound 1, with a 12-week dosing period followed by a 4-week drug-free period. The objectives of this study were: 1) to evaluate the effect of compound 1 on LDL-C after 12 weeks of treatment compared to placebo; 2) to evaluate the effect of compound 1 on hepatic fat content compared to placebo, measured by magnetic resonance imaging-proton density fat fraction (MRI-PDFF); 3) to evaluate the percentage change in liver stiffness from baseline at week 12, as assessed by MR elastography (MRE); 4) to evaluate changes in other lipid parameters, including total cholesterol (TC), triglycerides (TG), non-HDL-C, HDL-C, very low-density lipoprotein cholesterol (VLDL-C), apolipoprotein B (apo B), and lipoprotein(a), [Lp(a)]; and 5) to evaluate the safety and duration of lipid efficacy at 4 weeks post-treatment. Individuals with at least 10% hepatic fat, aged 18–75 years at screening, and with a body mass index (BMI) of 18.50–40.00 kg / m² were selected, as assessed by MRI-proton density fat fraction (PDFF). 2 At the time of screening, fasting serum LDL-C >130 mg / dL or lipid-lowering medication >110, free T3 and free T4 within the normal range, and baseline values ​​for AST, ALT, ALP, and total bilirubin established by at least two samples over at least several weeks (i.e., 4–12 weeks), with the level difference of these repeated measurements <20%. Individuals included in the study must also meet any three of the following criteria: 1) type 2 diabetes or HbA1c >5.7 on prescription medication; 2) triglycerides >150 mg / dL or on prescription medication for elevated triglycerides; 3) systolic blood pressure >130 mmHg or diastolic blood pressure >85 mmHg or on prescription medication for hypertension; 4) waist circumference >40 inches (men) or >35 inches (women); or 5) HDL <40 mg / dL (men) or <50 mg / dL (women), or on prescription medication for low HDL. Individuals were randomly assigned to one of four separate treatment groups: daily oral placebo (PO); daily compound 1 dose of 5 mg PO; daily compound 1 dose of 10 mg PO; and every other day (QOD) compound 1 dose of 10 mg PO. Compound 1 was administered in tablet form containing either 5 mg or 10 mg of compound 1.

[0286] Total thyroid function was assessed at different time points during treatment, at the end of treatment, and 4 weeks post-treatment. When assessing total thyroid function, total T4, total T3, free T4, free T3, and thyroid-stimulating hormone (TSH) were evaluated. Individuals were also monitored periodically for cardiac side effects, such as by monitoring blood pressure, C-reactive protein, cardiac troponin I (cTnI), creatine kinase (CK), and creatine kinase MB isoenzymes, via regular electrocardiograms and / or Holter monitoring, or by other appropriate means. Thyroid function, cardiac health, and clinical endpoints were assessed periodically during treatment. Final measurements were taken at 12 weeks of discontinuation of treatment and after a 4-week clearance period at 16 weeks. After 16 weeks, data were compiled and subjected to appropriate statistical analysis.

