MXPA06007422A - Phosphonates, monophosphonamidates, bisphosphonamidates for the treatment of viral diseases - Google Patents

Abstract

Compounds and compositions of Formula (I) are described, useful as anti-proliferative agents, and in particular anti-HPV.

Description

PHOSPHONATES, MONOPHOSPHONAMIDATES, BISPHOSPHONAMIDATES FOR THE TREATMENT OF VIRAL DISEASES FIELD OF THE INVENTION The present invention relates to the compounds and compositions and methods of use thereof, useful for treating viral infections, in particular human papillomavirus. BACKGROUND OF THE INVENTION The human papillomavirus (HPV) is one of the most prevalent sexually transmitted infections in the world. There are more than 100 different types of HPV, most of which are harmless. However, there are approximately 30 types that are spread through sexual contact. Some types of HPV cause genital warts, which appear as simple or multiple protuberances in the genital areas of men and women including the vagina, cervix, vulva (outer area of the vagina), penis and rectum. Although many people infected with HPV have no symptoms. While most HPV subtypes result in benign lesions, certain subtypes can lead to more serious injuries. Anogenital infections arising from HPV-16 and HPV-18, while less common than HPV-6 and HPV-11, are the most common REF.:173864 associated with precancerous lesions in cervical and anal tissues, called dysplasias. Patients with dysplasias are frequently asymptomatic and can only discover their lesion after examination. High-grade dysplasias, left untreated, can turn into cancerous tissues. The lower grade lesions can spontaneously revert, while others can progress to high grade lesions. HPV-16 and HPV-18 are most frequently associated with dysplasias, although several other subtypes of HPV transformants are also associated with dysplasias. Recent studies indicate that 89% of HIV-positive homosexual men may be infected with these high-risk subtypes of HPV. HIV-positive patients are more likely to be infected with multiple subtypes of HPV at the same time, which is associated with a higher risk of dysplasia progression. Genital warts are the most common sexually transmitted disease in the world, and are more prevalent in people 17-33 years of age. HPV-6 and HPV-11 are responsible for almost 90% of all genital warts, but are rarely associated with neoplastic growths. According to the North American Association of Social Health, at least 20 million people in the United States are currently infected with HPV, with 5.5 million new cases of sexually transmitted HPV infections occurring annually. Genital warts probably produce itchy, colorless bumps located near or above the genitals, but without treatment, they may progress to more pronounced and larger cauliflower growth. Approximately two-thirds of people who have sexual contact with a person infected with warts will develop warts within three months of contact. Spontaneous regression of genital warts occurs in 10-20% of cases of genital warts. However, even if an injury is reversed, the recurrence of genital warts is common with 50% recurrence after one year. As a result of unpleasant looking injuries, the treatment of genital warts is common. Evidence over the past two decades has led to widespread acceptance that HPV infection is necessary, but not sufficient, for the development of cervical cancer. The presence of HPV in cervical cancer is estimated at 99.7%. It is thought that anal cancer has a similar association between infection with HPV and the development of anal dysplasia and anal cancer, as is the case with cervical cancer. In a study of HIV-negative patients with anal cancer, HPV infection was found in 88% of anal cancers. In the United States in 2003, 12,000 new cases of cervical cancer and 4,100 deaths from cervical cancer are predicted along with 4,000 new cases of anal cancer and 500 deaths from anal cancer. While the incidence of cervical cancer has declined in the last four decades due to widespread classification, the incidence of anal cancer is increasing. The increase in the incidence of anal cancer can be attributed in part to HIV infection because HIV-positive patients have a higher incidence of anal cancer than the general population. While anal cancer has an incidence of 0.9 cases per 100,000 in the general population, anal cancer has an incidence of 35 cases per 100,000 in the homosexual male population, and 70-100 cases per 100,000 in the homosexual male population positive for HIV . In fact, due to the high prevalence of anal dysplasia among HIV-infected patients and an increasing trend of anal cancers, the USPHA / IDSA 2003 routes for the Treatment of Opportunistic Diseases in HIV Positive Patients will include the guidelines of Treatment for patients diagnosed with anal dysplasia. There is no known cure for HPV. There are treatments for the genital routes, although these often disappear even without treatment. The method of treatment depends on factors such as size and location of genital warts. Among the treatments used are Imiquimod cream, podophyllin 20% antifungal solution, 0.5 percent podofilox solution, 5 percent fluorouracil cream and trichloroacetic acid. The use of podophyllin or podofilox is not recommended for pregnant women, because they are absorbed by the skin and can cause birth defects. The use of 5-fluorouracil cream is also not recommended for pregnant women. Small genital warts can typically be removed by freezing (cryosurgery), burns (electrocautery), or laser treatment. Large warts that did not respond to another treatment may have to be removed by surgery. It has been known that genital warts return after physical removal, in those cases, a-interferon has been used to inject directly into these warts. However, a-interferon is expensive, and its use does not reduce the rate of regression rate of genital warts. As such, there continues to be an unfulfilled need for effective treatment against HPV. Surprisingly, the compounds that meet this need have now been discovered, and provide other benefits as well. Relevant antecedent technique: Snoeck et al., Antimicrobial Agents and Chemotheraphy, vol. 46 (11), pp. 3356-3361 (Nov. 2002); Keith et al., Antimicrobial Agents and Chemotherapy, vol. 47 (7), pp. 2193-2198 (July 2003), Christensen et al., Antiviral Research, vol. 48, pp. 131-142 (2000); U.S. Patent Publication No. 2003/0072814 Al; Patent of the United States No. 5,798,340; and PCT Application? o. PCT / CZ96 / 00011. BRIEF DESCRIPTION OF THE INVENTION A compound of the formula I, where: Y and Y 7-1B are independently AND R, x ?? X and R -, X? 2¿: are independently Rx; Y1 is = 0, -0 (RX), = S, -? (RX), -N (0) (Rx), -N (ORx) -N (O) (ORx), -N (N (RX) (Rx)); R x is independently R 1, R 2, R 4, W 3 or a protecting group; R1 is independently -H or alkyl of 1 to 18 carbon atoms; R 2 is independently R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups, or taken together at a carbon atom, two R 2 groups form a ring of 3 to 8 carbon atoms and the ring may be substituted with 0 to 3 groups R3; R3 is R3, R3b, R3c or R3d, with the proviso that when R3 is linked to a heteroatom, then R3 is R3c or R3d; R3a is -H, -F, -Cl, "-Br, -I-, -CF3, -CN, -N3, -? 02, -OR4 '* R3b is -0; -0 (R4), = S, -N (R4), -? (0) (R4), -? (0R4), -N (0) (OR4), or N (? (R4) (R4)); R3c is -R4, -N (R4) (R4), SR4, S (0) R4, -S (0) 2R4, -S (0) (0R4), -S (0) 2 (OR4), -OC (R3) R4,, -OC (R3b) (N (R4) (R4)), SC (R3b) R4, -SC (R3b) OR4, -SC (R3b)? (R4) (R4)), -N (R4) C (R3b) R4, -? (R) C (R3b) OR4, - N (R4) C (R3b) (? (R4) (R4)), W3 or -R5W3; R3d is -C (R3b) R4, -C (R3b) OR4, C (R3b) W3, C (R3) O3, or C (R3b) (N (R4) (R4)); R 4 is -H, or an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms; R5 is alguylene of 1 to 18 carbon atoms, alkenylene of 2 to 18 carbon atoms, or alkynylene of 2 to 18 carbon atoms; W3 is W4 or W5; W4 is R6, -C (R3b) R6, -C (R3b) W5, -SOM2R6 or -SOM2W5, wherein R6 and R4, wherein each R4 is substituted with 0 to 3 R3 groups; W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 groups R2; and M2 is 0, 1 or 2; and the pharmaceutically acceptable salts thereof. DETAILED DESCRIPTION OF THE INVENTION The present invention provides a compound of the formula, where: Rxl RX2 O *, C. - C ^ A is < í '^, / \, or < and -v .-? iA and yiB are indefinitely Y1; Rxl and Rx2 are independently Rx; Y1 is = 0, -0 (RX), = S, -N (RX), -N (0) (Rx), -N (0Rx) -? (0) (0Rx), -? (N (RX) (Rx)); R x is independently R 1, R 2, R 4, W 3 or a protecting group; R1 is independently -H or alkyl of 1 to 18 carbon atoms; R 2 is independently R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups, or taken together at a carbon atom, two R 2 groups form a ring of 3 to 8 carbon atoms and the ring may be substituted with 0 to 3 groups R3; R3 is R3a, R3b, R3c or R3d, with the proviso that when R3 is linked to a heteroatom, then R3 is R3c or R3d; R3a is -H, -F, -C1, -Br, -I-, -CF3, -CN, -? 3, -? 02 / -0R4 R3b is -0; -0 (R4), = S, -N (R4), -N (0) (R4), -N (0R4), -N (0) (0R4), -N (N (R4) (R4), or N (N (R4) (R4)); R3c is -R4, -N (R4) (R4), SR4, S (0) R4, -S (0) 2R4, -S (0) (0R4), -S (0) 2 (OR4), -OC (R3) R4, -OC (R3b) (? (R4) (R4)), SC (R3b) R4, -SC (R3) 0R4, -SC (R3b) (R4) (R4)), -N (R4) C (R3b) R4, N (R4) C (R3b) OR4, -N (R4) C (R3b) (N (R4) (R4)), W3 or -R5W3; R3d is -C (R3b) R4, -C (R3b) OR4, C (R3b) W3, C (R3b) OW3, or C (R3b) (N (R4) (R4)); R 4 is -H, or an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms; R 5 is alkylene of 1 to 18 carbon atoms, alkenylene of 2 to 18 carbon atoms, or alkynylene of 2 to 18 carbon atoms; W3 is W4 or W5; W4 is R6, -C (R3b) R6, -C (R3b) W0 -SCteR5 or -SQcW5, where Rd and R4, wherein each R4 is substituted with 0 to 3 R3 groups; W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 groups R2; and M2 is 0, 1 or 2; and the pharmaceutically acceptable salts thereof. One embodiment of the present invention provides a compound of formula I, where? iA and? iB are independently Y1; Rxl and Rx2 are independently Rx; Y1 is = 0, -0 (RX), = S, -N (RX), -N (O) (Rx), -N (0Rx) -? (0) (0RX), -N (? (RX) (Rx)); R x is independently R 1, R 2, R 4, W 3 or a protecting group; R1 is independently -H or alkenyl of 1 to 18 carbon atoms; R 2 is independently R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups, or taken together at a carbon atom, two R 2 groups form a ring of 3 to 8 carbon atoms and the ring may be substituted with 0 to 3 groups R3; R3 is R3a, R3b, R3c or R3d, with the proviso that when R3 is linked to a heteroatom, then R3 is R3c or R3d; R3a is -H, -F, -C1, -Br, -I-, -CF3, -CN, -N3, -? 02, or -OR4; R3b is -0; -0 (R4), = S, -N (R4), -N (0) (R4), -N (0R4), -N (0) (0R4), -N (N (R4) (R4), or? (? (R4) (R4)); R3c is -R4, -N (R4) (R4), SR4, S (0) R4, -S (0) 2R4, -S (0) (0R4), -S (0) 2 (OR4), -OC (R3b) R4, -OC (R3b) (N (R4) (R4)), SC (R3b) R4, -SC (R3b) OR4, -SC (R3b) N (R4) (R4)), "-N (R4) C (R3b) R4, -? (R4) C (R3) 0R4, -N (R4) C (R3b) (? (R4) (R4)) , W3 OR-R5W3; R3d is -C (R3b) R4, -C (R3b) OR4, C (R3b) W3, C (R3b) OW3, or C (R3b) (N (R4) (R4)); R 4 is -H, or an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms; R 5 is alkylene of 1 to 18 carbon atoms, alkenylene of 2 to 18 carbon atoms, or alkynylene of 2 to 18 carbon atoms; W3 is W4 or W5; W4 is R6, -C (R3b) R6, -C (R3b) W5, -SOM2R6 or -SOM2W5, wherein R6 and R4, wherein each R4 is substituted with 0 to 3 R3 groups; W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 groups R2; and M2 is 0, 1 or 2; and the pharmaceutically acceptable salts thereof.

