TW201210602A - Phosphorus-containing prodrugs and their therapeutic use - Google Patents

Abstract

The present invention relates to phosphorus-containing prodrug of formula I: wherein the symbols are as defined in the specification, and of pharmaceutically acceptable salts and prodrugs thereof, for effectively delivering biologically active phosphonates including nucleoside phosphonates and nucleoside monophosphates in biological system. The present invention also relates to the therapeutic uses of compound of formula I.

Description

201210602 VI. INSTRUCTIONS: This patent application claims the priority of the US provisional application 6 1 /2 75,72 8 (application dated September 1, 2000). The disclosure of the above-referenced application is hereby incorporated by reference in its entirety. TECHNICAL FIELD OF THE INVENTION The present invention relates generally to phosphorus-containing prodrugs and their therapeutic use for the treatment and prevention of viral infections and cancer, particularly hepatitis infections and other liver diseases including cancer. [Prior Art] The toxicity and pharmacological side effects caused by the agent are usually caused by the interaction or interference of the agent or agent metabolite with the metabolic pathway required for the growth or maintenance of normal cells in the tissue. • In many cases, it is difficult to achieve the desired pharmacological effect due to dose-limiting toxicity or unadjusted drug concentration in the subject tissue. Nucleoside analogs have been used as antiviral and anticancer agents. In the former, the pharmacological specificity of the viral-encoded nucleoside kinase and NA (DNA and RNA) polymerase was less developed than that of the cytogene. Nucleotide kinases phosphorylate nucleosides to their corresponding 5'-monophosphates, which are further converted to their di- and tri-phosphates by cellular nucleotide kinases. The pseudonucleoside triphosphate selectively interacts with the viral NA polymerase; is incorporated into the extended NA, and in many cases terminates the ΝΑ chain (when the 3' position has no sulfhydryl group), or contains a nucleoside similar These defects of the substance lose their normal function. In the latter, rapidly differentiated cancer cells pour pseudonucleotides into nucleic acids at a higher frequency than normal cells. In any case, the nucleoside agent is activated by the conversion of the cellular kinase by the monophosphate and the diphosphate to its corresponding triphosphate. -4- 201210602 Herpesvirus is a typical DNA virus 'glycosidase kinase that phosphorylates nucleoside analogs quite selectively, inhibiting normal functional virulence nucleic acids after further kinase conversion to its corresponding triphosphate Manufacturing. Human immunodeficiency virus (HI V) and hepatitis B (HBV) are DNA-dependent RNA viruses, and the viral letter of the RNA is transcribed to DNA (reverse transcription), and then RNA is produced from DNA (messenger RNA). The nucleoside inhibitors are almost all reverse transcription. Although a small number of potential nucleoside agents are occurring, they have not been treated very well for hepatitis C virus (HCV) infection. HCV is an RNA-dependent RNA virus, and in all cases the glycoside agent is activated to the corresponding nucleoside triphosphate. It has been known that some nucleosides are weakly active, simply because they are not effective for kinase phosphorylation or not at all, and like some inactive glycosides, when chemically converted to their triphosphates, they become potent and effective in vitro. Fight against certain viruses. Nucleoside phosphates (nucleotides) are not normally used as agents because they are dephosphorylated by membrane nucleoside other hydrolases before entering the cell, or too polar to enter the cell. To improve the biological activity of nucleosides, the phosphate prodrugs have been thoroughly investigated for their potential to overcome the rate-limiting first step of phosphorylation, and the aminophosphate prodrug route has been shown to be over-phosphorylation. The rate-limiting first step is an efficient method for the biotransformation of a non-activated nucleoside to an activated nucleotide ester [/. Med. 5 0 (22), 5463 - 2007]. Nucleoside phosphoramidates have been reported to efficiently transport nucleoside 5' acid esters into the liver (WO 2008/1 2 1 634; WO 2008/082601 J 2008/082602). In recent years, there have been many patent applications that reveal that the use of virulence cells is a messenger. The nuclear nucleus is nucleated and the acid is used. Near-speed monophosphorus 5470, -monophosphorus ^ WO amine group 201210602 phosphate ester as a prodrug to transport nucleoside monophosphate to tissues, especially to the liver (us 6455513, WO 2009/052050, WC) 2008/121634, WO 200 8/0 8 3 3 1 0 1 , WO 2 00 8/0 622 06, WO 2007/00293 1, WO 200 8/0 8 5 5 0 8 ' W Ο 2 0 0 7 / 0 9 5 2 6 9 ' W Ο 2 0 0 6 / 0 1 2 0 7 8 ' WO 2006/100439). The nucleoside monophosphate can be further phosphorylated to a diphosphate followed by a biologically active triphosphate. However, due to the potential neurotoxicity and liver and kidney damage caused by the phenol released by the prodrug, the amino-based acid ester pathway based on McGuigan technology (US 645 5 5 13) is limited (Carcinogenesis 1993, 14: 2477-24 86 ; Mutat. Res. 1 99 1, 249,1 : 2 Ό 1 - 2 0 9). Aminophosphates of nucleosides generally exhibit maximum biological activity in cell line assays because they rapidly release nucleosides or nucleotides into cells. It has been reported that d4T amino phosphate prodrugs cannot be detected in plasma after oral administration (Drug Metab. Dispos. 2001, 29, 1035). Amino phosphates are stable in gastric juice and are absorbed in the stomach, which rapidly hydrolyzes in the blood. On the other hand, the amino phosphate is rapidly decomposed into ala-d4T-MP in the intestinal fluid, and this metabolite can be absorbed in the intestinal tract and further metabolized to produce nucleoside d4T. Another possibility is that the metabolite is not effectively absorbed in the intestine due to its polar nature. Therefore, the bioavailability of such amino-pureate prodrugs is relatively low, most likely due to their vinegar-sensitive ester groups. For example, GS-7340 is a isopropyl propyl sulfhydryl monodecyl phenyl monoester of tenofovir (ten0f0vir), which is bioavailable in male rice compared to the intravenous administration of tenofovir. The beagle dog is 17% (Gilead Sciences, Antimicrob. Agents Chemother. 2005 49, 1898) » 201210602 The nucleoside phosphonate diamine prodrug has also been studied and, in some cases, this The pathway presents improved efficacy and/or pharmacokinetic profile. However, only very limited studies have been obtained on the application of diammonium phosphate to nucleosides (anti-HI V agents, FLT, AZT; Polish J. Chem. 1 993, 67, 75 5 ; Drug Design and Discovery 1 99 5 , 1 3, 4 3 ; Antiviral Chem.

Chemother. 1992, 3, 107 ; 1 9 9 1, 2, 3 5 ; 1995, 6, 50). The PMEA diamine precursor does not provide satisfactory bioavailability of the parent drug, probably because it is more polar than tenofovir phosphinate (J. Med. Chem. 200 8, 5 1 , 4 3 3 1; Antimicrob. Agents Chemother. 2 0 0 5, 49, 1898) ° Many diseases can cause liver disorders, including hepatitis infections (especially hepatitis B and C viruses), liver cancer, and metabolic diseases, such as Diabetes, hyperlipidemia, atherosclerosis, and obesity. For the treatment of these diseases, the liver-based prodrug can effectively reduce the exposure of the agent to other organs, thereby reducing the side effects associated with the drug. For example, 9-(2-phosphonium methoxyethyl) adenine (PME A) exhibits a very low amount of distribution, presumably because of its high negative charge. In humans, due to the presence of an organic anion conveyor on the basal side of the tubular cells, it helps to promote renal clearance of PMEA, with 98% of the drug being excreted by the kidneys. Ρ Μ E A treatment is associated with severe nephrotoxicity, probably because PMEA and related phosphorylated forms are exposed and accumulate in the kidneys. Known aminophosphates and diamine precursors of nucleotides or nucleosides release the parent drug in a similar mechanism (the following reaction formula, J_ Med. Chem. 2008, 51, 2 3 2 8). For example, hydrolysis of an ester prodrug (1) begins with an esterase, and the carboxylic acid (2) undergoes intermolecular cyclization and phenol substitution to form a transient five-membered ring intermediate (3), 201210602