[0287] Example 5: Second-alternative dosing study of compound 1 in humans. A phase 2, randomized, double-blind, placebo-controlled, multicenter study was conducted in patients with primary hypercholesterolemia and non-alcoholic fatty liver disease to evaluate the efficacy, safety, and tolerability of compound 1, with a 12-week dosing period followed by a 4-week drug-free period. The objectives of this study were: 1) to evaluate the effect of compound 1 on LDL-C after 12 weeks of treatment compared to placebo; 2) to evaluate the effect of compound 1 on hepatic fat content compared to placebo, measured by magnetic resonance imaging-proton density fat fraction (MRI-PDFF); 3) to evaluate the percentage change in liver stiffness from baseline at week 12, such as by MR elastography (MRE); 4) to evaluate changes in other lipid parameters, including total cholesterol (TC), triglycerides (TG), non-HDL-C, HDL-C, very low-density lipoprotein cholesterol (VLDL-C), apolipoprotein B (apo B), and lipoprotein(a), [Lp(a)]; and 5) to evaluate the safety and duration of lipid efficacy at 4 weeks post-treatment. Individuals with at least 10% hepatic fat, aged 18–75 years at screening, and with a body mass index (BMI) of 18.50–40.00 kg / m² were selected, as measured by MRI-proton density fat fraction (PDFF). 2At the time of screening, fasting serum LDL-C >130 mg / dL or lipid-lowering drugs >110, free T3 and free T4 within the normal range, and baseline values ​​of AST, ALT, ALP, and total bilirubin were established from at least two samples over at least several weeks (i.e., 4–12 weeks), with the level difference of these repeated measurements <20%. Individuals included in the study must also meet any three of the following criteria: 1) type 2 diabetes or HbA1c >5.7 on prescription medication; 2) triglycerides >150 mg / dL or on prescription medication for elevated triglycerides; 3) systolic blood pressure >130 mmHg or diastolic blood pressure >85 mmHg or on prescription medication for hypertension; 4) waist circumference >40 inches (men) or >35 inches (women); or 5) HDL <40 mg / dL (men) or <50 mg / dL (women), or on prescription medication for low HDL. Individuals were randomly assigned to one of seven separate treatment groups: daily oral placebo (PO); a loading dose of 250 mg of compound 1, followed by a daily dose of 5 mg of compound 1 PO; a loading dose of 250 mg of compound 1, followed by a daily dose of 10 mg of compound 1 PO; a loading dose of 250 mg of compound 1, followed by a daily dose of 10 mg of compound 1 PO every other day (QOD); a loading dose of 100 mg of compound 1, followed by a daily dose of 5 mg of compound 1 PO; a loading dose of 100 mg of compound 1, followed by a daily dose of 10 mg of compound 1 PO; and a loading dose of 100 mg of compound 1, followed by a daily dose of 10 mg of compound 1 PO every other day (QOD). Compound 1 was administered in tablet form containing either 5 mg or 10 mg of compound 1.

[0288] Total thyroid function was assessed at different time points during treatment, at the end of treatment, and 4 weeks post-treatment. When assessing total thyroid function, total T4, total T3, free T4, free T3, and thyroid-stimulating hormone (TSH) were evaluated. Individuals were also monitored periodically for cardiac side effects, such as by monitoring blood pressure, C-reactive protein, cardiac troponin I (cTnI), creatine kinase (CK), and creatine kinase MB isoenzymes, via regular electrocardiograms and / or Holter monitoring, or by other appropriate means. Thyroid function, cardiac health, and clinical endpoints were assessed periodically during treatment. Final measurements were taken at 12 weeks of discontinuation of treatment and after a 4-week clearance period at 16 weeks. After 16 weeks, data were compiled and subjected to appropriate statistical analysis.

[0289] Example 6: Alternative dosing study of compound 1 in humans. A phase 1b, randomized, double-blind, placebo-controlled study was conducted in patients with primary hypercholesterolemia and non-alcoholic fatty liver disease to evaluate the efficacy, safety, and tolerability of compound 1, with a 12-week dosing period followed by a 4-week drug-free period.

[0290] In the current clinical study, the maximum cumulative weekly dose did not exceed 40 mg. In this phase 1b study, during a 4-week treatment period, doses of compound 1, including 5 mg daily and up to 40 mg weekly, produced dose- and / or time-dependent reductions in LDL-C and triglycerides. At a dose of 40 mg weekly, the projected systemic exposure to the active metabolite (AUC0-168hr [i.e., exposure over a week]) was 5570 ng. hr / mL. Pharmacokinetic modeling shows AUC 0-168hr is 18300 ng. hr / mL. Therefore, the estimated exposure for people receiving 40 mg once a week is approximately 3 times lower than the previously determined exposure of 5 mg / kg / day, with no observable adverse effect level (NOAEL).

[0291] Approximately 32 individuals were recruited and randomly assigned in a 6:2 ratio (Compound 1: Placebo) to one of the following treatment groups: (1) 5 mg of Compound 1 or placebo once daily, (2) 20 mg of Compound 1 or placebo once weekly, (3) 40 mg of Compound 1 or placebo once weekly, and (4) 10 mg of Compound 1 or placebo every other day. The primary endpoint was the percentage change in LDL-C from baseline up to day 29. A 20% reduction in LDL-C or a reduction in LDL-C to the normal range was considered clinically significant. Individuals were also monitored for adverse effects and / or clinically relevant changes in health status or laboratory analysis results. Changes in health status or laboratory results were screened for in each individual 28 days after the last administration of the test product.