One embodiment of the present invention provides a compound of the formula IA, wherein Y1A and Y1B are as defined above. One embodiment of the present invention provides a compound of the formula, One embodiment of the present invention provides a compound of the formula, One embodiment of the present invention provides a compound of the formula, One embodiment of the present invention provides a compound of the formula, One embodiment of the present invention provides a compound of the formula, One embodiment of the present invention provides a compound of the formula, One embodiment of the present invention provides a compound of the formula, One embodiment of the present invention provides a compound of the formula, One embodiment of the present invention provides a compound of the formula, One embodiment of the present invention provides a compound of the formula, One embodiment of the present invention provides a compound of the formula, One embodiment of the present invention provides a compound useful as an antiproliferative agent. One embodiment of the present invention provides a compound useful as an apoptotic agent.

One embodiment of the present invention provides a compound useful as an anti-HPV agent. One aspect of the present invention provides a compound useful as a topical anti-HPV agent. One embodiment of the present invention provides a pharmaceutical composition comprising an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable carrier. One aspect of the present invention provides a pharmaceutical composition, wherein the composition is a gel composition. Yet another aspect of the present invention provides a pharmaceutical composition, wherein the composition is an ointment composition. An aspect of the present invention provides a pharmaceutical composition, comprising an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, and an effective amount of at least one antiviral agent, and a pharmaceutically acceptable carrier. One aspect of the present embodiment provides a pharmaceutical composition, wherein the composition is a gel composition. Yet another aspect of the present embodiment provides a pharmaceutical composition, wherein the composition is an ointment composition. Definitions The term "PMEG" refers to the compound 9- (2-phosphonylmethoxyethyl) guanidine, The term "PMEDAP" refers to the compound 9- (2-phosphonylmethoxyethyl) -2,6-diaminopurine, The term "cprPMEDAP" refers to the compound 9- (2-phosphonylmethoxyethyl) -2-amino-6- (cyclopropyl) purine, "Bioavailability" is the degree to which the pharmaceutically active agent becomes available to the target tissue after the introduction of the agent into the body. Increasing the bioavailability of a pharmaceutically active agent can result in a more efficient and effective treatment for patients because, for a given dose, more of the pharmaceutically active agent will be available at the target tissue sites. The terms "phosphonate" and "phosphonate group" include the functional groups or portions within a molecule that comprise a phosphorus that is 1) bonded to a single carbon, 2) linked with a double bond to a heteroatom, 3) linked with a bond simple to a heteroatom, and 4) linked with a single bond to another heteroatom, where each heteroatom can be the same or different. The terms "phosphonate" and "phosphonate group" also include functional groups or portions comprising a phosphorus in the same oxidation state as the phosphorus described above, as well as functional groups or portions comprising a prodrug portion that can be separated from a compound, so that the compound retains a phosphorus having the characteristics described above. For example, the terms "phosphonate" and "phosphonate group" include phosphonic acid, phosphonic monoester, phosphonic diester, phosphonamidate, and phosphonothioate functional groups. In a specific embodiment of the invention, the terms "phosphonate" and "phosphonate group" include functional groups or portions within a molecule comprising a phosphorus that is 1) bonded to a carbon, 2) bonded with double bond to an oxygen, 3) bound by a single bond to an oxygen, and 4) linked by a single bond to another oxygen atom, as well as functional groups or portions comprising a prodrug portion that can be separated from a compound, so that the compound retains a phosphorus that has such characteristics. In another specific embodiment of the invention, the terms "phosphonate" and "phosphonate group" include functional groups or portions within a molecule that comprise a phosphorus that is 1) bonded to a carbon, 2) linked with a double bond to an oxygen, 3) bonded to an oxygen or nitrogen bond and 4) bonded to another oxygen or nitrogen, as well as functional groups or portions comprising a prodrug portion that can be separated from a compound, so that the compound retains a phosphorus that has such characteristics. The recipes and methods for determining the stability of the compounds in substitute gastrointestinal secretions are known. The compounds are defined herein as being stable in the gastrointestinal tract where less than about 50 mole percent of the protected groups are protected in intestinal or gastric substitute juice after incubation for 1 hour at 37SC. Such compounds are suitable for use in this embodiment. Note that simply because the compounds are stable to the gastrointestinal tract, that does not mean they can not be hydrolyzed in vivo. Prodrugs will typically be stable in the digestive system, but are substantially hydrolyzed to the parent drug in the digestive lumen, liver or other metabolic organ or within cells in general. The compounds of the invention may also exist as tautomeric isomers in certain cases. For example, eno-amine tautomers may exist for imidazole, guanidine, amidine, and tetrazole systems, and all their possible tautomeric forms are within the scope of the invention. The term "prodrug" as used herein refers to any compound that when administered to a biological system generates the pharmacological substance, e.g., the active ingredient, as a result of the spontaneous chemical reaction (s).; the chemical reactions or reactions catalyzed by enzyme, photolysis and / or one or more metabolic chemical reactions. A prodrug is thus a covalently modified analog or latent form of a therapeutically active compound. A "prodrug portion" refers to a labile functional group that is separated from the active inhibitory compound during metabolism, systemically, within a cell, by hydrolysis, by enzymatic cleavage, or by some other process (Bundgaard, Hans, "Design and Application of Produgs "in A Texbook of Drug Design and Development (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191). Enzymes that are capable of performing an enzymatic activation mechanism with the prodrug phosphonate compounds of the invention include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphases. The prodrug portions can serve to increase solubility, absorption and lipophilicity, to optimize drug distribution, bioavailability and efficacy. A prodrug portion may include an active metabolite or the drug itself. Exemplary prodrug moieties include the hydrolytically responsive or labile acyloxymethyl esters -CH2OC (= 0) R and the acyloxymethyl carbonates -CH2OC (= 0) OR wherein R in this case is alkyl of 1 to 6 carbon atoms, alkyl from 1 to 6 carbon atoms substituted, aryl of 6 to 20 carbon atoms, or substituted aryl of 6 to 20 carbon atoms. The acyloxyalkyl ester was first used as a prodrug strategy for carboxylic acids, and then applied to phosphates and phosphonates by Farquhar et al. (1983) J. Pharm. Sci. 72: 324; also Patents of the United States Nos. 4816570, 4968788, 5663159 and 5792756. Subsequently, the acyloxyalkyl ester was used to distribute the phosphonic acids through cell membranes and to increase oral bioavailability. A close variant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester (carbonate), may also increase oral bioavailability as a prodrug moiety in the compounds of the combinations of the invention. An exemplary acyloxymethyl ester is isopropylcarbonyloxy ethoxy, -OCH2OC (= 0) C (CH3) 2. An exemplary acryloxymethyl carbonate prodrug portion is isopropylcarbonyloxymethyl carbonate, HOC (= 0) 0CH20C (= 0) C (CH3) 2. The phosphonate group may be a prodrug portion of phosphonate. The prodrug portion may be sensitive to hydrolysis, such as, but not limited to, an isopropylcarbonyl-oximetoxy group or isopropylcarbonyloxymethyl carbonate. Alternatively, the prodrug portion may be sensitive to enzymatic enhanced cleavage, such as a lactate ester or a phosphonate-idato ester group. Aryl esters or phosphorus groups, especially phenyl esters, are reported as oral bioavailability enhancers (De Lombaert et al. (1994) J. "Med. Chem. 37: 498.) Phenyl esters containing an ester carboxylic in position ortho to phosphate, have also been described (Khamnei and Torrence, (1996), J.