Activation of the arylaminophosphate prodrug is hydrolyzed to Phosphoramidic acid (4). The cleavage of the monoamidamine into the active form (5) can be catalyzed by a second enzyme (aminophosphatase) or by simple hydrolysis in the cell compartment of the acid (Molecular Pharmacol 1 999, 56, 69 3 ) ° Efforts to search for phosphonate prodrugs that are cleaved by an esterase-independent mechanism have led to the discovery of two prodrug types that have progressed to human clinical trials, namely diphenyl esters and HepDirect prodrugs (J. Med. Chem. 1 994, 37, 498; J. Am. Chem. Soc. 2004, 1 26, 5 1 54; J. Pharmacol. Exp. Ther. 2005, 312, 554). Dibenzyl esters have also been studied, but the simple unsubstituted benzyl ester cleavage is too slow to be used as a prodrug (Bioorg. Med. Chem. Lett. 2007, 17, 3412). Erion et al. disclose cyclic phosphonate or phosphonate prodrugs which are stable in the presence of esterases and which increase the delivery of specific agents in the liver (Erion, M et al US 73037 39 and its reference). The prodrug of E r i ο η is activated in the liver via P 4 50 . However, the clinical application of this pathway may be limited by the potentially harmful side effects caused by aromatic metabolites, and the efficiency of releasing biologically active phosphates or phosphonates is rather uncertain. 201210602 Recently, bis[(p-methoxy)benzyl]phosphonate prodrugs have been reported to exhibit improved stability and increased cell permeability (Bioorg. Med. Chem. Lett. 2007, 17, 34 12). However, there is no further detailed explanation. Since benzyl alcohol and its oxidative metabolite (benzoic acid) are relatively non-toxic compounds, we have a phosphate or phosphonate prodrug with a benzyl group which has a linkage to a benzyl group to a phosphate or phosphonate. The bond is unstable. These prodrugs surprisingly release benzyl moieties in cells, possibly involving dealkylation controlled by cytochrome P(450) (CYP) enzymes (J. Med. C he m. 1967, 10,861; J. Chem. Soc. Perkin Trans. 1992, 2, 1 1 4 5 ) or other mechanisms or simple hydrolysis in the more acidic subcellular compartment. Accordingly, the present invention (1) provides a novel nucleoside, a nucleotide, a C-nucleoside, a C-nucleotide aminophosphate and an aminophosphonate prodrug, a phosphonate, and an alcohol-containing agent, And (2) by using the aminophosphate and aminophosphonate prodrugs of the present invention, the delivery of the parent drug to the cells, particularly into the liver cell target, is effectively achieved. These prodrugs herein are capable of combating esterases. SUMMARY OF THE INVENTION The present invention relates to a compound for use in enhancing therapeutic potential, particularly for cancers such as leukemia, viral infections (including HIV, HBV and HCV) and liver disorders, including liver cancer and metabolic diseases, for example Therapeutic potential of diabetes, hyperlipidemia, atherosclerosis and obesity. The present invention provides nucleoside amino phosphates and aminophosphonate compounds of various therapeutic agents, including methods for their manufacture and use in the treatment of various conventional disorders, particularly liver disorders. In some embodiments, 201210602 can be used to administer a high concentration of therapeutic agent in the liver. In a specific embodiment, the compound is a substituted benzylamino phosphate and an aminophosphonate. As used herein, 'a nucleoside amino phosphate or an amino phosphonate as a therapeutic agent' includes nucleosides derived from amino phosphates and aminophosphonates (a non-cyclic nucleoside and C-nucleus) The therapeutic agent, the amino phosphate and the uric acid vinegar having a benzyl group and the following substituents (but not limited thereto), such as an amine group, a CrCw decyloxy group, a Cl_c2G alkyl group, an aryl group, C| -C2G alkoxy, aryloxy or aryloxy can be optionally substituted. The therapeutic agent can, for example, be an antiviral agent that includes or has been derivatized to include a reactive group (e.g., a trans-group) to attach an amino phosphate, or an amine phosphonate group. Such therapeutic agents include, but are not limited to, nucleosides, nucleoside analogs, including acyclic nucleosides, c-nucleosides, and alcohol-containing agents. In some embodiments, aminophosphates of nucleosides and nucleotide analogs, such as 1,-, 2,-, 3,- and 4'-branched or disubstituted nucleosides, are also provided. Amino phosphate. Effective amounts of such compounds can be administered to treat infectious diseases, liver disorders, including cancers and deep-rooted diseases, such as hepatitis B and hepatitis C infections, including resistant strains thereof. In certain embodiments, although not limited to any theory, it is likely that the parent drug is primarily obtained in the liver by selective metabolism of an amino phosphate or an amino phosphonate compound. Therefore, the parent drug can accumulate in the host liver. By selectively calibrating and activating the compound in the liver, the undesired distribution of the active compound in the gastrointestinal tract can be reduced. In addition, the therapeutic amount of active compound at the site of liver infection can be increased. In certain embodiments, the monophosphate or phosphonate of the parent nucleoside (or nucleoside derivative) agent is formed in the liver by the metabolism of an amino phosphate or an amino phosphonate compound-10-201210602, such that Phosphate or phosphonate forms and accumulates in the host liver. Thus, in certain embodiments, the amino phosphate or aminophosphonate disclosed herein provides a stabilized phosphate or phosphonate prodrug of a nucleoside or a nuclear analog of the liver. In certain embodiments, 'where the compound needs to be activated by triphosphorylation, this advantageously removes the need for an initial phosphorylation step, promotes easier formation of the active triphosphate', its inhibitory enzyme, and enhances the nucleus. The overall activity of the glucoside or nucleoside analog. In certain embodiments, the amine phosphate or alanine phosphonate prodrugs of the alcohol-containing agents disclosed herein effectively deliver the parent drug into the liver, which increases the bioavailability and/or drug motility of the parent drug, and Reduce the exposure of the parent drug to other organs. - Some nucleosides are biologically inactive simply because they are not phosphorylated by kinases. In certain embodiments, prodrugs of the invention derived from such nucleosides can become biologically active because the prodrug directly transports the nucleoside monophosphate to limit the first step by the rate of phosphorylation. Without being bound by any theory, in one embodiment, an aminophosphate or an aminophosphonate of a nucleoside, such as 5-fluoro-2'-deoxyuridine, which is selective for hepatic administration after oral administration is provided. Concentrated and metabolized in liver cells to produce 5'-monophosphate, which inhibits thymidine synthetase. Thus, the potential therapeutic dose can be reduced as compared to the administration of the parent nucleoside molecule. These prodrugs are effective in reducing the decomposition of 5-fluoro-2'-deoxyuridine by pyrimidine nucleoside phosphorylase into a more toxic 5-fluorouracil (5-f luorour acil) so that these prodrugs can be administered orally. Cast and replace perfusion. Thus, in some embodiments, after oral administration of the amino phosphate and alanine phosphonate compounds described herein, the compound can advantageously be concentrated in liver cells of the -11 - 201210602 scale and converted into The monophosphate or sulphate is then further phosphorylated to produce its therapeutic effect. Because such methods are capable of accumulating the nucleoside phosphate or phosphonate compounds described herein in the host liver, the methods described herein can be used, for example, to treat and/or prevent liver disease or disorders, such as liver cancer, hepatitis B or C. Hepatitis. Also provided is a method of treating a liver disorder comprising administering an effective amount of a compound provided herein, optionally in a pharmaceutically acceptable carrier, alone or in combination with another therapeutically effective agent, or alternatively with other therapeutically effective agents. versus. The benzyl ester of this type of aminophosphate or aminophosphonate of the parent drug has been found to be a potent therapeutic agent by virtue of the instability of the benzyl-OP bond obtained by the substituent on the phenyl ring. It directly transports the parent drug into the tissue. The prodrugs of the present invention having high lipophilicity rapidly pass through the cell membrane to improve the pharmacokinetics and/or bioavailability of the parent drug. These prodrugs can be activated by P450 and/or other enzymes enriched in the liver. This compound can also be used in some embodiments to increase delivery of the parent drug to the liver. Providing the form of aminophosphate and alanine phosphonate compounds of various therapeutic agents of the invention, and their use in treating hepatitis infections (especially hepatitis B and C viruses) and liver disorders, including cancer, malaria And fibrotic and metabolic diseases such as diabetes, hyperlipidemia, atherosclerosis and obesity. [Embodiment] In one embodiment, the present invention provides a compound of formula I: -12- 201210602 Ο Μ^Χ—ρ—q R1

Or a pharmaceutically acceptable prodrug, metameric or polymorphic form thereof, wherein: X is selected from the group consisting of oxygen (oxime), CH2' but not limited thereto to represent nucleoside or acyclic if X is oxygen (0), Μ -ΧΗ is Μ-ΟΗ, nucleoside, C-nucleoside or alcohol-containing compound; Μ-0-Ρ(0)(0Η)2 represents biological activity of nucleoside or acyclic nucleoside or c_nucleoside Monophosphate; MX can be a cyclic or acyclic system; including the formula Μ-Χ-Ρ(0)(0Η) 2 is a biologically active phosphonate M-CH2-P(0)(0H)2 Nucleoside phosphonate, if X and p are linked by a P bond; R1 is selected from the group consisting of a thiol group, a decyloxy group, an alkoxy group, an aryloxy group, an aryloxyalkyl aryloxy group, an amino acid residue, Benzylamino group, alkylamino group, aryl group, alkylarylamino group, arylalkylamino group, dialkylamino group, ~amino group, but not limited to: dialkylamino group The dialkyl group may form a ring, and & ^ is preferably a 4 to 7 membered ring, such as pyrrolidine, all of which may be optionally substituted; R2 is selected from the group consisting of anthracene, alkyl, aryl, alkynyl, alkenyl, cycloalkane a heterocyclic group or a heteroaryl group having one to three hetero atoms (for example, 0, S, fluorene) And all of them may be optionally substituted; 201210602 R3 is a substituent, at least one such substituent is attached to the phenyl ring at various positions, preferably at the 2 and/or 4-position, which is selected from R2C〇〇 (醯Oxy), mercapto-NH, CH3, methoxy, alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkoxy, cycloalkylamino, aryl, aryloxy, aryl Amino group, arylalkyl group, but not limited thereto, all of which may be optionally substituted; Y represents oxime or one to three substituents at various positions on the benzene ring, including halogen (I, Cl, Br, F) ), CN, azido-oxime, mercaptoamine, alkoxy, alkylamino, alkenyl, alkenylamino, alkenyloxy, alkynyl, alkynyloxy, alkynylamino, An arylalkoxy group, an arylalkylamino group, an alkoxy-based group, but not limited thereto, all of which may be optionally substituted; R1 and [MX] may together form a cyclic phosphate such as nucleoside 3, , 5, _ ring disc acid ester; the amine group and / or hydroxyl group in MX can be selectively protected; the compound of formula I can be a non-image isomer or the non-image isomerism caused by the palmitic phosphorus center The mixture, for example Ia and 1 b:

〇 R2 Μ—Χ»-ρ—(

Π -14- 201210602 wherein: Z is a substituent at various positions of the phenyl ring selected from the group consisting of H, F, Cl, Br, I, azide, CN, CONH2, COOR2, OR2' SR2, COSR2' O -COR2, NH2, NH-fluorenyl, NR2-indenyl, but not limited thereto, all of which may be optionally substituted; R4 is selected from the group consisting of R2C〇〇 (decyloxy), fluorenyl-NH, alkyl, alkane Oxyl, alkylamino, cycloalkyl, cycloalkoxy, cycloalkylamino, aryl, aryloxy, arylamino, arylalkyl, but not limited thereto, all of which are R2 is selected as defined above; R5 is selected from the group consisting of R2CO (fluorenyl), CH3, alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, but not limited thereto, all of which may be The choice is replaced. For example, the compound of formula I is preferably a compound of formula: η

Μ—X— It will be understood by those skilled in the art that the compound of formula I can be prepared via, for example, a reaction such as condensation or dehydration on the hydroxyl group of the agent. Such derivatives can be prepared, for example, by removing a hydrogen group from the hydroxyl group of the agent, for example, in a dehydration reaction. With regard to phosphonates, such as tenofovir, the two hydroxy groups are derivatized into bis-amino phosphonates. Provided herein are compounds, compositions, and methods for treating hepatitis infection (HBV and HCV) and liver disorders, such as treating cancer, or metabolic diseases such as diabetes, hyperlipidemia, atherosclerosis, and obesity. •15- 201210602 When referring to a compound provided herein, the following terms have the following meanings unless otherwise indicated. The term "alkyl" as used herein, includes saturated straight chain, branched or cyclic, usually (:, to C2G, optionally substituted hydrocarbons, specifically methyl, cf3, cci3, cfci2 Cf2ci, ethyl, ch2cf3, cf2cf3, propyl, isopropyl, cyclopropyl, etc. Non-limiting examples of groups in which an alkyl group may be substituted are selected from halogen (fluoro, chloro, bromo or iodo), hydroxyl, amine a group consisting of an alkyl group, an alkylamino group, an arylamine group, an alkoxy group, an aryloxy group, a nitro group, a cyano group, etc. "Alkenyl" includes a monovalent olefinic unsaturated hydrocarbon group, in certain embodiments Having up to 11 carbon atoms which may be straight or branched and having at least 1 or 1 to 2 positions of ethylenic unsaturation. Exemplary alkenyl groups include ethenyl (-CH = CH2), N-propenyl (_CH2CH = CH2), isopropyl (-C(CH3) = CH2), vinyl (vinyl) and substituted ethylene, etc. "fast base" includes acetylenically unsaturated hydrocarbons, In certain embodiments, there are up to 11 carbon atoms, which may be straight or branched, and have at least i or 1 to 2 positions. Non-limiting examples of alkynyl groups include acetylenic, ethynyl, propyl propyl, etc. As used herein, the term "aryl" includes phenyl, biphenyl or naphthyl. 'and preferably phenyl. The term includes both substituted and unsubstituted groups. The aryl group may be substituted with any of the groups', including ~ or more selected from halo (fluoro, chloro, bromo or iodo), alkyl , hydroxy, amine, alkylamino, arylamine, alkoxy, aryloxy, nitro, cyano, sulfoxime sulfato, phosphino ), a group of phosphate (ph〇sphate) or -16 - 201210602 phosphonate (ph〇Sph〇n〇xy), but not limited thereto, and may be unprotected or protected as needed. "Circular base" includes hydrocarbons of the 3-7-membered ring, such as cyclopropyl, all of which may be optionally substituted. "Heterocycle" includes 3- to 3, for example, 0, S, N heteroatoms in the ring. a 7-membered ring carbon compound, all of which may be optionally substituted. "Heteroaryl" includes an aromatic ring containing 1-3 hetero atoms such as 0, S, N, for example Alkyl and pyrimidinyl. "Alkoxy" includes -OR group, wherein R is alkyl. In particular, alkoxy' includes n-pentyloxy, n-hexyloxy, 12. dimethylbutoxy and the like. The "base group" includes a residue of -C(O)-homolyl, wherein the alkoxy group is as defined herein. "Amine" includes -NH2 residue. "Carbonyl" includes -C(0)0H residue. The term "alkylamino" or "arylamino" includes the radicals each having one or two alkyl or aryl substituents. "Halogen" or "halo" includes chlorine (C1), bromine (Br). , fluorine (F) or iodine (I). "Single-yard amine group" includes fluorenyl-NHR'-, wherein R is selected from a hospital group or an aryl group. "Thioalkyl" includes -SR groups wherein R is alkyl or aryl. The term "protected" as used herein, unless otherwise indicated, indicates that a group is added to an oxygen, nitrogen or phosphorus atom to prevent further reaction or for other purposes. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis. -17- 201210602 The term "nuclear" includes natural or modified nucleosides, acyclic nucleosides and C-nucleosides. The term "C-nucleoside" means a nucleoside in which a glycosyl bond is attached to a carbon on a modified nucleobase, rather than a nitrogen of a nucleoside (see the reference for c_ nucleoside reviews for details): Chemistry of Nucleosides and Nucleotides by Leroy B Townsend 1 994,Science, Chapter 5

The Chemistry of C-nucleosides, Kyoichi A Watanabe pp421). The C-nucleoside is not limited to the compounds exemplified in the review. "Pharmaceutically acceptable salts" include any of the salts of the compounds provided herein that retain their biological properties and are non-toxic or otherwise undesirable for medical use. This salt can be derived from various organic and inorganic counter-ions known in the art. The salts include: (1) acid addition salts with organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, aminosulfonic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid , propionic acid, caproic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, Tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzhydryl)benzoic acid, picric acid, cinnamic acid, mandelic acid, citric acid, lauric acid, methanesulfonic acid, ethanesulfonic acid, 1,2-B - Disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2 .2]-octyl-2-ene-p-formic acid, glucoheptanoic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, benzoic acid, glutamic acid, hydroxyl An acid such as naphthoic acid, salicylic acid, stearic acid, cyclohexylaminosulfonic acid, quinolinic acid or muconic acid; or (2) a salt formed by the presence of an acidic proton in the parent compound Either (a) or (b) '(a) -18 - 201210602 is replaced by a metal ion such as an alkali metal ion, an alkaline earth metal ion, an aluminum ion or an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide or hydrogen Potassium oxide, hydrogen hydroxide, magnesium hydroxide, aluminum hydroxide, lithium hydroxide, zinc hydroxide and barium hydroxide 'ammonia, or (b) coordinated with an organic base, such as an aliphatic, alicyclic or aromatic organic Amines such as ammonia 'methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, auramine, choline, n, N'-two-segment ethyl-diamine, chloroprocaine, diethanolamine, procaine, N-mercaptophenethylamine, N-methylglucosamine pipe trap, tris(hydroxymethyl) Aminomethane, tetramethylammonium hydroxide, and the like. Salts include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium salts, and the like, and salts of non-toxic organic or inorganic acids when the compound contains basic functionality. Classes such as hydrochloride, hydrobromide, sulfate, phosphate, amine sulfonate, nitrate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentane Propionate, glycolate, glutarate, pyruvate, lactate, malonate, stearate, succinate, sorbate, ascorbic acid, malate, maleate, Fumarate, tartrate, citrate, benzoate, 3-(4-hydroxybenzhydryl)benzoate, picrate, cinnamate, mandelate, citrate , laurate, methanesulfonate, ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, besylate '4-chlorobenzenesulfonate, 2- Naphthalene sulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, grape heptanoate, 3 -phenylpropionate, trimethyl b Salt, tert-butyl acetate, lauryl sulphate, glucose