[0292] Clinical parameters to be observed during the trial may include one or more of the following: physical examination; monitoring of concomitant medications; assessment / monitoring of hyperthyroidism / thyrotoxicosis; vital signs (sitting ≥5 minutes); weight; assessment of alcohol intake; assessment / monitoring of lifestyle habits; 12-lead ECG (supine ≥10 minutes); assessment / monitoring of medication adherence; AE / SAE assessment; and / or 24-hour Holter monitoring. A complete physical examination includes, but is not limited to: general appearance, skin, HEENT (including neck / laryngeal examination to assess thyroid), respiratory examination, cardiovascular assessment (including any heart rhythm and presence, abnormalities (e.g., gallop rhythm, murmurs, cardiomegaly)), abdominal examination, musculoskeletal, neurological examination to record the presence of mental, status, motor and sensory abnormalities (including reflex examination), gastrointestinal, genitourinary (if applicable), and / or any other assessment required to establish baseline status or assessment, symptoms, or adverse experiences. In addition, laboratory tests may be performed, including any one or more of the following: hematological tests, including platelet count, WBC and differential (% and absolute count), hematocrit, hemoglobin, RBC, mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), and mean corpuscular hemoglobin (MCH); lipid profiles (randomized and unknowingly), including LDL-C, non-HDL-C, VLDL-C (calculated), total cholesterol, triglycerides, HDL-C, Lp(a), and apo directly quantified by β. B; Serum chemicals, including BUN, creatinine, calcium, glucose, sodium, potassium, chloride, bicarbonate, phosphorus, uric acid, and creatine kinase; Liver panel, including AST (SGOT), ALT (SGPT), alkaline phosphatase (ALP), and bilirubin (total, direct, and indirect); Additional liver tests, including INR / PT, total protein, albumin, sex hormone-binding globulin (SHBG) and thyroxine-binding globulin (TBG); Thyroid panel (randomized and uninformed), including TSH, total T4, and free T4. T4, and total free T3; cardiac biomarkers, including CK, CK-MB, and cardiac troponin I (cTnI); urinalysis, including color, appearance, specific gravity, pH, protein, leukocyte esterase, glucose, ketones, bilirubin, urobilinogen, nitrates, and microscopic analysis if abnormal; other samples, including FSH (postmenopausal women), pregnancy serum, HBsAg serology, HCV and HIV, HbA1c, fasting insulin and HOMA glucose, alcohol and drug tests, and PK samples. Other clinical parameters may be monitored or evaluated as needed.