Med. Chem. 39: 4109-4115). It is reported that benzyl esters generate the parent phosphonic acid. In some cases, substituents in the ortho or para moiety may accelerate hydrolysis. Benzyl analogs with an acylated phenyl or an alkylated phenol can generate the phenolic compound through the action of enzymes, for example, esterases, oxidases, etc., which in turn undergo cleavage of the benzylic C-0 bond to generate the phosphoric acid and the quinone methylide intermediate. Examples of this class of prodrugs are described by Mitchel et al (1992) J. Chem. Soc. Perkin Trans. II 2345; Glazier WO 91/19721. Even other benzylic prodrugs have been described containing a group containing carboxylic ester bonded to benzylic methylene (Glazier WO 91/19721). Prodrugs containing thio are reported as useful for the intracellular distribution of phosphonate drugs. These proesters contain an ethylthio group in which the thiol group is either esterified by an acyl group or combined by other thiol groups to form a disulfide. Deesterification or reduction of the disulfide generates the free thio intermediate which subsequently breaks down to phosphoric acid and disulfide (Puech et al (1993) Antiviral Res. 22: 155-174; Benzaria et al. (1996) J. Med. Chem. 39: 4958). Cyclic phosphonate ethers have also been described as prodrugs of the phosphorus-containing compounds (Erion et al., U.S. Patent No. 6312662). "Protective group" refers to a portion of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See for example, Protective Groups in Oganic Chemistry, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protective groups are often used to mask the reactivity of certain functional groups, to assist in the efficiency of the desired chemical reactions, for example, by making and breaking chemical bonds in an orderly and planned manner. . The protection of the functional groups of a compound alters the physical properties in addition to the reactivity of the protected functional group, such as polarity, lipophilicity (hydrophobicity), and other properties that can be measured by common analytical tools. Chemically protected intermediates can themselves be biologically active or inactive. The protected compounds may also exhibit altered, and in some cases, optimized, in vitro or in vivo properties, such as passage through cell membranes and resistance to enzymatic degradation or sequestration. In this role, the compounds protected with the intended therapeutic effects can be referred to as prodrugs. Yet another function of the protecting group is to convert the parent drug to a prodrug, whereby the parent drug is released after conversion of the prodrug in vivo. Because active profancans can be absorbed more effectively than the parent drug, the prodrugs may possess greater potency in vivo than the parent prodrug. Protective groups are removed either in vitro, in the case of chemical intermediates or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting products after deprotection, for example, alcohols, are physiologically acceptable, although in general it is more desirable if the products are pharmacologically harmless. Any reference to any of the compounds of the invention also includes a reference to a physiologically acceptable salt thereof. Examples of physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal (e.g., sodium), an alkaline earth metal (e.g., magnesium), ammonium and NX4 + (wherein X it is alkyl of 1 to 4 carbon atoms). Physiologically acceptable salts of a hydrogen atom or an amino group include organic carboxylic acid salts such as benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids.; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids, The physiologically acceptable salts of a hydroxyl group compound include the anion of the compound in combination with suitable cation such as Na + and X + (wherein X is independently selected). of hydrogen or an alkyl group of 1 to 4 carbon atoms) As used herein, the term "gel" refers to semi-solid systems consisting of either suspensions consisting of small inorganic particles or large organic molecules that enclose and that are interpenetrated by a liquid.Where the gel mass consists of small particle flocs, the gel is classified as a two-phase system and is sometimes called a magma.The aluminum hydroxide gel and the bentonite magma are examples of two-phase systems.Single-phase gels consist of uniformly distributed organic macromolecules at All along a liquid, in such a way that there are no apparent limits between the dispersed macromolecules and the liquid. Examples of such gels are sodium carboxymethyl cellulose and tragacanth. Although gels are commonly aqueous, alcohols and oils can be used as a continuous phase. As used herein, the term "ointment" refers to a semi-solid preparation for external application of a consistency such that they can be easily applied to the skin by anointing. These should be of such composition that they soften but do not necessarily melt when applied to the body. These serve as vehicles for the topical application of medicinal substances, and also function as protectors and emollients for the skin. For the therapeutic use of the salts of the active ingredients of the compounds of the invention it will be physiologically acceptable, for example, these will be salts derived from a physiologically acceptable acid or base. However, salts of acids or bases that are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically stable compound. All salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the present invention. "Alkyl" is a hydrocarbon of 1 to 18 carbon atoms containing normal, secondary, tertiary, cyclic carbon atoms. Examples are methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3) 2-propyl (i-Pr, i-propyl, -CH (CH3 ) 2, 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, CH2CH (CH3) 2), 2-butyl (s-Bu, s-butyl, -CH (CH3) CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH3) 3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2- pentyl (-CH (CH3) CH2CH2CH3), 3-pentyl (-CH (CH2CH3) 2), 2-methyl-2-butyl (-C (CH3) 2CH2CH3), 3-methyl-2-butyl (-CH (CH3 ) CH (CH3) 2), 3-methyl-l-butyl (-CH2CH2CH (CH3)), 2-methyl-l-butyl (-CHCH (CH3) CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH (CH3) CH2CH2CHCH3), 3-hexyl (-CH (CH2) 3CH2CH2CH3)), 2-methyl-2-pentyl (-C (CH3) 2CH2CH2CH3), 3-methyl-2-pentyl (-CH (CH3) CH (CH3) CH2CH3), 4-methyl- 2-pentyl (- C (CH3) (CH2CH (CH3) 2), 3-methyl-3-pentyl (-C (CH3) (CH2CH3) 2), 2-methyl-3-pentyl (-CH (CH2CH3) CH (CH 3) 2), 2,3-dimethyl-2-butyl (-C (CH 3) 2 CH (CH 3) 2), 3,3-dimethyl-2-butyl (-CH (CH 3) C (CH 3) 3. " "Alkenyl" is a hydrocarbon of 2 to 18 carbon atoms containing normal, secondary, tertiary or cyclic carbon atoms with at least one unsaturation site, eg, a double bond, carbon-carbon, sp2. Examples include, but are not limited to ethylene or vinyl (-CH = CH2), allyl (-CH2CH = CH2), cyclopentyl (-C5H7), and 5-hexenyl (-CH2CH2CH2CH = CH2). "Alkynyl" is a hydrocarbon of 2 to 18 atoms carbon containing carbon atoms, normal, secondary, tertiary or cyclic, with at least one site of instauration, for example, a triple carbon-carbon sp bond.Examples include but are not limited to, acetylene (-C = CH) and propargyl (-CH2C = CH). "Alkylene" refers to a straight or branched or cyclic hydrocarbon radical, or saturated of 1-18 carbon atoms, and having two centers of monovalent radicals derived by the removal of two hydrogen atoms from the same or two different atoms carbon atoms of a parent alkane. Typical alkylene radicals include, but are not limited to, methylene - (CH2-), 1,2-ethyl (-CH2CH2-), 1,3-propyl (-CH2CH2CH2-), 1,4-butyl (-CH2CH2CH2CH2- ), and the like. "Alkenylene" refers to a straight or branched or cyclic, or unsaturated, hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or from two different atoms of a parent alkene carbon. Typical alkenylene radicals include, but are not limited to, 1,2-ethylene (-CH = CH-). "Alkynylene" refers to a straight or branched chain or cyclic, or unsaturated hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or from two different atoms of carbon from a parent alkyne. Typical alkynylene radicals include, but are not limited to, acetylene (-C = C-), propargyl (-CH2C = C-), and 4-pentynyl (-CH2CH2CH2C = CH-). "Aryl" means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms, derived by removal of a hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups, include but are not limited to, radicals derived from benzene, substituted benzene, naphthalene, .. anthracene, biphenyl and the like. "Arylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl radical. Arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthyletan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like. The arylalkyl group comprises 6 to 20 carbon atoms, for example, the alkyl portion, which includes the alkyl, alkenyl or alkynyl groups, the arylalkyl group of 1 to 6 carbon atoms and the aryl portion is from 5 to 14 carbon atoms . "Substituted alkyl", "substituted aryl" and "substituted arylalkyl" mean alkyl, aryl, and arylalkyl respectively, in which, one or more hydrogen atoms are each independently replaced with a substituent other than hydrogen. Typical substituents include but are not limited to, -X, -R, -0, -OR, -SR, -S, -NR2, -NR3, -NR, -CX3, -CN, -OCN, -SCN, - N = C = 0, -NCS, -NO, -N02, = N2, -N3, NC (= 0) R, -C (= 0) R, -C (= 0)? RR, -S (= 0 ) 20, -S (= 0) 20H, -S (= 0) 2R, -0S (= 0) 20R, -S (= 0) 2? HR, -S (= 0) R, -0P (= 0 ) O2RR, P (= 0) 02RR -P (= 0) (0 ~) 2, -P (= 0) (0H) 2, -C (= 0) R, -C (= 0) X, -C (S) R, -C (0) OR, -C (0) 0-, -C (S) 0R, -C (0) SR, -C (S) SR, -C (0)? RR, - C (S) NRR, -C (? R)? RR, wherein each X is independently a halogen: fluorine, chlorine, bromine or iodine; and each R is independently -H, alkyl, aryl, heterocycle, a protecting group or a prodrug moiety. The alkylene, alkenylene, and alkynylene groups can also be similarly substituted. "Heterocycle" as used herein, includes by way of example, and not limitation, those heterocycles described in Paquette, Leo A.; Principies of Modern Heterocyclic Chemistry (W.A. Benjamin, New York, 1968), particularly chapters 1, 3, 4, 6, 7 and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs " (John Wiley &Sons,? Ew York, 1950 to present), in particular volumes 13, 14, 16, 19 and 28; and J. Am. Chem. Soc. (1960) 82: 5566. In a specific embodiment of the invention "heterocycle" includes a "carbocycle" as defined herein, wherein one or more (eg, 1, 2, 3 or 4) carbon atoms have been replaced with a heteroatom (by example, oxygen, nitrogen or sulfur).