C -19- 201210602 acid salt, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylamine sulfonate, quinolinate, mucate Wait. The term "prodrug" as used herein denotes any compound which, when administered to a biological system, produces a biologically active compound due to spontaneous chemical reactions, enzyme catalyzed reactions, and/or metabolic processes or combinations thereof. . The standard prodrug is formed using a functional group attached to an agent such as -OH, -NH2, which is cleaved in vivo. The prodrugs of the present invention are illustrated by way of example and are not limited thereto, and those skilled in the art can prepare other prodrugs known in the art. The term "L-nucleoside" means a mirror image isomer of a naturally occurring and modified beta._〇-nucleoside analog. The term "arabinofuranosyl nucleoside" means that the nucleoside analog contains arabinofuranosylose (i.e., the natural (general) nucleoside of the ribofuranosyl sugar 2, the hydroxy group is located in the sugar ring. The term "dioxolane sugar" means a sugar containing an oxygen atom instead of a ribofuranosyl sugar. The term "fluorinated sugar" means having 1-3 fluorine atoms. A saccharide attached to a carbon of a glycosyl group. The term "nucleoside" means a hydrazone or a pyrimidine base or an analog thereof which is attached to a glycosyl group, including a heterocyclic group and a carbon cyclic analog thereof. The term "quantity" means an amount which has any beneficial effect in treating a disease or condition. The term "phosphate" means -〇-Ρ〇32-. The term "amino phosphate" means _Ν-Ρ〇32-. -20- 201210602 The term "phosphonate" means -CHR.p〇32-. The term "parental" means nucleoside and/or acyclic nucleus (mo-po32.). The term also means phosphine-containing [r-ch2-p(o)(oh)2]. The term "biologically active agent or agent" means a chemical substance. In the present invention, biologically active | (M-OH), nucleoside monophosphate (Μ·〇_ρ〇32-), nucleus (Μ-0-Ρ2063 ·), nucleoside tricaprate (μ_ 〇Ρ3〇94-) [M_CH2P(〇; K〇H)2, m_ch2p〇32·], non-nucleoside phospholipid (M-CH2P2〇63·) or its two pity vinegar (M-CH2P3094). The term "base" or "hospital base" includes aryl. The term arylalkyl or arylalkyl includes the aryl group " 嘌呤" or "pyrimidine". The term includes adenine oxime, N6-mercapto-6-aminopurine (wherein the fluorenyl group is an aryl group, a aryl group or an aryl group), N6-benzyl-6-® vinyl-6-amino fluorene, N6-ethynyl -6_aminopurine, 7-deazapurine, modified 7-deazapurine, thymus pg N4-decyl cytosine, 5-fluorocytosine, 5-methylcytosine. Uracil, 5- Fluorouracil, 5-alkyluracil, 5-ethynyl uracil, 5-hydroxymethyluracil, 5-guanamine uracil, 5-iodouracil, 5-Br-vinyl uracil, 5- Nitrouracil, triazolopyridine, imidazopyridine, pyrpyrazolopyrimidinyl, but not limited thereto. The base 1 = mono-phosphate ester acid agent agent biological effect pen agent means nucleoside diphosphate, nucleoside phosphonate ester, monophosphate _), alkenyl group containing alcohol alkyl substituent Alkyl., N6-alkyl-6-C(0) (alkyl, g-based oxime, N6-, 6-cyclic amino oxime I pyridine, cytosine, 16-azacytosine, alkenylpyrimidine, 5 · 丨: bet D, 5-cyano 5-azacytosine, pyridopyrimidinyl and guanine, gland-21 · 201210602 嘌呤, 2 · fluoroadenine, 2-chloroadenine, hypoxanthine, 7-deazaguanine, 7-deaza adenine, 2,6-diaminoguanidine, and 6-chloropurine, 6-alkoxyanthracene, 6-deoxyguanine, 6-alkylthiopurine, But not limited to this. The functional oxygen and nitrogen groups on the base can be protected as needed or desired. Suitable protecting groups are well known to those skilled in the art and include trimethyldecyl, dimethylhexyldecyl, tert-butyldimethylalkyl, and tert-butyldiphenylalkyl, triphenyl Base, alkyl and sulfhydryl groups, such as ethenyl and propyl sulfonyl, methylsulfonyl and p-toluenesulfonyl. The term "mercapto" or "0-linked ester" includes the radical of the formula C(0)R' wherein R' is straight-chain, branched or cyclic alkyl or aryl. The term "amino acid" includes the natural discovery and synthesis of alpha-, beta-, gamma- or delta-amino acids, and includes the amino acids found in proteins, namely glycine, alanine, proline, Aleucine, isoleucine, methionine, phenylalanine, tryptophan, valine, serine, threonine, cysteine, tyrosine, aspartate, bran Promethamine, aspartate, glutamate, lysine, arginine and histidine, but not limited thereto. In a preferred embodiment, the amino acid is in the L-configuration. Alternatively, the amino acid may be an amidino group, a prolyl group, an leucine group, an isoleucine group, a valine group, a phenylalanine group, a tryptophan group, a methionine group, Glycosyl group, serine group, threonate group, cysteine group, tyrosine group, aspartic acid group, glutamic acid group, aspartame group, glutamine sulfhydryl group, Amino acid group, arginine group, histidine group, β-alaninyl group, β-proline group, β-leucine group, β-isoleucine group, β·proline group, --phenylalanine, β-tryptophan, β-methionine, β-glycine, β-serin, β-threonate, β-cystein Base, Ρ-tyrosine group, β-aspartate, β-glutamic acid group, β_asparagus-22- 201210602 Amine thiol, β·glutaramine sulfhydryl, P-lysine a derivative of a P, arginine or P-histidine group. "Solvate" includes a compound provided herein or a salt thereof' which further includes a metered or non-metered amount of solvent combined by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate. The terms "individual" and "patient" as used herein are used interchangeably. The term "individual" means that an animal, such as a mammal, includes non-primates (such as cattle, pigs, horses, cats, dogs, rats, and mice) and primates (such as monkeys, such as cynomolgus monkeys). , chimpanzee). In a specific embodiment, the individual is a human. As used herein, "therapeutic agent" and "therapeutic agent" mean any agent that can be used to treat or prevent a disorder or one or more of its symptoms. In certain embodiments, the term "therapeutic agent" includes the compounds provided herein. In a specific embodiment, the therapeutic agent is an agent that is known to be useful or has been used or has recently been used to treat or prevent a disorder or one or more of its symptoms. "Therapeutically effective amount" includes the amount of a compound or composition that is sufficient to cause treatment of the disease when administered to a body. The "therapeutically effective amount" may vary depending on the disease and its severity, and the age, weight, etc. of the individual to be treated, in addition to the compound. The "treatment" of any disease or disorder in a particular embodiment indicates an improvement in the disease or disorder that is present in the individual. In another embodiment, "treatment" includes improving at least one physical parameter that is not recognized by the individual. In another embodiment, "treatment" includes modulating a disease or disorder, either physically (e.g., stabilizing a detectable condition) or physiologically (e.g., stabilizing a body parameter) or being 2-23-201210602. In another embodiment, "treatment" includes delaying the onset of a disease or disorder. In another embodiment, the preferred formula! The compound is a compound of the formula ηι:

Or a pharmaceutically acceptable prodrug, salt, solvate, stereoisomeric, tautomeric or polymorphic form thereof, wherein: R and Han 7 are each independently selected from the group consisting of hydrazine, alkyl, aryl, alkynyl, alkenyl , a ring-based group, a heterocyclic group or a heterocyclic group having 1 to 3 hetero atoms (for example, hydrazine, s, hydrazine) 'but not limited thereto, all of which may be optionally substituted; R and R 7 may form 4 to A 7-membered ring, such as pyrrolidine, all of which may be optionally substituted; R2, R3, X, Y, and JV1-XH are as defined above. Soil Specific Embodiments The preferred compound of formula III is a compound of formula IV.

Μ, X, γ = β R are as defined above. Suitable for the present invention, a drug that is a drug-derived drug

C -24- 201210602 Different kinds of parent drugs can be obtained from the prodrug method of the present invention. Preferably, the prodrug protecting group is attached to the hydroxyl group on the parent drug. In many cases, the parent drug will have many such functional groups. The preferred group selected for attachment to the prodrug is the group most important for biological activity and is chemically suitable for attachment to the parent drug. Therefore, the phosphorus-containing prodrug group will prevent the prodrug from being biologically active. Inactive prodrugs should reduce systemic side effects because higher drug concentrations are located in the target organ (liver) relative to non-liver tissues. There are many classes of therapeutically useful agents (including nucleosides or non-nucleosides) containing hydroxyl functional groups which can be used to derivatize the amine phosphate or alanine phosphonate prodrugs of the invention. Such compounds include nucleosides, C-nucleosides, nucleotides, phosphonates, and other alcohol containing compounds. The prodrugs disclosed herein are derived from such compounds and are considered to be within the scope of the invention. The following compounds are examples of such compounds. A therapeutically useful and derivable derivative of one of the class of prodrugs of the invention is an exemplary nucleoside agent (D- and L-) which is a compound of formula V:

Or a pharmaceutically acceptable prodrug thereof, wherein: (A) is selected from the group consisting of hydrazine, S, CH2, CHF, C = CH2, C=CHF, CF2; r8 and R9 are independently selected from the group consisting of H, OH, CH30, F, CM, Br , I, CN, N3, methyl, ethyl, vinyl, ethynyl, chlorovinyl, fluoromethyl, 25-201210602, difluoromethyl, trifluoromethyl, but not limited thereto, all Optionally substituted; R8 and R9 form a vinyl group optionally substituted by F, difluoro, CM, Br, I, CN, N 3 ; R1G is selected from the group consisting of hydrazine, methyl, ethyl, vinyl, ethynyl, Chlorovinyl, fluoromethyl, difluoromethyl, trifluoromethyl, but not limited thereto; R11 is selected from the group consisting of H, CN, Ν3, methyl, ethyl, vinyl, ethynyl, chlorovinyl, Fluoromethyl, difluoromethyl, trifluoromethyl, but not limited to this: R12 is selected from the group consisting of hydrazine, OH, F, cyano and azide, but is not limited thereto. Β-2 or Β-3 pyrimidine and guanidine, but not the stomach limit:

Wherein X2 is H, NH2, NHMe, NMe2 or halogen (I, ΒΓ, F), but not limited thereto, all of which may be optionally substituted; X4 is NH2 or OH; X5 is halogen (I, Br, Cl, F), OH, NH2, methyl, ethyl bromo 2-bromovinyl, ethynyl; food: ring X6 is H, OH, OMe, OEt, SMe, alkoxy, aromatoxy, alkane Thiothio, arylthio, cycloalkylthio, furyl, alkylamino 'dialkylamino, arylamino, arylamino, cycloalkylamino, cyclopropylamino, -26- 201210602 X7 is an anthracene, a vinyl group, an ethynyl group, a halogen (1, Br, cl' F), all of which may be optionally substituted; the amine group and the hydroxyl group may be selectively protected. Other modified pyrimidines or purines, such as 5-aziridine, 6-aziridine, 3-deazapyridine, 3-fluoro-3-deazapyrimidine, 8-indol-7, deazapurine, but not It is also considered to be within the scope of the invention. The first hydroxyl group of the nucleoside of the formula V is derived from the aminophosphate prodrug of the invention. For example, Fluxuridine can be derivatized as an amino phosphate as follows:

0

〇 FVV \ y^O-P-O-| dΗ. Fluorouridine Aminophosphate prodrugs An exemplary therapeutically useful and suitable derivative of the prodrug of the invention. Another nucleoside agent (D- and L-) is a compound of formula VI:

VI or a pharmaceutically acceptable prodrug thereof, wherein: ruthenium, osmium and R11 are as defined above; R13 and R14 are independently selected from H, N3, F, CN, CH3, alkyl or vinyl 'but not limited thereto, All can be replaced. -27- 201210602 Other types of parent drugs which are suitable for the prodrugs of the present invention are the compounds of the formulae VII and VIII (D- and L-isomers):

HO

HO

Vm or a pharmaceutically acceptable prodrug thereof, wherein: B is as defined above. Other types of parent drugs suitable for the prodrugs of the invention are selected from the group consisting of nucleoside phosphonates (Table 1, Biochem Pharmacol. 2007, 73, 911), but are not limited thereto: Table 1 Acyclic nucleoside phosphines Acid ester example

-28-201210602 Other biologically active phosphonates of the formula m-x_p(o)(oh)2 wherein M-X can be a ring system include the following exemplary compounds (WO 2008/082602):

Other types of parent drugs that are suitable for the prodrugs of the present invention are an acyclic nucleoside, including acyclovir, ganciclovir, and pencyclovir, but not Limited. Other classes of parent drugs that are suitable for the prodrugs of the present invention are C-nucleosides, a particular class of nucleosides (for details see C-nucleoside reviews: Chemistry of Nucleosides and Nucleotides by Leroy B Townsend 1 9 9 4, Science, Chapter 5 The Chemistry of C-nucleosides, Kyoichi A Watanabe pp421), C-nucleosides are not limited to the compounds cited in the review. When a nucleoside can be phosphorylated to the active triphosphate form, the nucleoside is referred to as a parent drug. For example, acyclovir (ACV) can be considered a parent drug in the form of M-OH (X = 0 in Formula I). ACV is first phosphorylated to ACV-P032_ and then further phosphorylated in vivo to form ACV-triphosphate, which is in a biologically active form. When some nucleosides are not excellent acceptors of kinases and exhibit abiotic activity, and their nucleotides or nucleoside monophosphates are biologically active, the parent drug is referred to as the corresponding nucleoside monophosphate. When an alcohol-containing compound is derived from a prodrug of the invention, the parent drug is referred to as a corresponding alcohol-containing agent. -29- 201210602 The following well-known pharmaceutical agents (but not limited to them) are mentioned in the specification and patent application (also abbreviated and common names): araA; 9-PD-arabinofuranosyl adenine (arabinary gland) Viranabine) araC; β-D-arabinofuranosylcytosine araU; 9-β-ϋ-arabinofuranosyl uracil d4T; 2',3'-dihydro-3'-deoxythymidine ( Stavudine) ddl; 2',3'-dideoxyinosine (Dardanosine) ddA; 2',3'-dideoxyadenosine ddC; 2',3'- Deoxycytidine (zaxitabine; Zalcitabine) L-ddC; L-2',3,-dideoxycytidine L-FddC; L-2',3'-dideoxy-5-fluorocytidine L-d4C; L-3'-deoxy-2',3'-dihydrocytidine L-Fd4C; L-3'-deoxy-2',3'-dihydro-5-fluorocytidine L-FMAU; Lpl-(2-fluoro-2-deoxy-arabinofuranosyl) thymine (Clavudine; Clevudine) 3TC; (-)_2',3'-dideoxy-3'-sulfur Cytidine 2,R,5'S(-)-l-[2-(hydroxymethyl)oxathiolan-5-yl]cytosine (lamivudine; lamivudine) Ι-β-D-furan Sugar-1,2,4-triazole-3-Amides (ribavirin;

Ribavirin) FIAU-deoxy-2_gas-β-D-arabinofuranosyl)-5-moth urinary FIAC; Bu (2_deoxy-2-fluoro-β-D-arabinofuranosyl)- 5-iodocytosine-30- 201210602 8-form 〇; ( + )- (1(1,20,3(1)-9-[2,3-bis(transmethyl)cyclobutyl]guanine FMAU 2'-Fluoro-5-methyl-β-L-arabino-furanosyl uracil BvaraU; Ι-β-D-arabinofuranosyl-£_5_(2_bromovinyl) urinary spray steep (Solif Ding: Sorivudine) E-5-(2-bromovinyl)-2'-deoxyuridine TFT; trifluorothymidine (Triflu〇r〇thyrnidine) 5-propyne-1-arabinose Pyrimidine CDG; carbocyclic 2'-deoxyguanosine DAPD; (-)-pD-2,6-diaminophosphoniumdioxolane FDOC; (-)-pD-5-fluoro-b [2-( Hydroxymethyldioxocyclopentane] cytosine d4C; 3'-deoxy-2',3'.dihydrocytidine DXG; dioxolane guanosine FEAU; 2'-deoxy-2'- Fluor-1-0_〇_arabinofuranosyl-5·ethyluracil: FLG; 2',3'-dideoxy-3'-fluorine bird FTC; (-)-cis-5-fluoro 1-[2-(hydroxymethyl)-i,3-oxothiapentane-5-yl]-cello-deep 5-amino-carbocyclic 2'-deoxyguanosine BmS200, 475) [1-(4-based-1,2-butane-based) cell spray steep] (Cytallene) Otto new A (Oxetanocin A); 9-(2_ deoxy-2-hydroxymethyl - β-D-erythro-oxetanosyl) adenine Otano new G; 9-(2-deoxy-2-hydroxymethyl-β-D-erythro-oxocycle Butyryl) guanine ddAPR: 2,6-diaminopurine-2,,3,-dideoxynucleoside-31- 201210602 3TC; (-)-2',3'-dideoxy-3' Thiocytidine; (2R, 5S) 1-[2-(hydroxymethyl)-13-oxathiapentan-5-yl]cytosine (Lamivudine) Cyclobut A; ( + )-9-[(1 loan, 2〇1,30)-2,3-bis(hydroxymethyl)-1-cyclobutyl]adenine ring G; ( + )-9-[(4 , 2(1,30)-2,3-bis(hydroxymethyl)-1-cyclobutyl]guanine 5-fluoro-2'-deoxyuridine (fluorouridine) dFdC; 2',2' -difluorodeoxycytidine (Gemcitabine) araC; arabinose cytosine (cytarabine) bromodeoxyuridine IDU; 5-exchange-2'-deoxyuridine (yasidine; idoxuridine)

CdA; 2-chlorodeoxyadenosine (Cladribine; Cladribine) 2-chloro-2'-fluoro-araA (Crofarabine) F-ara-A; fluoroarabinoadenosine (fludarabine; Fludarabine) ACV; 9-(2-hydroxyindoleoxymethyl)guanine (acyclovir) GCV; 9-(1,3-dihydroxy-2-propoxymethyl)guanine (more Lovir) 9-(4-hydroxy-3-hydroxymethylbutan-1-yl)guanine (penciclovir; Penciclovir)

(R)-9-(3,4-dihydroxybutyl)guanine (Buciclovir) araT; 9-PD-arabinofuranosyl thymine FMdC; (E)-2'-deoxy- 2'-(fluoromethylene) cytidine AICAR; 5-aminoimidazole-4-carboxamide-1-furan ribosyl CNDAC; 2'-cyano-2'-deoxycytidine palmitoyl CNDAC - 32- 201210602 2'-Fluoro-2'-deoxy- 4'-azido-β-D-arabinofuranosylcytosine (RO-0622) 2'-fluoro-2'-deoxy-4'- Azido-9-卩-0-arabinofuranosyluracil 2'-fluoro-2'-deoxy-4'-azido-9-卩-〇-arabinofuranosyl adenine 2'- Fluorin-2'-deoxy-4'-azido-9-oxime-0-arabinofuranosylguanine 4 azide-β-D-arabinofuranosylcytosine 4'-azido- 9 -PD-arabinofuranosyluracil 4'-azido- 9-P-D-arabinofuranosyl adenine 4 '-azido-9 - β-D-arabinofuranosylguanine 4'- Azidouridine 4'-azidocytidine 4'-azidoadenosine 4'.; azidoinosine 4'-azidoguanosine 2'-C-methyluridine 2'- C-methylcytidine 2'-C-methyladenosine 2'-C- Inosine 2'-C-methylguanosine 2'-C-(fluoromethyl)uridine 2'-C-(fluoromethyl)cytidine 2'-C-(fluoromethyl)adenosine-33 - 201210602 2,-C-(fluoromethyl)inosine 2'-C-(fluoromethyl)guanosine 4,-azido-2'-C-methyluridine 4,-azido-2 '-C-Methylcytidine 4'-Laminated 2'-C-methylglycine 4'-azido!-Methylglycine 4,-azido-2'-C-methyl Guanosine 2,-fluoro-2'-deoxy-2'-C-methyluridine 2,-fluoro-2'-deoxy-2'-C-methylcytidine 2,-fluoro-2'- Deoxy-2'-C-methyl-based adenosine 2,-fluoro-2'-deoxy-2'-C-methylinosine 2,-fluoro-2'-deoxy-2'-C- Guanosine 2,-fluoro-2'-deoxy-2'-<:-(fluoromethyl)uridine 2,-fluoro-2'-deoxy-2'-C-(fluoromethyl) Glycoside 2, _fluoro-2,-deoxy-2'-€-(fluoromethyl)adenosine 2,-fluoro-2'-deoxy-2'-(3-(fluoromethyl)inosine 2, -Fluoro-2,-deoxy-2'-(:-(fluoromethyl)guanosine All 6-alkoxy groups of all the above guanosine analogs and 6-deoxy analogs All monophosphates of the above nucleosides The amine groups and/or hydroxyl groups of all nucleosides may be optionally protected. Used in the field of anti-cancer. Several characteristics of ara-C (cytarabine), such as metabolic deamination, low affinity for dCK and rapid clearance of ara-CTP, limit its cytotoxic activity. (Lancet Oncol. 2002, 3, 415). In order to overcome these problems, several chemical modifications of ara-C have been synthesized. The ara-C prodrugs that have a lipophilicity at the base or in the sugar group -34-201210602 side chain have been designed to increase the deaminating action and clearance of neostigler (Cancer Res. Nucleosides & Nucleotides 1 999, 18 P h arm ac ο 1. 2 0 0 4 , 6 7,5 0 3 ). This molecularly motivating mechanism enters the cell and may increase intracellular (Biochem. Pharmacol. 2004, 67, 503; Br. 95 7). In contrast to ara-C itself, these prodrugs have activity, which may be The drug is preferably infiltrated. One of these prodrugs, CP-4055, is undergoing pre-treatment of 6-17 patients with solid tumors (J. Clin. Oncol. 2004, 22, 2049) ° Pronuclear ig analog analogue UA9 11 Resistance to human follicular lymphoma RL-G cells for a 5'-ara-CMP (Int. J. Cancer 2003, 1 07, 1 49) ° Prodrug technology of the invention applied to nucleoside agents With these agents; the properties of several such compounds will be retained for a longer period of time. These features allow for the treatment of such analog areas. Preferably, it is suitable for prodrug-derived nucleosides (including prodrugs thereof) disclosed herein (Table 2), but not as shown in Table 2. Examples of parent nucleosides ingestion of ara-C and extensions 1999, 59, 2944 ; , 877; Biochem. By the non-dependent ara-C half-life J. Cancer 1995, 71, against the solid tumor pattern I and subsequent retention of the first phase of clinical evaluation, suffering from unstable disease Γ M (pronucleotide) Pre-drug, its ara-C can regulate the AK-C can be used as an oral formulation to produce a parent drug in body fluids suitable for the treatment of a wide range of compounds including the following formula: -35- 201210602