Claims

1. A method for treating a disease or condition, comprising the following steps in sequence: Administer the first-day dose of the compound to the individual in need for the first day; Discontinue the administration of the compound, or administer the second day dose of the compound on the second day, wherein the second day dose of the compound is less than the first day dose; as well as The third dose of the compound was administered to the individual on the third day. The diseases or conditions described are selected from obesity, hyperlipidemia, hypercholesterolemia, diabetes, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, atherosclerosis, cardiovascular disease, hypothyroidism, and thyroid cancer; and The compound described above has the structure of Formula I: in: G is selected from -O-, -S-, -S(=O)-, -S(=O)2-, -Se-, -CH2-, -CF2-, -CHF-, -C(O)-, -CH(OH)-, -CH(C1-C4 alkyl)-, -CH(C1-C4 alkoxy)-, -C(=CH2)-, -NH- and -N(C1-C4 alkyl)-; T is selected from -(CR a 2) k -, -CR b =CR b -(CR a 2) n -, -(CR a 2) n -CR b =CR b -, -(CR a 2)-CR b =CR b -(CR a 2)-, -O(CR b 2)(CR a 2) n -, -S(CR b 2)(CR a 2) n -, N(R c )(CR b 2)(CR a 2) n -, N(R b ))C(O)(CR a 2) n , -C(O)(CR a 2) m -, -(CR a 2) m C(O)-, -(CR a 2)C(O)(CR a 2) n , -(CR a 2) n C(O)(CR a 2)- and -C(O)NH(CR b 2)(CR a 2) p -; k is an integer from 1 to 4; m is an integer from 0 to 3; n is an integer from 0 to 2; p is an integer between 0 and 1; Each R a Independently selected from hydrogen, optionally substituted -C1-C4 alkyl, halogen, -OH, optionally substituted -O-C1-C4 alkyl, -OCF3, optionally substituted -S-C1-C4 alkyl, -NR b R c Optionally substituted -C2-C4 alkenyl and optionally substituted -C2-C4 ynyl; the condition being that when one R a When C is connected via O, S, or N atoms, other R atoms connected to the same C atom... a It is hydrogen, or linked via carbon atoms; Each R b Independently selected from hydrogen and optionally substituted -C1-C4 alkyl groups; Each R c Independently selected from hydrogen and optionally substituted -C1-C4 alkyl, optionally substituted -C(O)-C1-C4 alkyl and -C(O)H; R 1 and R 2 Each is independently selected from halogens, optionally substituted -C1-C4 alkyl groups, optionally substituted -S-C1-C3 alkyl groups, optionally substituted -C2-C4 alkenyl groups, optionally substituted -C2-C4 alkynyl groups, -CF3, -OCF3, optionally substituted -O-C1-C3 alkyl groups, and cyano groups; R 6 R 7 R 8 and R 9 Each is independently selected from hydrogen, halogen, optionally substituted -C C1-C4 alkyl, optionally substituted -S-C1-C3 alkyl, optionally substituted -C2-C4 alkenyl, optionally substituted -C2-C4 ynyl, -CF3, -OCF3, optionally substituted -O-C1-C3 alkyl and cyano; or R 6 And T together with the carbons they are attached to form including independently selected from -NR i -, -O-, and -S- rings of 0 to 2 heteroatoms of 5 to 6 atoms, provided that when there are 2 heteroatoms in the ring and both heteroatoms are different from nitrogen, the two heteroatoms must be separated by at least one carbon atom; and X is separated by a direct bond to the ring carbon, or by a -(CR) bond to the ring carbon or ring nitrogen. a 2) - or - C(O) - connected to the ring; R i Selected from hydrogen, -C(O)C1-C4 alkyl, -C1-C4 alkyl, and -C1-C4 aryl; R 3 and R 4 Independently selected from hydrogen, halogen, -CF3, -OCF3, cyano, or optionally substituted -C1-C 12 Alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl group, -SR d -S(=O)R e -S(=O)2R e -S(=O)2NR f R g -C(O)OR h -C(O)R e -N(R) b )C(O)NR f R g -N(R) b )S(=O)2R e -N(R) b )S(=O)2NR f R g and -NR f R g ; Each R d Selected from the optional substitution -C1-C 12 Alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -(CR) b 2) n aryl, optionally substituted -(CR b 2) n cycloalkyl, optionally substituted -(CR b 2) n Heterocyclic alkyl groups and -C(O)NR f R g ; Each R e Selected from the optional substitution -C1-C 12 Alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -(CR) a 2) n aryl, optionally substituted -(CR a 2) n cycloalkyl and optionally substituted -(CR a 2) n Heterocyclic alkyl groups; R f and R g Each is independently selected from hydrogen, with optional substitution of -C1-C. 12 Alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -(CR) b 2) n aryl, optionally substituted -(CR b 2) n cycloalkyl and optionally substituted -(CR b 2) n Heterocyclic alkyl, or R f and R g They can together form optionally substituted heterocycles, which may contain elements selected from O and NR. C The second heterogroup of S, wherein the optionally substituted heterocycle may be selected from optionally substituted -C1-C4 alkyl, -OR b Oxygenated, cyano, -CF3, optionally substituted phenyl groups and -C(O)OR h 0-4 substituents; Each R h Selected from the optional substitution -C1-C 12 Alkyl, optionally substituted -C2-C 12 alkenyl, optionally substituted -C2-C 12 alkynyl, optionally substituted -(CR) b 2) n aryl, optionally substituted -(CR b 2) n cycloalkyl and optionally substituted -(CR b 2) n Heterocyclic alkyl groups; R 5 Selected from -OH, optionally substituted -OC1-C6 alkyl groups, OC(O)R e -OC(O)OR h -F, -NHC(O)R e -NHS(=O)R e -NHS(=O)2R e -NHC(=S)NH(R) h ) and -NHC(O)NH(R h ); X is P(O)YR 11 The R 11 ; Y and Y' are each independently selected from -O- and -NR. v -; When Y and Y' are -O-, R connected to -O- 11 Independently selected from -H, alkyl, optionally substituted aryl, optionally substituted heterocyclic alkyl, optionally substituted CH2-heterocyclic alkyl wherein the cyclic moiety contains carbonate or thiocarbonate, optionally substituted -alkylaryl, -C(R z )2OC(O)NR z 2. -NR z -C(O)-R y -C(R) z )2-OC(O)R y -C(R) z )2-OC(O)OR y -C(R) z )2OC(O)SR y ,-alkyl-SC(O)R y -alkyl-SS-alkylhydroxyl and -alkyl-SSS-alkylhydroxyl; When Y and Y' are -NR v - when, then with -NR v -Connected R 11 Independently selected from -H, -[C(R) z )2] q -COOR y -C(R) x )2COOR Y -[C(R) z )2] q -C(O)SR y and -cycloalkylene-COOR y ; When Y is -O- and Y' is NR v When, R connected to -O- 11 Independently selected from -H, alkyl, optionally substituted aryl, optionally substituted heterocyclic alkyl, optionally substituted CH2-heterocyclic alkyl wherein the cyclic moiety contains carbonate or thiocarbonate, optionally substituted -alkylaryl, -C(R z )2OC(O)NR z 2. -NR z -C(O)-R y -C(R) z )2-OC(O)R y -C(R) z )2-OC(O)OR y -C(R) z )2OC(O)SR y ,-alkyl-SC(O)R y -alkyl-SS-alkylhydroxyl and -alkyl-SSS-alkylhydroxyl; and with -NR v -Connected R 11 Independently selected from H, -[C(R) z )2] q -COOR y -C(R) x )2COOR y -[C(R) z )2] q -C(O)SR y and -cycloalkylene-COOR y ; Or when Y and Y′ are independently selected from -O- and NR v When, then R 11 and R 11 Together they are -alkyl-SS-alkyl- to form cyclic groups, or R 11 and R 11 Together is a group: in: V, W, and W' are independently selected from hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocyclic alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-ynyl. Alternatively, V and Z can be linked together by another 3-5 atoms to form a cyclic group containing 5-7 atoms, where 0-1 atoms are heteroatoms and the remaining atoms are carbon atoms. The cyclic group containing 5-7 atoms is replaced by a hydroxyl, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy group linked to the carbon atom. The carbon atom is three atoms away from the two Y groups linked to the same phosphorus. Alternatively, V and Z can be linked together by another 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and the cyclic group is fused with aryl groups at the β and γ positions of Y connected to phosphorus. Alternatively, V and W can be linked together via three additional carbon atoms to form an optionally substituted cyclic group containing six carbon atoms, and substituted by a substituent selected from hydroxyl, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy linked to one of the carbon atoms, wherein the carbon atom is three atoms away from the phosphorus-linked Y. Alternatively, Z and W can be linked together by another 3-5 atoms to form a cyclic group, where 0-1 atoms are heteroatoms, the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl. Alternatively, W and W′ can be linked together by another 2-5 atoms to form a cyclic group, where 0-2 atoms are heteroatoms, the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl. Z is selected from -CHR z OH, -CHR z OC(O)R y -CHR z OC(S)R y -CHR z OC(S)OR y -CHR z OC(O)SR y -CHR z OCO2R y -OR z -SR z -CHR z N3, -CH2-aryl, -CH(aryl)OH, -CH(CH=CR) z 2) OH, -CH(C≡CR z )OH、-R z -NR z 2. -OCOR y -OCO2R y -SCOR y -SCO2R y -NHCOR z -NHCO2R y -CH2NH-aryl, -(CH2)q-OR z and -(CH2)q-SR z ; q is an integer of 2 or 3; Each R z Selected from R y and -H; Each R y Selected from alkyl, aryl, heterocyclic alkyl, and aralkyl groups; Each R x Independently selected from -H and alkyl, or R x and R x Together they form cycloalkyl groups; and Each R v Selected from -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl and lower acyl groups; And its pharmaceutically acceptable salts and prodrugs; and pharmaceutically acceptable salts of said prodrugs.

2. The method of claim 1, wherein the compound to be applied comprises one or more compounds having a structure selected from: 、 、 ,as well as ； Or a salt acceptable for its medication.

3. The method of claim 1, wherein the first day dose and the third day dose are the same.

4. The method of claim 1, wherein the third-day dose is less than the first-day dose.

5. The method of claim 1, wherein the second-day dose and the third-day dose are the same.

6. The method of any one of claims 1 to 4, wherein the third-day dose is greater than the second-day dose.

7. The method of any one of claims 1 to 6, wherein the number of the first day and the number of the third day are the same.

8. The method of any one of claims 1 to 7, wherein the number of the first day, the number of the second day, and the number of the third day are the same.

9. The method of any one of claims 1 to 6, wherein the third number of days is less than the first number of days.

10. The method of any one of claims 1 to 9, wherein the number of the first day, the number of the second day, and the number of the third day are independently selected from 1 to 90.

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