Examples of heterocycles include, by way of example and not limitation, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, tetrahydrothiophenyl oxidized in sulfur, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, tianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetraMdrc? ^ inolinyl, tetxa droisoquinolinyl, deca droquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2 , 5-thiadiazinyl, 2H, 6H-1, 5, 2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofranyl, chloroenyl, xanthenyl, phenoxatinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H -indolyl, IH-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinolinyl, pteridinyl, 4aH-carbazolyl, ca rbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthroline, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, isatinoyl, and bis-tetrahydrofranyl.

By way of example and not limitation, heterocycles with carbon bonds are linked in the 2, 3, 4, 5 or 6 position of a pyridine, the 3, 4, 5, or 6 position of a pyrazine, the position 2, 4, 5 or 6 of a pyridine, position 2, 3, 5 or 6 of a pyrazine, position 2, 3, 4 or 5 of a furan, tetrahydrofuran, thiofuran, thiophene or pyrrole or tetrahydropyrrole, position 2 , 4 or 5 of an oxazole, imidazole or thiazole, the 3, 4 or 5 position of an isoxazole, pyrazole, or isothiazole, the 2 or 3 position of a azaridine, the 2, 3 or 4 position of an azetidine, the position 2, 3, 4, 5, 6, 7 or 8 of a quinoline or the 1, 3, 4, 5, 6, 7, or 8 position of an isoquinoline. Still more typically, carbon-linked heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl. By way of example and not limitation, the heterocycles linked with nitrogen are linked at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperadine, piperazine, indole, indoline, HH-indazole, position 2 of an isoindol or isoindolite, position 4 of a morpholine, and position 9 of a carbazole, or ß -carbolina. Still more typically, heterocycles linked with nitrogen include 1-aziridyl, 1-azetidyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl. "Carbocycle" refers to a saturated, unsaturated or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicyclic, and up to about 20 carbon atoms as a polycycle. Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, for example accommodated as a bicycle system [4,5], [5,5], [5,6] or [6,6], or 9 to 10 atoms in the ring accommodated as a bicycle system [5,6] or [6,6]. Examples of monocyclic carbocycles include cyclopropyl (cPropyl), cyclobutyl (cButyl), cyclopentyl (cPentyl), 1-cyclopentyl-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1-cyclohex -l-enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, phenyl, spiroyl, and naphthyl. "Linker" "link" refers to a chemical moiety comprising a covalent bond or a chain or group of atoms that covalently binds a phosphonate group to a drug. The linkers include portions such as: repeated alkyloxy units (eg, polyethyleneoxy, PEG, polymethyleneoxy), and alkylamino (eg, polyethyleneamino, Jeffamine1111); and diacid ester and amides including succinate, succinamide, diglycolate, malonate and caproamide. As used herein, the term "Aba" refers to a divalent portion of 2-aminobutanoic acid, where the link points are designated by "*". As used herein, the term "Ala" refers to a divalent portion of alanine, where the link points are designated by "*". As used herein, the term "Phe" refers to a divalent portion of phenylalanine, wherein the linking points are designated by As used herein, the term "POC" refers to a divalent portion of the hydroxymethyl isopropyl carbonate, where the link point is designated by "*". The substituent groups Y1A and Y1B can be described using the nomenclature incorporating the aforementioned divalent amino acid portions, and the alkyl portions, such as in the Table 80-3. For example, the compound of the formula, can be described using the nomenclature of Formula I, wherein Y1A and Y1B are -N (RX), where Rx is R2, where R2 is R4 substituted with R3d, where R4 is ethyl substituted with R3d where further R3d is -C (R3b) OW3, where R3b is = 0, where W3 is W5, where W5 is a carbocycle, where R4 is propyl substituted with R3d, where R3d is -C (R3b = OR4, where R3b is = 0, and where R4 is ethyl.Alternatively, the compound can be described, as in Table 80-3, as Formula I, where Y ^ and Y? are "Aba-Et", which describes the portion (where "*" indicates the link point), which is "Aba" linked to "Et" (ethyl). For example, the compound of the formula, can be described using the nomenclature of Formula I, where Y ^ and Y18 are -NYP ^), where Rx is R2, where R2 is R4 substituted with R3d, where R4 is ethyl substituted with R3d, wherein R3d is - C (R3) OR4, where R3b is = 0, and where R4 is n-propyl. Alternatively, the compound can be described as in Table 80-3, such as Formula I, wherein Y1A and Y1B are "Ala-nPr", which describes the portion (where the "*" sign indicates the link point), which is "Ala" linked to "nPr" (n-propyl) The term "chiral" refers to the molecules that have the property of non-superimposability of the partner image in the mirror, while the term "achiral" refers to the molecules that are superimposable on their image in the mirror. The term "stereoisomers" refers to compounds that have chemical constitution, identical, but that differ with respect to the arrangement of atoms or groups in space. "Diastereoisomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereoisomers have different physical properties, for example, melting points, boiling points, spectral properties and reactivities. Mixtures of diastereomers can be separated under high resolution analytical methods such as electrophoresis and chromatography. "Enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. The term "treatment" or "treatment" to the extent that it refers to a disease or condition includes preventing the occurrence of the disease or condition, inhibition of the disease or condition, elimination of the host or condition, and / or relief. of one or more symptoms of the disease or condition.

The term "antiproliferative" refers to the activities used for or tending to inhibit cell growth, such as the antiproliferative effects on solid tumors or antiproliferative effects on virally infected cells. The term "apoptosis" refers to one of the main types of programmed cell death. As such, this is a deliberate suicide process by an unwanted cell, in a multicellular organism. In contrast to necrosis, which is a form of cell death resulting from acute tissue damage, apoptosis is carried out in an orderly process that generally confers advantages during the life cycle of an organism. Apoptosis is a type of cell death in which the cell uses specialized cellular machinery to kill itself; and the mechanism of cell suicide that makes metazoans possible controls the number of cells and eliminates threatening cells in the survival of the animal. Apoptosis can occur, for example, when a cell is damaged beyond repair or infected with a virus. The stimuli for apoptosis can come from the cell itself, from its surrounding tissue or from a cell that is part of the immune system, this can be chemical, biological or physical. The related term "apoptotic" refers to the process of apoptosis.

The stereochemical definitions and conventions used herein, in general, follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Willey & Sons, Inc., New York ,. There are many organic compounds in optically active form, for example, these have the ability to rotate the plane of polarized light in the plane. In the description of an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule around its or its chiral centers. The prefixes d and 1 or (+) or (-) are used to designate the sign of rotation of the polarized light in the plane by the compound, with (-) or 1 which means that the compound is levorotatory. The compound with the prefix (+) or d is dextrorotatory. For a given chemical structure, these stereosomers are identical except that they are mirror images of each other. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or a racemate, which can appear where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity. Protective groups In the context of the present invention, the protecting groups include the prodrug portions and the chemical protecting groups. Protective groups are available, commonly known and used, and are optionally used to prevent collateral reactions with the protected group during synthetic procedures, for example, routes or methods for preparing the compounds of the invention. For most of the decision regarding which groups to protect, when to perform it and the nature of the chemical protective group "PG" will be dependent on the chemistry of the reaction against which it will be protected (eg, acidic, alkaline, oxidizing conditions). , reducers or others) and the intended direction of the synthesis. PG groups do not need to be, and in general are not, the same if the compound is substituted with multiple PGs. In general, PG will be used to protect functional groups such as carboxyl, hydroxyl, thio or amino groups and to thereby prevent collateral reactions or to otherwise facilitate synthetic efficiency. The order of deprotection to produce unprotected, free groups is dependent on the intended direction of the synthesis and on the reaction conditions that are to be encountered, and can appear in any order as determined by the expert. Various functional groups of the compounds of the invention can be protected. For example, the protecting groups for the -OH groups (either hydroxyl, carboxylic acid, phosphonic acid or other functional groups) include the "ether or ester forming groups". The ether or ester forming groups are capable of functioning as chemical protecting groups in the synthetic schemes described herein. However, some hydroxyl and thio protecting groups are neither ether nor ester formers, as will be understood by those skilled in the art, and are included with the amides, discussed below. A very large number of hydroxyl protecting groups and amide-forming groups and the corresponding chemical cleavage reactions are described in Protective Groups in Organic Synthesis, Theodora W. Greene (John Wiley &Sons, Inc., New Jersey, 1991, ISB 0-471-62301-6) ("Greene"). See also Kocienski, Philip J .; Protecting Groups (Georg Thieme Verlag Stuttgart, York, 1994), which is incorporated by reference herein in its entirety. In particular, Chapter 1, Protective Groups: A Revision, pages 1-20, Chapter 2, hydroxyl protecting groups, pages 21-94, Chapter 3, Diol protecting groups, pages 95-117, Chapter 4, carboxyl protecting groups, pages 118-154, Chapter 5, carbonyl protecting groups, pages 155-184. The protective groups for carboxylic acid, phosphonic acid, phosphonate, sulfonic acid and other acid protecting groups, see Greene as described below. Such groups include, by way of example and not limitation, esters, amides, hydrazides, and the like. Ether and ester forming protecting groups The ester forming groups include: (1) phosphonate ester-forming groups, such as phosphonamidate esters, phosphorothioate ethers, phosphonate esters and phosphon-bis-amidates; (2) carboxyl ester forming groups; (3) sulfur ester forming groups, such as sulfonate, sulfate and sulfinate. The phosphonate portions of the compounds of the invention may or may not be the prodrug portions, for example, they may or may not be susceptible to cleavage or hydrolytic or enzymatic modification. Certain phosphonate portions are stable under most or almost all metabolic conditions. For example, a dialkylphosphonate, wherein the alkyl groups are two or more carbons, may have appreciable stability in vivo due to the slow rate of hydrolysis.