-36- 201210602

201210602

Prodrugs derived from alcohol-containing agents are also considered to be within the scope of the invention by the techniques disclosed herein. Therapeutic use -38- 201210602 The present invention also provides nucleosides, nucleotides, C-nucleosides, C nucleotides, nucleoside monophosphates, phosphonates, non-nucleoside phosphonates and phosphorus-containing compounds before phosphorus-containing compounds medicine. The therapeutic use of the prodrugs herein is also used to treat viral infections, cancer and other liver disorders. Such prodrugs can be used to enhance the bioavailability and/or pharmacokinetics of the parent drug. The prodrugs and compositions disclosed herein can be administered alone or in combination with other therapeutically effective agents. The aminophosphate and aminophosphonate compounds of the various therapeutic agents disclosed herein can be used in response to diseases for which the parent drug is used for treatment. In some embodiments, the prodrugs disclosed herein can also be used to treat a virus that is resistant to the parent drug. Such amino phosphate and amino phosphonate compounds advantageously enhance delivery of the agent to the liver. In some embodiments, the compound allows for the transport of the active 5'-monophosphate of the nucleoside to the liver, which enhances the formation of the active triphosphorylated compound. In a specific embodiment, provided herein is a method of treating a liver disorder comprising administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the method comprises the steps of administering a compound effective to treat the liver disorder, and combining the second agent effective to treat the disease to the desired individual. The compound can be any of the compounds described herein, and the second agent can be any second agent in the art or described herein. The prodrug technique of the present invention can be applied to prodrugs that convert large amounts of inactive nucleosides into therapeutically useful nucleotides. Thus, the amine-based acid vinegar prodrugs disclosed herein for all alcohol-containing agents are considered to be within the scope of the invention. -39- 201210602 The therapeutic use of the previous drugs is also used to treat liver HBV and HCV) and liver disorders, including liver cancer and metabolic diabetes, hyperlipidemia, atherosclerosis and obesity. Second or More Agents for Use in Methods In certain embodiments, the compositions provided herein are directed to a method of treating liver disorders comprising a second agent that is otherwise administered a disorder of treatment (e.g., liver cancer). The second agent is a pharmaceutical agent known to the physician, which is effective for treating disorders, and is approved by the approver. In certain embodiments, the compounds provided herein are administered. In another embodiment, the second agent is administered in combination. In another embodiment, the second agent is administered in combination with two agents. Preparation of Compounds The compounds provided herein can be prepared, isolated or obtained by those skilled in the art. The exemplified preparation methods are detailed in Sections. The amine-based method for the nucleoside 5-fluoro-2'-deoxyuridine (fluorouridine) is illustrated in Scheme 1. Phosphorus oxychloride (1 eq., containing triethylamine (leq.) and 3-fluoro-4-methoxybenzyl alcohol (1 solution at -78 °C to obtain monoester 2, which Treatment with benzyl triethylamine (1 eq.) in THF to obtain 3 in the presence of chloramine phosphatidyl imidazole (NMI) to react with fluorouridine to produce phosphate 4. Inflammation (including sexual diseases, such as The composition may be an individual effective agent, and may be any of the exemplified P(Cl3) THF of any of the following examples of the first embodiment of the FDA, the second compound, or the second drug. 1 eq.) of THF amine (1 eq.) and ester 3. N-alpha nucleoside amine-40- 201210602

NMI Ο

Flowchart 1 Exemplary Process for Amino Phosphate Flowchart 1 can be applied to the general process of other alcohol-containing compounds, as shown in Scheme 2.

〇 CI-P-CI R-0H --- Et3N 5

0 R-0-P-CI I Cl E Η Ν r6'r7

EtsN

0 R—0 —p—Cl I R-OH: R—〇H is an alcohol-containing agent and R7 is as defined above

NMI 〇R-〇-P-〇-Drug R6 R7 8 Flowchart 2 General method for the preparation of aminophosphates For the general preparation of aminophosphates (Scheme 2), p〇C13 is the corresponding alcohol solution (5, Treatment with 1 eq) and triethylamine (1 eq) gave the dichlorophosphate 6. The resulting 6 is further treated with an amine solution (leq) corresponding to -41 to 201210602 in the presence of triethylamine (1 eq) to provide chloroamino phosphate 7. In the presence of N-methylimidazole, 7 is treated with an alcohol-containing agent comprising a nucleoside to produce an aminophosphate prodrug 8. An exemplary method for the preparation of an aminophosphonate of a nucleoside phosphonate according to the patented method (US 2005/0124583) is illustrated in Scheme 3. Phosphate 9 is treated with the corresponding alcohol in the presence of DCC and triethylamine to give the compound 1 oxime. After the chlorination of 10° by S0C12, the produced chloride 11 is reacted with the corresponding amine to obtain

Flowchart 3 Preparation of phosphoniumamine Biological evaluation 1. Anticancer activity assay Compounds synthesized as anticancer agents were tested in leukemia cell lines to evaluate their anticancer efficacy. Compounds were tested using MTS assay reagents obtained from Promega (CellTiter 96 Aqueous One solution proliferation assay) and tested at 5 μΜ concentration (WO 2006/100439). 2. Anti-Hepatitis C Activity -42- 201210602 The anti-HCV activity and cytotoxicity of the compounds disclosed herein can be analyzed according to the gamma patent method (wo 2007/027248). 3. Anti-HBV Analysis The compounds of the invention can be assayed for anti-HBV activity according to any analytical method known in the art. 4 In addition, the accumulation of the compound in individual liver cells can be analyzed according to any analytical method known in the art. In certain embodiments, individual liver cells can be used to analyze liver accumulation of a compound or a derivative thereof (e.g., a nucleoside, nucleoside phosphate, or nucleoside triphosphate derivative thereof). EXAMPLES The following examples illustrate the synthesis of representative compounds provided herein, and such examples are not intended to be construed as limiting the scope of the invention. It is obvious that the scope of the claimed subject matter can be implemented unless otherwise stated herein. In view of the teachings in this article, there are many modifications and variations to the subject matter, and therefore are within the scope of the subject matter. Due to the newly formed phosphorus-to-palm center, the product of the amino phosphate prepared according to the present invention is a mixture of non-image isomers and tested as a mixture in a biochemical analysis. The non-image isomers of the prodrugs of the invention can be isolated into a single isomer by chromatography. Example 1 Preparation of Fluorouridine Amino Phosphate (DGX-101) -43- 201210602

4 (DGX-101)

In a solution of phosphorus oxychloride (3.07 g, 20 mmol) in THF (40 mL), EtOAc (3········· A solution of THF (10 mL) was added and the mixture was stirred at -7 8 ° C for 3 hours. A solution of benzylamine (2.14 g, 20 mmol) and triethylamine (2.02 g, 20 mmol) in THF (10 mL) was added at -78 ° C and stirred at -7 8 ° C. This mixture was allowed to stand for 1 hour and then stirred at room temperature overnight. The THF was removed in vacuo and EtOAc EtOAc (EtOAc m. Next reaction. In a suspension of CH2C12 (40 mL) containing nucleoside (2.42 g, 10 mm), N-methylimidazole (5 mL) was added and the solution was cooled in an ice bath. A solution of 3 was added to the solution, and the resulting solution was stirred in an ice bath for 3 hours. Water (5 mL) was added and the mixture was crystallised eluted with EtOAc EtOAc EtOAc The solvent was concentrated in vacuo, and the residue was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc (EtOAc)

δΗ yMR (CDCL3): 7.70, 7.6 7 (dd, J = 6.4Hz, 1H), 6.90 -7.42 (m, 8H), 6.15 (m, 1H), 4.90 - 5.11 (m, 2H), 3.B8 ( s, 3H), 3.71 - 4.46 (m, 6H), 1.96 - 2.41 (m, 2H). LC-MS (ESI): 5 54 [M+l] + . According to the same procedure, but using the corresponding nucleoside or Reagents, the following compounds were prepared: Example 2 DGX-102: δ NMR (CDCL3): 7.70, 7.67 (dd, J = 6.4 Hz, 1H), 7.13 - 7.31 (m, 9H), 6.15 (m, 1H), 4.90 - 5.11 (m, 2H), 3.71 -4.46 (m, 6H), 2.26, 2.2 5 (ss, 3H), 1.96 - 2.41 (m, 2H). LC-MS (ESI) : 5 2 0 [M+ 1 ] + .