Salts and hydrates The compositions of this invention optionally comprise salts of the compounds of the present invention, especially pharmaceutically acceptable non-toxic salts containing, for example, Na +, Li +, K +, Ca ++ and Mg ++. Such salts can include those derived by combination of suitable cations such as alkali metal and alkaline earth metal ions or ammonium and quaternary amino ions, with an acidic anion portion. Monovalent salts are preferred and a water soluble salt is desired. Metal salts are typically prepared by the reaction of a compound of this invention with a compound of this invention with metal hydroxide. Examples of metal salts that are prepared in this manner are salts containing Li +, Na +, and ¥ Y. A metal salt less soluble in water can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound. In addition, the salts can be formed from the addition of acid of certain organic and inorganic acids, for example, HCl, HBr, HS04, or organic sulfonic acids, to the basic centers, or to the acid centers. Finally, it should be understood that the compositions herein comprise the compounds of the invention in their non-ionized as well as amphoteric forms, and combinations with stoichiometric amounts of water such as hydrates.

Also included within the scope of the invention are the salts of the parent compounds with one or more amino acids. Any of the amino acids described above are suitable, especially naturally occurring amino acids found as protein components, although the amino acid is typically one that possesses a side chain with a basic or acid group, for example, lysine, arginine, or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine. Methods of inhibiting HPV Another aspect of the invention relates to methods for inhibiting HPV activity, comprising the step of treating a sample suspected of containing HPV with a compound of the invention. The compositions of the invention are as HPV inhibitors, as intermediates for such inhibitors or have other abilities as described below. The treatment step of the invention comprises the addition of the composition of the invention, to the sample, or comprises the addition of a precursor of the composition to the sample. The addition step comprises any method of administration as described above. If desired, the HPV activity after application of the composition can be observed by any method including direct and indirect HPV detection methods. The quantitative, qualitative and semi-qualitative methods to determine HPV activity are all contemplated. Typically, one of the screening methods described above is applied, however, any other methods such as observation of the physical properties of a living organism are also applicable. Selections for inhibiting HPV The compounds and compositions of the invention are selected for therapeutic utility by measuring the EC50, which is the concentration of the compound that achieves 50% inhibition of cell growth. The ratio of Ec50 in the uninfected cells and infected by the PHV provides a measure of the selectivity of the compound for the cells infected with virus. The protocols used to obtain these measurements are shown in the examples. Pharmaceutical Formulations and Administration Routes The compounds of this invention are formulators with conventional carriers and excipients, which will be selected in accordance with ordinary practice. The tablets will obtain containers, glidants, fillers, binders and the like. The aqueous formulations are prepared in sterile form and when they are intended for distribution by a different administration from the oral, will be generally isotonic. All formulations will optionally contain excipients such as those described in the "Handbook of Pharmaceutical Excipients" (1986). The excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid and the like. The pH of the formulations is in the range of about 3 to about 11, but is ordinarily about 7 to 10. One or more compounds of the invention (referred to herein as active ingredients) are administered by any appropriate route for condition that is going to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) routes, and the like. It will be appreciated that the preferred route may vary with the condition of the patient. An advantage of the compounds of this invention is that they are orally bioavailable and can be dosed orally. While it is possible for the active ingredients to be administered alone it may be preferable to present them as pharmaceutical formulations. The formulations, for veterinary use and for human use of the invention, comprise at least one active ingredient, as defined above, together with one or more acceptable carriers therefor, and optionally other therapeutic ingredients. The carrier (s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically safe for the container thereof. The formulations include those suitable for the aforementioned administration routes. The formulations can be conveniently presented in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy. The techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary, shaping the product. Formulations of the invention, suitable for oral administration are prepared as discrete units such as capsules, sacks or tablets each containing a predetermined amount of the active ingredient.; like a powder or granule; as a solution or suspension in an aqueous liquid or a non-aqueous liquid, or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be presented as a bolus, electuario pasta. A tablet is made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active agent or dispersing agent. The molded tablets can be made by molding, in a suitable machine a mixture of the active ingredient powder moistened with an inert liquid diluent. The tablets may optionally be coated or chewed and optionally formulated to provide slow or controlled release of the active ingredient therefrom. For infections of the eyes or other external tissues, for example, the mouth and the skin, formulations are preferably applied as a topical ointment or cream containing the active ingredient (s) in an amount of, for example, 0.75 to 20% p / p (including the active ingredient (s) in a range of 0.1% and 20% in increments of 0.1% w / w such as 0.6% w / w, 0.7% w / w, etc.), preferably 0.2 to 15% w / w p and most preferably 0.5 to 10% w / w. When formulated in an ointment, the active ingredients can be used either as a paraffinic ointment base or water miscible. Alternatively, the active ingredients can be formulated in a cream with a base of cream oil in water. If desired, the aqueous phase of the cream base may include, for example, at least 30% w / w of a polyhydric alcohol, for example, an alcohol having two or more hydroxyl groups such as propylene glycol, butan-1. , 3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. Topical formulations may desirably include a compound that increases the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogues. The aqueous phase of the emulsions of this invention can be constituted of other known ingredients, in a known manner. While the phase may merely comprise an emulsifier (otherwise known as an emulsifier), it desirably comprises a mixture of at least one emulsifier with an oil or a fat, or with a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include an oil and a fat. Together, the emulsifier (s) with or without stabilizers constitute the so-called emulsifying wax, and the wax together with the oil and the fat constitute the so-called emulsifying ointment base which form the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium laurisulfate. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. The cream should preferably be a non-greasy, non-staining and washable product, with adequate consistency to prevent leakage from the tubes or other containers. Mono- or dibasic, straight-chain or branched alkyl esters, such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a mixture of branched chain esters known as Crodamol CAP can be used, the last three being the preferred esters. These can be used alone or in combination, depending on the properties required. Alternatively, high melting lipids such as white soft paraffin and / or liquid paraffin or other mineral oils are also used. Formulations suitable for topical administration to the eye also include ophthalmic drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%, particularly about 1.5% w / w. Formulations suitable for topical administration in the mouth include tablets comprising the active ingredient in a flavored base, usually sucrose and acacia and tragacanth.; the tablets comprising the active ingredient in an inert base such as gelatin and glycine, or sucrose and acacia; and buccal washes comprising the active ingredient in a suitable liquid carrier. Formulations for rectal administration may be presented as a suppository on a suitable base comprising, for example, cocoa butter or a salicylate.

Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 micrometers (including particle sizes in a range between 0.1 and 500 micrometers in micrometer increments such as 0.5, 1, 30 micrometers , 35 micrometers), which are administered by rapid inhalation through the nasal passages or by inhalation through the mouth, to reach the alveolar sacs. Suitable formulations include aqueous oily solutions of the active ingredient. Formulations suitable for the administration of dry powder aerosol can be prepared according to conventional methods and can be distributed with other therapeutic agents such as compounds used hitherto in the treatment or prophylaxis of influenza A or B infections as described further ahead. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient, carriers such as are known in the art as appropriate. Formulations suitable for parenteral administration include solutions for sterile aqueous and non-aqueous injections which may contain antioxidants, buffers, bacteriostats, and solutes, render the formulation isotonic with the blood of the intended container; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations are presented in unit dose or multi-dose containers, for example, sealed ampoules and flasks, and can be stored in a freeze-dried condition (lyophilized) requiring only the addition of the sterile liquid carrier, eg, water by injection , immediately before use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the type previously described. Preferred unit dose formulations are those containing a daily dose or unit daily sub-dose, as described hereinabove, or an appropriate fraction thereof of the active ingredient. It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art, with respect to the type of formulation in question, for example, those suitable for oral administration may include flavoring agents. The invention further provides veterinary compositions comprising at least one active ingredient as defined above, together with a veterinary carrier therefor.

Veterinary carriers are useful materials for the purpose of administering the composition and can be solid, liquid or gaseous materials that are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions can be administered orally, parenterally or by any other desired route. The compounds of the invention can be used to provide controlled release pharmaceutical formulations containing as active ingredient one or more compounds of the invention ("controlled release formulations") in which the release of the active ingredient is controlled and regulated to allow dosage less frequent, or to improve the pharmacokinetic or toxicity profile of a given active ingredient. The effective dose depends at least on the nature of the condition being treated, on the toxicity, whether the compound is being used prophylactically (lower doses) or against an active influenza infection, the method or distribution, and the pharmaceutical formulation, and will be administered by the clinician using conventional dose scale studies. It can be expected that this is from about 0.0001 to about 1000 mg / kg of body weight per day; typically, from about 0.01 to about 10 mg / kg of body weight per day; more typically, from about 0.01 to about 5 mg / kg of body weight per day; more typically, about 0.05 mg / kg of body weight per day. For example, for inhalation the candidate daily dose for a human adult of approximately 70 kg of body weight will be in the range of 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and may take the form of a single dose or multiple doses. The active ingredients of the invention are also used in combination with other active ingredients. Such combinations are selected based on the condition being treated, the cross-reactivities of the ingredients and the pharmacokinetic properties of the combination. For example, when it comes to viral infections of the respiratory system, in particular influenza infection, the compositions of the invention are combined with antivirals (such as amantidine, rimantadine and ribavirin), mucolytics, expectorants, bronchodilators, antibiotics, antipyretics or analgesics. Ordinarily, antibiotics are antipyretics, and analgesics are administered together with the compounds of this invention. Metabolites of the compounds of the invention The present invention also provides the in vivo metabolic products of the compounds described herein, to the extent that such products are novel and not obvious from the prior art. - Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the compound administered, mainly due to the enzymatic processes. Accordingly, the invention includes novel and non-obvious compounds produced by a compound comprising contacting a compound of this invention with a mammal, for a period of time sufficient to produce a metabolic product thereof. Such products are typically identified by the preparation of a radiolabeled compound (e.g., C14 or H13) of the invention, by administering it parenterally in a detectable dose (e.g., greater than about 0.5 mg / kg) to an animal such as a rat, mouse, guinea pig, monkey or a human, allowing sufficient time for metabolism to occur (typically approximately 30 seconds to 30 hours) and isolating their conversion products from urine, blood or other biological samples. These products are easily isolated, since they are marked (others are isolated by the use of antibodies capable of binding to the epitopes that survive in the metabolite). The structures of the metabolites are determined in a conventional manner, for example, by mass spectrometry (MS) or nuclear magnetic resonance (NMR) analysis. In general, metabolite analysis is performed in the same manner as conventional drug metabolism studies, well known to those skilled in the art. The conversion products, as long as they are not otherwise found in vivo, are useful in a diagnostic assay for the therapeutic dosing of the compounds of the invention even if they do not possess neuraminidase inhibitory activity on their own. Additional uses for the compounds of this invention The compounds of this invention, or the biologically active substances produced from the compounds by hydrolysis or metabolites in vivo, are used as immunogens or for conjugation to proteins, whereby they serve as components of immunogenic compositions for preparing antibodies capable of binding specifically to the protein, to the compounds or to their metabolic products that preserve immunologically recognized epitopes (antibody binding sites). Immunogenic compositions are therefore useful as intermediates in the preparation of antibodies for use in diagnosis, quality control or the like, the methods or in trials for the compounds or their new metabolic products. The compounds are useful for producing antibodies against otherwise non-immunogenic polypeptides, since the compounds serve as haptenic sites that stimulate an immune response that cross-reacts with the unmodified, conjugated protein. The hydrolysis products of interest include products of the hydrolysis of the acidic and basic groups protected and discussed above. As noted above, acid or basic amides comprising immunogenic polypeptides such as albumin or keyhole limpet hemocyanin are generally useful as immunogens. The metabolic products described above can retain a substantial degree of cross-immunological reactivity with the compounds of this invention. Thus, the antibodies of this invention will be capable of binding to the unprotected compounds of the invention, without binding to the protected compounds; alternatively, the metabolic products will be able to bind to the protected compounds and / or the metabolic products without binding to the protected compounds of the invention, or they will be able to bind specifically to one or all three of them. The antibodies desirably will not substantially cross-react with materials of natural origin. The substantial cross-reactivity is the reactivity under the necessary conditions specific for specific analytes, sufficient to interfere with the assay results.

The immunogens of this invention contain the compound of this invention having the desired epitope in association with an immunogenic substance. Within the context of the invention, such an association means the covalent bond to form an immunogenic conjugate (when applicable) or a mixture of non-covalently bound materials, or a combination of the foregoing. Immunogenic substances include adjuvants such as Freund's adjuvants, immunogenic proteins such as viral, bacterial, yeast, plant and animal polypeptides, in particular keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin or soybean trypsin inhibitor, and polysaccharides immunogenic Typically, the compound having the desired epitope structure is covalently conjugated to an immunogenic polypeptide or polysaccharide by the use of a polyfunctional (ordinarily bifunctional) crosslinking agent. The methods for the manufacture of the hapten immunogens are conventional per se, and any of the methods used hitherto to conjugate haptens to the immunogenic polypeptides or the like are suitably employed here as well, taking into account the functional groups on the precursors or on the hydrolytic products that are available for cross-linking, and the likelihood of producing antibodies specific to the epitope in question, as opposed to the immunogenic substance.

Typically, the polypeptide is conjugated to a site on the compound of the invention, distant from the epitope to be recognized. The conjugates are prepared in a conventional manner. For example, the cross-linking agents N-draxysuccinimide, succinic anhydride or alkN-C-Nalk are useful in the preparation of the conjugates of this invention. The conjugates comprise a compound of the invention linked by a bond or linking group of 1-100, typically 1-25, more typically 1-10 carbon atoms to the irimonogenic substance. The conjugates are separated from the starting materials and by products using chromatography or the like, and then they are sterilized by filtration and placed in jars for storage. The animals are typically immunized against the immunogenic conjugates or derivatives, and the antisera or monoclonal antibodies prepared in a conventional manner. The compounds of this invention are useful as linkers or spacers in the preparation of affinity absorption matrices, immobilized enzymes for process control, or immunoassay reagents. The compounds herein contain a plurality of functional groups that are suitable as sites for crosslinking desired substances. For example, it is conventional to bind affinity reagents such as hormones, peptides, antibodies, drugs and the like, to insoluble substrates. These insolubilized reagents are employed in a known manner to absorb binding partners for the affinity reagents from manufactured preparations, diagnostic samples and other impure mixtures. Similarly, immobilized enzymes are used to perform catalytic conversions with easy recovery of the enzyme. Bifunctional compounds are commonly used to bind analytes to detectable groups in the preparation of diagnostic reagents. Selection tests preferably use cells from particular tissues that are susceptible to HPV infection. The assays known in the art are suitable for determining bioavailability in vivo, including intestinal lumen stability, cell permeation, stability of hepatic homogenates and stability assays in plasma. However, even if the ester, amide or other protected derivatives are not converted in vivo to the free carboxyl, amino or hydroxyl groups, they remain useful as clinical intermediates. The utility for the present invention was taught using antiproliferation assays. Antiproliferation assays measure the effect of the compounds on the proliferation of cultured cells. The cells are cultured for 7 days in the presence of various concentrations of the compounds. On the 7th day, the cells are stained with dye, and the intensity of the staining (proportional to the number of cells) is measured with a spectrophotometer. The data are plotted against the concentrations of the compound, adjusted to the sigmoidal dose response curve, from which the concentration of the compound that reduces the rate of cell proliferation rate by 50% (effective concentration to 50% or Ec50). The active compounds in antiproliferation assays can be cytostatic (inhibit cell division) and / or cytocidal (kill cells). By performing proliferation assays on HPV-positive cancer cells and normal cells, compounds that inhibit the proliferation of HPV-positive cancer cells more efficiently than cells from normal human tissues were identified. Exemplary Methods of Making the Compounds of the Invention The invention also relates to the manufacturing methods and compositions of the invention. The compositions are prepared by any of the applicable techniques of organic synthesis. Many such techniques are well known in the art. However, many of the known techniques are elaborated in "Compendium of Organic Synthetic Methods" (John Wiley & amp; amp;; Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; vol. 4, Leroy G. Wade, Jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6, Michael B. Smith, as well as March, J., "Advanced Organic Chemistry, Third Edition," (John Wiley &Sons, New York, 1985), "Comprehensive Organic Synthesis, Selectivity, Strategy &Efficiency in Modern Organic Chemistry, In 9 Volumes, "Barry M. Trost, Editor-in-Chief (Pergamon Press, New York, 1993 printing). A number of exemplary methods for the preparation of the compositions of the invention are provided below. These methods are intended to illustrate the nature of such preparations and are not intended to limit the scope of the applicable methods. In general, the reaction conditions such as temperature, reaction time, solvents, treatment procedures and the like, will be those common in the art for the particular reaction to be performed. The cited reference material, together with the material cited herein, contains detailed descriptions of such conditions. Typically, the temperature will be from -100aC to 200SC, the solvents will be aprotic or protic, and the reaction times will be from 10 seconds to 10 days. The treatment consists essentially of quenching any unreacted reagents, followed by division between a water / organic layer system (extraction) and separating the layer containing the product. The oxidation and reduction reactions are typically carried out at temperatures close to room temperature (approximately 202C), although for metal hydride reactions the temperature is often reduced to 0aC to -100 aC, the solvents are typically aprotic for reductions, and they can be either protic or aprotic for oxidations. The reaction times are adjusted to achieve the desired conversions. Condensation reactions are typically carried out at temperatures close to room temperature, although for kinetically controlled condensations, not in equilibrium, they are also common at reduced temperatures (0aC to -100aC). Solvents can be either protic (common in equilibrium reactions) or aprotic (common in kinetically controlled reactions). Standard synthetic techniques such as the azeotropic removal of reaction by-products and the use of anhydrous reaction conditions (e.g., inert gas environments) are common in the art, and will be applied where applicable. Exemplary methods for preparing the compounds of the invention are shown in the following reaction schemes. Detailed descriptions of the methods are found in the experimental section below, and are referred to the specific reaction schemes.