O

Example 3 DGX-104: δΗ NMR (CDC13): 8.93 (ss, 1H), 6.9 5 - 7.40 (m, 9H), 6.11 (d, 1H), 5.44 (dd, 1H), 5.00, 4.85 (mm, 2H), 3.48-4.40 (m, 11H), 1.36 (dd, 3H). LC-MS (ESI) 568 [M + H] + . -45- 201210602

DGX-103 DGX-104 Example 4 DGX-105: NMR (CDC13): 8.90 (br. S, 1H), 7.18-7.38 (m, 10H), 6.12 (d, 1H), 5.42 (dd, 1H), 5.05 (mm, 2H), 3.40-4.40 (m, 7H), 2.55 (s, 3H), 1.36 (dd, 3H). LC-MS (ESI) 534 [M + ] + .

DGX-105 Example 5 DGX-106: NMR, (CDC13): 8.91 (br. S, 1H), 7.15-7.36 (m, 11H), 6.11 (d, 1H), 5.43 (dd, 1H), 5.08 ( Mm, 2H), 3.40-4.40 (m, 7H), 1.36 (dd, 3H). LC-MS (ESI) 5 20 [M + ] + . Example 6

DGX-106 -46 - 201210602 DGX-108: δΗ NMR, (CD3〇D): 7.57 (d, J = 8.0Hz, 1H), T-24 (m,9H), 6.10 (m,1H), 5.73 ( m,1H), 5.00 (m,2 H),4.2 6 O' 2H), 4.01 (m, 4H), 2.32 (s, 3H). LC-MS (ESI) 5 5 9 [M + ] + ·

O

DGX-107

Preparation of the compound of Example 7 DGX-110: containing 2,-C-methyl-2',3',5'-0-tritylmercapto-6-chloroguanosine (DGX-109, 3.13 g, 5 mmol) of MeOH (30 mL) EtOAc (EtOAc EtOAc (EtOAc) Purification by gel column chromatography (CHzCh containing 0-15% MeOH) afforded DGX-110 (1.45 g, 93.5%) as a white solid. NMR, (DMSO-d6): 8.19 (s, 1H), 6.47 (s, 2H), 5.80 (s, 1H), 5.21. (d, J = 6.8 Hz, 1H), 5.14 (t, J = 5.2 Hz, 1H), 5.08 (s,1H), 3.94 (s, 3H), 3.98 (m, 1H), 3.80 (m, 2H), 3.65 (m, 1H), 〇-77 (s, 3H). LC-MS (ESI) 3 12 [M + ] + .

Example 8 DGX-111: 47-201210602 DGX-111° (5H NMR, (CDC13): 7.80, 7.75 (ss, 1H, H) was prepared as a white foam from DGX-110 according to the procedure described above for the amino phosphate. -8), 7.20 (m, 10H, NH2, Ph-H), 5.98 (ss, 1H, H-l'), 5.40 (ss, 2H, PhCH2), 5.00 (m, 2H, PhCH2N), 4.80-4.00 ( 1 0H, OCH3, 20H, 3'-, 4,-, 5'-H), 2.25 (ss, 3H, Me), 0.95 (s, 3H, Me). LC-MS (ESI) 5 8 5 [ M + ] + .

Example 9 According to the above procedure, the compound corresponding to the compound in Table 2 can be prepared. Example 10 Anticancer assay (WO 2006/1 0043 9) Compounds synthesized as anticancer agents were each tested in leukemia cell lines to evaluate their anticancer efficacy. Compounds were tested using MTS assay reagents obtained from Promega (CellTiter 96 Aqueous Ope Proliferation Assay) and tested at 5 μΜ concentration (WO 2006/100439). The label (+) indicates that the compound inhibits cell growth by more than 50%. Example 11 HCV Replicon Analysis The anti-HCV activity and toxicity of the exemplified compounds can be tested in two biological assays, cell line HCV replication assay and cytotoxicity assay (WO 2007/027248). I. Anti-HCV analysis Evaluation of compounds using a hepatocellular carcinoma cell line (Huh-7) containing a replication HCV subgenomic replicon and a luciferase reporter gene (luc-ubi-neo) It is resistant to HCV activity. In this assay, the extent of luciferase signaling is associated with direct replication of viral RNA. The HCV replicon-reporter cell line (NK/luc-ubi-neo) was cultured in DMEM medium supplemented with 10% fetal calf serum and 0.5 mg/ml Geneticin (G418). The cells are maintained in a subCOnfluent state to ensure a high degree of HCV replicon RNA synthesis. To assess the antiviral activity of the compounds, serial dilutions were prepared at a concentration range of 11.4 to 300 μΜ. The diluted compound was transferred to a 96-well plate, followed by the addition of replicon cells (6000 cells per well). After measuring the luciferase activity of the compound, it was incubated with the compound for 48 hours. The decrease in the luciferase signal reflects a decrease in the H C V replicon RN in the treated cells and is used to determine EC5 〇値 (which produces a concentration that reduces 50% luciferase activity). 11. Cytotoxicity assay A Huh-7 cell line carrying a luciferase reporter gene (driven by the HIV LTR promoter) stably inserted into the chromosome was used to analyze the cytotoxic effect of the selected compound. This cell strain (LTR-luc) was measured in DMEM medium with 10% FBS. The design of the cytotoxicity assay is similar to the HCV replication subanalysis. In the treated cells, the decrease in luciferase activity was correlated with the cytotoxic effect of the test compound and was used to calculate CC5Q(R) (concentration of inhibition of 50% cell growth). The biological activity of the subgenomic genotype la replicon and the cytotoxicity of the selected compounds were summarized in Table 3. -49- 201210602 Table 3 Reactive compound replicon (μΜ) CC5〇(pM) DGX-103 > 100 > 100 DGX-104 4.1 > 100 DGX-105 1.9 >100 DGX- 106 >100 > 100 DGX-110 0.9 > 100 DGX-111 0.3 69 The result of the anti-HCV activity of the selected nucleoside and its prodrugs summarized in Table 3 indicates that the prodrug technology of the present invention can directly transport the nucleus Monophosphate monophosphates enter biological systems, such as cells and/or tissues. The prodrug technique of the present invention converts biologically inactive nucleosides (e.g., DGX-103) into biologically active nucleoside prodrugs, such as DGX-104 and DGX-105. The prodrug technique of the present invention also converts biologically active nucleosides (e.g., DGX-110) into more biologically active nucleoside prodrugs, such as DGX-111. It has been found that the substitution on the phenyl ring of the benzyl ester dramatically alters the biological properties of the amino phosphate of the present invention. For example, compounds DGX-104 and DGX-105 each having a 4-methoxy and 2-methyl substitution on the phenyl ring have been shown to have potent anti-HCV activity' and the unsubstituted compound DGX-106 does not show any Significant anti-HCV activity. The prodrug technology of the present invention can be applied to most nucleoside agents to increase their therapeutic potential or to improve their biological properties. Example 12 Anti-HBV Assay -50-201210602 The anti-HBV activity of the compounds of the invention can be assayed according to any assay known to those skilled in the art. Example 13 The accumulation of a compound in an individual liver cell can be analyzed according to any assay known to those skilled in the art. In certain embodiments, an individual's liver cells can be used to analyze the accumulation of a compound or a derivative thereof (e.g., a nucleoside, a nucleoside phosphate, or a nucleoside triphosphate derivative thereof) in the liver. [Simple description of the diagram] None. [Main component symbol description] None. -51-

Claims (1)