Outlines Schematic of reaction 1 9 ^ \ O AcCI, ZnCI2.Et2O ^ / ^^ 0 ^, CI P (OiPr) 3, Heat '- f? E = tt2 ~ nO, Ac0 * " TMSBr, CH3CN Reaction Scheme 2 Reaction scheme 3 HCl H2N XC02Pr / TEA / PhOH 6 A Ilddririthio | MR-2 / PPh3 Pyridine, 60 ° c Reaction scheme 4 Scheme of 'reaction 5 Jjgj.MaN CQ2Et / TEA / PhDH AIdrit folMR-2 / PP 'Pyridine, ßo ° c Reaction Scheme 6 Reaction Scheme 7 Reaction scheme 8 Reaction scheme 9 Reaction scheme 10 Reaction scheme 11 Reaction scheme 12 Diagram of reaction 13 44 Reaction scheme 14 Reaction scheme 15 fifteen Reaction scheme 16 TMSBr, CH3CN Reaction scheme 17 Reaction scheme 18 Scheme of reaction 19 Reaction Scheme 20 Reaction Scheme 21 end 60 Reaction Scheme 22 Reaction Scheme 23 Each of the products of the following processes is optionally separated, isolated and purified before its use in subsequent processes. The terms "treated", "treatment" and the like, as used in the context of a chemical process, protocol or preparation, means contacting, mixing, reacting, allowing reaction, contact, or other common terms, in the technique to indicate that one or more chemical entities are treated in such a way as to convert it to one or more other chemical entities. This means that the "treatment of compound one with compound two" is synonymous with "allowing compound one to react with compound two", "contacting compound one or compound two", "reacting compound one with compound two ", and other common expressions in the art of organic synthesis to reasonably indicate that compound one was" treated, "" reacted, "" left to react, "etc. , with compound two. In the context of a chemical process, protocol, or preparation, "treat or treat" indicates the reasonable and usual manner in which organic chemicals are allowed to react. Normal concentrations "(O.O.LM at 10M, typically 0.1M to 1M), temperatures (-100aC to 2502C, typically -78aC to 1502C, more typically -78 aC to 100 SC, still more typically 0 aC a 100aC), reaction vessels (typically glass, plastic, metal), solvents, pressures, atmospheres (typically air for reactions insensitive to oxygen and water or nitrogen or argon for reactions sensitive to oxygen or water), etc. , are considered, unless indicated otherwise. The knowledge of similar reactions known in the technique of organic synthesis is used in the selection of conditions and apparatuses for the "treatment" in a given process. In particular, a person of ordinary experience in the technique of organic synthesis selects the conditions of apparatus reasonably expected to successfully carry out the chemical reactions of the processes described, based on knowledge in the art. The modifications of each of the above reaction schemes leads to various analogs of the specific exemplary materials produced above. The aforementioned citations describing the appropriate methods of organic synthesis are applicable to such modifications. In each of the above exemplary schemes it may be advantageous to separate the reaction products from each other and from the starting materials. The desired products of each step or series of steps are separated and / or purified (hereinafter separated) to the desired degree of homogeneity by the common technique in the art. Typically, such separations involve the extraction of multiple phases, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods that include, for example, size exclusion or ion exchange chromatography, medium pressure or low pressure liquid chromatography, small scale and preparative thin or thick layer chromatography, as well as small scale thin layer chromatography and flash chromatography . Another class of separation method involves treatments of a mixture with a reagent selected to bind to or otherwise be separable from a desired product, unreacted starting material, reaction by product, or the like. Such reagents include adsorbents or absorbers such as activated carbon, molecular sieves, ion exchange media, or the like. Alternatively, the reagents may be acidic in the case of a basic material, bases in the case of an acidic material, reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid / liquid ion extraction reactions (LIX). ) or similar. The selection of appropriate separation methods depends on the nature of the materials involved, for example, boiling point and molecular weight in distillation and sublimation, -the presence or absence of polar functional groups in chromatography, stability of materials in media acid and basic in multiple phase extraction, and the like. A person skilled in the art will apply the techniques most likely to achieve the desired separation. All literature and citations of prior patents are expressly incorporated by reference herein at the sites of your appointment. Specifically, the sections and pages cited in the aforementioned works are incorporated by reference with specificity. The invention has been described in sufficient detail to enable a person of ordinary skill in the art to make and use the subject matter of the following claims. It is apparent that certain modifications of the methods and compositions of the following claims can be made within the scope and spirit of the invention. The following examples are provided to exemplify the present invention, and in no way can they be considered as limiting the present invention. EXAMPLES General Some examples have been done multiple times. In repeated instances, the reaction conditions, such as time, temperature, concentration and the like, and the yields, were within the normal experimental ranges. In repeated cases where significant modifications were made, these have been noted where the results varied significantly from those described. In the examples where different initial materials were used, they are noted. When the repeated examples refer to a "corresponding" analogue of a "corresponding ethyl ester", this attempts that a group otherwise present, in this case typically, a methyl ester, be taken to be the same group modified as indicated. Examples 1 to 35 refer to schemes 1 to 9 above. Use 1 Acetoxyethyl oxymethyl Chloride 1: A 5-liter three-necked flask that was equipped with a mechanical stirrer, thermometer, 500 ml addition funnel and purged with argon. 1,3-dioxalan (140 ml, 2.00 mol) in 800 ml of anhydrous diethyl ester and ZnCl2 / Et20 (7.5 ml, 0.007 mol) was added. A solution of acetyl chloride (157 ml, 2.20 mmol) was added dropwise through an addition funnel in 20 minutes. A cold water bath was used to maintain the temperature between 19-272C throughout. Stirring was continued without external cooling for 4 hours, the self-heating reaction of 20-252C for about 1 hour. The clear colorless solution was retained under argon overnight. It was left standing for 3 days and an orange solution was formed. The diethyl ether was removed in a rotary evaporator (water aspirator) until it was no longer distilled in a 352C bath. A quantitative yield of the product 318 g was obtained (theoretical yield 306 g). Example 2 Isopropyl Phosphonate 2: A 500 ml three-necked flask was charged with crude chloromethyl ether (317 g, 2.00 mol). Triisopropyl phosphite (494 ml) was added dropwise through an addition funnel, while heating in an oil bath at 1252C and stirring vigorously. The 2-chloropropane distillate was collected by means of a short path head in a receiver used with dry ice, argon atmosphere, and 140 g of the distillate (theoretical 157 g) was collected. The phosphite bleached the reaction to a yellow color, the heating was continued for another 2 hours at 1252C in an oil bath, then it was accommodated for vacuum distillation using a vacuum pump. A yellow front cut (140 g, head at 1352C, tail at 1902C) was distilled, then changed to a clean receiver. The main fraction was collected at the head temperature of 178-1872C (mainly 185-18 2C) with unknown vacuum at bath temperature of 222-2282C. 258 g of product 2 were obtained (47% yield from 1,3-dioxolane). Example 3 Alcohol 3: A solution of compound 2 (125 g, 0.443 mol) in 440 ml of absolute methanol was treated with concentrated HCl (11.2 ml, 0.112 mmol) and heated to reflux for 6 hours under argon atmosphere. The methanol was removed in a rotary evaporator (water aspirator) at 55 ° C, leaving 115 g of the clear oil which was co-evaporated with toluene (2 x 200 ml). The crude product was then dried under vacuum to give an oil (102 g, 96%). Example 4 Diisopropylphosphonate 4: A solution of triphenylphosphine (25.57 g, 97.5 mmol) and alcohol 3 (18 g, 75 mmol) in DMF (120 mL) was treated with 6-chloropurine (12.72 g, 75 mmol) and cooled to -152C. A solution of diisopropyl azodicarboxylate (16.68 g, 82.5 mmol) in 50 ml of DMF was added dropwise through an addition funnel in 80 minutes. The reaction mixture was kept at -15 ° C for 2 hours and then warmed to room temperature and stirred for an additional 2 hours. A cloudy reaction mixture formed a bright yellow solution. The reaction solvent was evaporated under reduced pressure, co-evaporated with 3 portions of toluene, and dried under vacuum overnight before purification. The crude product was purified by column chromatography on silica gel (5% MeOH / CH2Cl2) to give the diisopropyl phosphonate (18.52 g, 63%) as a white solid: XH NMR (CDC13) d 7.95 (s, ÍH) , 4.70 (m, -2H), 4.31 (m, 2H), 3.93 (m, 2H), 3.73 (m, 2H), 1.29 (m, 12H); 31 P NMR (CDC13) d 18.42. Example 5 Diisopropyl Phosphonate 5: A mixture of compound 4 (11.00 g, 28.08 mmol) and cyclopropylamine (4.86 g, 85.16 mmol) in 80 ml of CH3C? it was placed in a reaction pump and heated to 1002C for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The product was partitioned between 15% methanol / methylene chloride (3x) and brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (5% to give compound 5 (10.42 g, 90%) as a pale yellow foam: RM? L (CDCI3) d 7.59 (s, ÍH), 5.83 (s broad, ÍH), 4.88 (broad s, 2H), 4.70 (m, 2H), 4.21 (m, 2H), 3.88 (m, 2H), ~ 3.72 (d, J = 8.4 Hz, 2H), 3.03 (broad s, 1H), 1.28 (m, 12H), 0. 84 (, 2H), 0.60 (m, 2H); 31 P NMR (CDCl 3) d 18.63. Example 6 cPrPMEDAP 6: A solution of compound 5 (11.00 g, 26.67 mmol) in CH3C? Anhydrous (120 ml) was treated with bromotrimethylsilane (21.1 ml, 160.02 mmol). The reaction was protected from the light by flask wrapping with aluminum foil. The reaction mixture was stirred at room temperature overnight. The volatile materials were evaporated under reduced pressure. The residue was dissolved in 250 ml of water and the pH adjusted to 9 with ammonium hydroxide. The reaction mixture was concentrated and a yellow solid was obtained. The solid was dissolved in 30 ml of water and the pH adjusted to 2 with 10% HCl. The fine solid was collected and dried in vacuo to give compound 6 (7.88 g, 90%) as a white solid. Example 7 Monophosphonic acid chloride 7: A mixture of acid 6 (3.00 g, 9.15 mmol) and 0.1 ml of DMF in 9.2 ml of sulfolane was heated to 70aC. Thionyl chloride (1.66 ml, 22.76 mmol) was added dropwise over a period of 1 hour. The temperature was increased to 902C and TMSOPh (1.74 ml, 9.61 mmol) was added and stirred for 1 hour. The reaction mixture was cooled to room temperature overnight. The reaction mixture was added dropwise to 100 ml of stirred well cooled acetone.