201210602 VII. Patent application scope: 1. A compound of formula I, Or a pharmaceutically acceptable prodrug, a salt, a solvate, a tautomer or a polymorphic form, " wherein: X is selected from the group consisting of oxygen (0), CH2, but not limited thereto, provided that X is Oxygen (〇), M_XH is M_oh, nucleus nucleus, C-nucleoside or alcohol-containing compound; Μ·0·Ρ(0)(〇Η)2 stands for nucleoside or acyclic nucleoside or biology The active monophosphate; Μ-Χ can be a cyclic or acyclic system; Μ·Χ_Ρ(0)(〇η)2 is a biologically active phosphonium phosphonate M_CH2-P(〇)(OH) a nucleoside phosphonate of 2, if the X CP bond is attached: R1 is selected from the group consisting of a hydroxyl group, a benzyloxy group, an alkoxy 'aryloxy group, a 5 alkylaryloxy group, an amino acid residue 'benzylamine group, an alkane 3 arylamino, alkylarylamino, arylalkylamino, bis; diarylamine, but not limited thereto; dialkylamine group opening < ring formation '4 is preferably 4 Up to 7-membered ring, for example, abruptly selected, substituted; isomer, acyclic C-nucleoside _, including formula and p via r-oxy group, & amine group, aryl-based amine group, The dialkyl group may be all -52 - 201210602 R2 is selected from the group consisting of H, methyl, alkyl, a base, an alkynyl group, an alkenyl group, a cycloalkyl group, or a heterocyclic group or a heteroaryl group having one to three hetero atoms (for example, anthracene, S, anthracene), but not limited thereto, all of which may be optionally substituted; R3 is a substituent, at least one such substituent is attached to the phenyl ring at various positions, preferably at the 2 and/or 4-position, selected from the group consisting of R2C 00 (decyloxy), fluorenyl-NH, methyl , alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkoxy, cycloalkylamino, aryl, aryloxy, arylamino, arylalkyl, but not Limits, all of which may be substituted: Y represents oxime or one to three substituents at various positions of the benzene ring, including halogen (I, Cl, Br, F), CN, azide, decyloxy, decylamine Alkyl, alkoxy, alkylamino, alkenyl, alkenylamino, alkenyloxy, alkynyl, alkynyloxy, alkynylamino, arylalkoxy, arylalkylamino, alkoxy a carbonyl group, but not limited thereto, all of which may be optionally substituted; R1 and [MX] may form a cyclic phosphate such as a nucleoside 3', a 5'-cyclic phosphoric acid of all compounds of the formula I and/or a hydroxyl group Can be selected Protected by the earth; the compound of formula I can be a non-mirror isomer or a mixture of such non-image isomers caused by the palmitic phosphorus center, such as I a and I b : 53- 201210602 base, selected from the group 2 - a preferred exemplary substitution of the compound of formula I _ $ Ila-d, but not limited to: Wherein: Z is a substituent at various positions of the benzene ring, and the stomach is derived from Cl, Br, I, azide, CN, CONH2, COOR2, SR2, COSR2, 0-C0R2, NH2, Nh, and the group nr2 but not To this end, all of them may be optionally substituted: R4 is selected from the group consisting of R2COO (decyloxy), fluorenyl-Nfl, methyl, alkoxy, alkylamino, cycloalkyl, cycloalkoxy, ring _ aryl 'aryloxy, arylamino, arylalkyl, but not all of them may be optionally substituted: R2 is as defined above; R5 is selected from R2CO (fluorenyl), ch3, alkyl, naphthenic The group, the arylalkyl group, the alkylaryl group, but not limited thereto, are all substituted. 3. A compound of the first aspect of the patent application, preferably Formula 11 {7, F, OR2, _ fluorenyl, alkyl, i-amino, hydrazine, aryl, optional compound: o R2 -54- 201210602 or a pharmaceutically acceptable prodrug, salt, solvate, stereoisomer, tautomer or polymorphic form thereof, wherein: R6 and R7 are each independently selected from the group consisting of hydrazine, methyl, alkyl. An aryl group, an alkynyl group, an alkenyl group, a cycloalkyl group, a heterocyclic group having 1 to 3 hetero atoms (for example, anthracene, S, N) or a heteroaryl group, but not limited thereto, all of which may be selected Substituted; R6 and R7 may form a 4 to 7 membered ring, such as piropyridine, all of which may be optionally substituted: R3, X, Y and MX are as defined above. 4. A compound of formula III, preferably a compound of formula IV: Or a pharmaceutical thereof may be a prodrug, a salt, a solvate, a stereoisomer, a tautomer or a polymorphic form, wherein 'M-X, X, Y and R3 are as defined above. 5. A parent drug which is suitable for derivatization into a compound of the formula 1, 3 or 4 which is a compound of the formula (D- and L-): (A) is selected from the group consisting of H, OH, CH30, F, Cl, Br, I , methyl 'ethyl, vinyl, ethynyl, chlorovinyl, fluoromethyl, difluoromethyl, trifluoromethyl; R8 and R9 can form F, difluoro, Cl, Br, I, CN, N3 substituted vinyl; R1G is selected from the group consisting of hydrazine, methyl, ethyl, vinyl, ethynyl, chlorovinyl, bromovinyl, iodovinyl, fluoromethyl, difluoromethyl, trifluoromethyl , but not limited to this; R11 is selected from the group consisting of 1^01^, hydrazine, methyl, ethyl, vinyl, ethynyl, chloroethylene, bromovinyl, iodovinyl, fluoromethyl, difluoromethyl , trifluoromethyl, but not limited to; R12 is selected from H, OH, F, cyano and azide, but not limited thereto; B is selected from the group consisting of Formula B, B-2 or B-3 Pyrimidine and hydrazine: Wherein: X2 is selected from H, NH2, NHMe, NMe2 or halogen (I, Br, C1, F), but not limited thereto; X4 is NH2 or OH; X5 is selected from halogen (I, Br, Cl, F) , OH, NH2, methyl, alkyl, vinyl, 2-bromovinyl, ethynyl, but not limited thereto; X6 is selected from H, OH, OMe, OEt, SMe, alkoxy, aryloxy , cycloalkoxy, alkylthio, arylthio, cycloalkylthio, thiophene-56-201210602, furyl, alkylamino, dialkylamino, alkylalkyl, ring Alkylamino group, cyclopropylamine group; arylamine group, aryl, but not X7 is oxime, vinyl, ethynyl, dentate (I, ^ can be selectively substituted; F) The amine group and the hydroxyl group may be selectively protected; other modified pyrimidines or purines such as 3-deazapyridine and 3-fluoro-3-deazapyrimidine are also considered to be within the scope of the present invention. Nitrogen-7-deazaring 6. A parent drug which is suitable for derivatization into a compound of the formula: which is a compound of the formula: 14 wherein: B, A and R11 are as defined above; R13 and R14 are independently selected from the group consisting of hydrazine, N3, F, CN, CH3, optionally substituted alkyl or vinyl, but not limited thereto. 3 or 4 items of a parent drug which is suitable for derivatization into a compound of the first application formula, which is a compound of the formula (D- and L-): HO—I Β Η〇>5 wherein: Β As defined above. -57- 201210602 8. A parent drug suitable for the derivatization of a compound as described in claim 1, 3 or 4, which is a biologically active scaly vinegar of the formula: 0 MX-P"oh OH Mx can be a cyclic or acyclic system 'e.g. m_ch2-p(〇)(〇h)2 nh2 丄NH2 cl j Η〇ΗΟ^ν i? V^o Ή H〇JR=CH3: Tenofo early Cidofovir (Tenofovir) R=H: Adefovir R=CH2OH : HPMPA nh2 η〇\_ </Νχ^Ν HO Ό nh2 0 N \ F GS-9148 PMDTA 9. A parent drug It is suitable for derivatization into the alpha-like substance of the 1st to the 3rd or 4th of the patent application, which is a C-nuclear and acyclic nuclear tone, including acyclovir, ganciclovir (ganeyCi) 〇vjr), pencyclovir and its prodrugs, but not limited to this. 10. A pharmaceutical acceptable substance, a phosphate vinegar, a salt, a solvate, a stereoisomer, a -0 to 201210602 tautomer or a compound of the compound of claim 1, paragraph 3, or 4 Polymorphic forms are also considered to be within the scope of the invention. The compound used as a nucleoside, an acyclic nucleoside, a c-nucleoside, a nucleotide, a phosphate, and other alcohol-containing agents, which is a compound of the first, third or fourth aspect of the patent application. 1 2 . A compound for use in a therapeutic method as claimed in claim 1, 3 or 4, suitable for the prevention or treatment of cancer, such as leukemia, viral infections (including HIV, HBV and HCV) and liver disorders, including liver cancer And metabolic diseases such as diabetes, hyperlipidemia, atherosclerosis and obesity. 1 3 . The use of a compound as claimed in claim 1, 3 or . 4 for the manufacture of a medicament for the prevention or treatment of cancer, such as leukemia, viral infections (including HIV, HBV and HCV) and liver Disorders, including liver cancer and metabolic diseases such as diabetes, hyperlipidemia, atherosclerosis and obesity. 14. A method of treating viral infections (including HIV, HBV, and HCV) and liver disorders, including liver cancer and metabolic diseases such as diabetes, hyperlipidemia, atherosclerosis, and obesity, the method comprising administering to humans An individual therapeutically effective amount of a compound as claimed in claim 1, 3 or 4. 15. A method of treating viral infections (including HIV, HBV, and HCV) and liver disorders, including liver cancer and metabolic diseases such as diabetes, hyperlipidemia, atherosclerosis, and obesity, the method comprising A therapeutically effective amount of a compound administered in accordance with claim 1, 3 or 4 of the patent and other therapeutically effective agents. -59- 201210602 1 6. A pharmaceutical composition comprising a compound as claimed in claim 1, 3 or 4 in combination with a pharmaceutically acceptable carrier or diluent. 1 7. A preferred parent drug, which is suitable for the derivatization of a compound (prodrug) of the formula 1, 3 or 4, which is a nucleoside of the various formulas in Table 2 (guanosine analogues, Including its guanine prodrugs or their monophosphates, but not limited thereto, Table 2. Examples of parent nucleosides -60- 201210602 -61 - 201210602 -62- 201210602 IV. Designated representative map: (1) The representative representative of the case is: None. (2) A brief description of the component symbols of this representative figure: te. 5. If there is a chemical formula in this case, please disclose the chemical formula M-X-P-Ο R1 which best shows the characteristics of the invention.