The product was precipitated. The solid was filtered under an argon atmosphere, washed with 100 ml of cold acetone, dried in vacuo to give the monophosphonic acid hydrochloride (3.70 g, 92%) as a solid. Example 8 Monophosphonidate 8: A mixture of monophosphonic acid 7 (0.22 g, 0.50 mmol), L-alanine methyl ester hydrochloride (0.14 g, 1.00 mmol), and triethylamine (0.21 ml, 1.50 mmol) in 3 ml of pyridine was heated at 60 ° C for 5 minutes. A freshly prepared bright yellow solution of aldrithiol (0.39 g, 1.75 mmol) and triphenylphosphine (0.46 g, 1.75 mmol) in 2 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between ethyl acetate and saturated NaHCO 3. The organic phase was washed with brine, dried with sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (7% methanol / CH2C1) to give the • monophosphonidate (97 mg., 39%, diastereomeric mixture 1: 1) as a whitish foam. Example 9 Monophosphonidate 9: A mixture of monophosphonic acid 7 (0.88 g, 2.00 mmol), D-alanine methyl ester hydrochloride (0.84 g, 6.00 mmol), and triethylamine (0.84 ml, 6.00 mmol) in 8 ml of pyridine. it was heated to 602C for 5 minutes. A fresh bright yellow solution of aldrithiol (1.56 g, 7.00 mmol) and triphenylphosphine 1.84 g, 7.00 mmol) in 8 ml of pyridine ml was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (7% methanol / CH2C1) to give monophosphonamidate 0.40 g, 41%, diastereomeric mixture 1: 1) as a whitish foam. Example 10 Monophosphonidate 10: A mixture of monophosphonic acid 7 (0.88 g, 2.00 mmol), L-alanine ester hydrochloride (1.31 g, 6.00 mmol), and triethylamine (0.84 ml, 6.00 mmol) in 8 ml of pyridine, heated to 602C for 5 minutes. A fresh bright yellow solution of aldrithiol was added (1.54 g, 7.00 mmol) and triphenylphosphine (1.84 g, 7.00 mmol) in 8 ml of pyridine were added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated aHC03. The organic phase was washed with brine, dried with? A2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (7% methanol / CH2C12) to give the monophosphonamidate (0.38 g, 36%, diastereoisomeric mixture 1: 1) as a pale orange foam. Example 11 Monophosphonidate 11: A mixture of phosphonic acid 6 (0.10 g, 0.30 mmol), L-alanine ethyl ester hydrochloride (94 mg, 0.60 mmol), phenol (0.14 g, 1.52 mmol) and triethylamine (0.51 ml, 3.60 mmol) in 1.0 ml of pyridine was heated at 602C for 5 minutes. A fresh bright yellow solution of aldrithiol (0.47 g, 2.13 mmol) and triphenylphosphine (0.56 g, 2.13 mmol) in 1.0 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO / filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (7% methanol / CH2C12) to give monophosphonamidate (74 mg, 48%, diastereoisomeric mixture 1: 1) as a pale yellow foam: RM? "" "H d 7.61 (d, J = 4.2 Hz, 1H), 7.26-7.08 (m, 5H), 4.23 (m, 2H), 4.13 (m, 2H), 4.09 (m, 1H), 3.92-3.85 (m, 4H), 3.03 (s broad, 1H), 1.30-1.26 (m, 3H), 1.24 (m, 3H), 0.88 (m, 2H), 0.63 (, 2H), RM? 31P (CDC13) d 21.94, 20.68.

Example 12 Monophosphonidate 12: A mixture of phosphonic acid 6 (1.50 g, 4.56 mmol), n-propyl ester hydrochloride of L-alanine (1.59 g, 9.49 mmol), phenol (2.25 g, 22.80 mmol) and triethylamine (10.50 ml) , 54.72 mmol) in 8.0 ml of pyridine was heated at 60 aC for 5 minutes. A fresh bright yellow solution of aldrithiol (6.54 g, 31.92 mmol) and triphenylphosphine (7.32 g, 31.92 mmol) in 8.0 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 aC overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (7% methanol / CH2C1) to give the monophosphonamidate (0.43 g, 18%, Compound E, diastereoisomeric mixture 1: 1) as a pale yellow foam: RM? XH (CDC13) d 7.61 (d, J = 5.1 Hz, ÍH), 7.27-7.09 (m, 5H), 4.27-4.20 (m, 2H), 4.16-4.00 (m, 3H), 3.93-3.82 (m, 4H), 3.04 (broad s, 1H), 1.63 (m, 2H), 1.30 (dd, 3H), 0.92 (m, 3H), 0.89 (m, 2H), 0.63 (m, 2H); RM? 31P (CDC13) d 21.89, 20.66. Example 13 Monophosphonidate 13: A mixture of phosphonic acid 6 10 g, 0.30 mmol), L-alanine isopropyl ester hydrochloride (0.10 g, 0.60 mmol), phenol (0.14 g, 1.52 mmol) and triethylamine (0.51 ml, 3.60 mmol) ) in 1.0 ml of pyridine was heated at 60 aC for 5 minutes. A fresh bright yellow solution of aldrithiol (0.47 g, 2.13 mmol) and triphenylphosphine (0.56 g, 2.13 mmol) in 1.0 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO 4, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (7% methanol / CH2C12) to give the monophosphonamidate (87 mg, 55%, diastereoisomeric mixture 1: 1) as a yellow foam: XH NMR (CDC13) d 7.60 (d, J = 2.1 Hz, 1H), 7.26-7.09 (m, 5H), 4.98 (m, 1H), 4.23 (m, 2H), 4.06 (, ÍH), 3.91-3.83 (, 4H), 3.04 ( s broad, ÍH), 1.29-1.21 (m, 9H), 0.89 (m, 2H), 0.63 (, 2H); RM? 13P (CDC13) d 21.85, 20.68. Example 14 Monophosphonidate 14: A mixture of phosphonic acid 6 (0.10 g, 0.30 mmol), L-alanine ester hydrochloride (0.11 g, 0.60 mmol), phenol (0.14 g, 1.52 mmol) and triethylamine (0.51 3.60 mmol) in 1.0 ml of pyridine was heated at 60aC for 5 minutes. A fresh bright yellow solution of aldrithiol (0.47 g, 2.13 mmol) and triphenylphosphine (0.56 g, 2.13 mmol) in 1.0 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (7% methanol / CH2C12) to give monophosphonamidate (80 mg, 50%, diastereoisomeric mixture 1: 1) as a pale yellow foam: NMR? I (CDC13) d 7.61 (d, J = 4.20 Hz, ÍH), 7.27-7.08 (m, 5H); 5.93 (broad s, 4.97 (broad s, 2H), 4.23 (m, 2H), 4.10-4.08 (m, 3H), 3.91-3.84 (m, 4H), 3.03 (s broad, ÍH), 1.58 (m, 2H), 1.34-1.27 (m, 5H), 0.92-0.89 (m, 5H), 0.63 (m, 2H), 13P NMR (CDC13) d 21.94, 20.68 Example 15 Monophosphonidate 15: A mixture of phosphonic acid 6 ( 0.10 g, 0.30 mmol), n-hexyl ester hydrochloride of L-alanine (0.13 g, 0.60 mmol), phenol (0.14 g, 1.52 mmol) and 0.51 mL triethylamine, 3.60 mmol) in 1.0 mL of pyridine was heated to 602C. for 5 minutes. A fresh bright yellow solution of aldrithiol (0.47 g, 2.13 mmol) and triphenylphosphine (0.56 g, 2.13 mmol) in 1.0 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on ISCO (2-propanol / CH2Cl2) to give the onophosphonamidate (0.10 g, 59%, diastereoisomeric mixture 1: 1) as a pale yellow foam: XH NMR (CDC13) d 7.59 (d, J = 4.20 Hz, 7.26-7.08 (m, 5H), 4.22 (m, 2H), 4.11 (m, 4.06 (m, 2H), 3.91-3.84 (m, 4H), 3.01 (s broad, ÍH), 1.59 ( m, 2H), 1.31-1.27 (m, 9H), 0.89 (m, 3H), 0.86 (m, 2H), 0.62 (m, 2H), 13P NMR (CDC13) d 21.94, 20.68 Example 16 Monophosphonamidate 16: A mixture of phosphonic acid 6 (0.10 g, 0.30 mmol), L-alanine ester hydrochloride (0.15 g, 0.60 mmol), phenol (0.14 g, 1.52 mmol) and triethylamine (0.51 ml, 3.60 mmol) in 1.0 ml of pyridine was heated to 602C by 5 minutes. A fresh bright yellow solution of aldrithiol (0.47 g, 2.13 mmol) and triphenylphosphine was added. (0.56 g, 2.13 mmol) in 1.0 ml of pyridine to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO 4, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on ISCO (2-propanol / CH2C12) to give the monophosphonamidate (0.13 g, 73% diastereomeric mixture 1: 1) as a pale yellow foam: XH NMR (CDC13) d 7.59 (d, J = 4.2 Hz, HH), 7.25-7.07 (m, 5H), 4.22 (m, 2H), 4.10 (m, HH), 4.07 (m, 2H), 3.90-3.84 (m, 4H), 3.02 (s broad, 1H), 1.59 (m, 2H), 1.29-1.26 (m, 13H), 0.88 (m, 3H), 0.85 (m, 0.60 (m, 2H); 13P NMR (CDC13) d 21.96, 20.69. Monophosphonidate 17: A mixture of phosphonic acid 6 (70 mg, 0.21 mmol), L-2-aminobutyric acid ethyl ester hydrochloride (72 mg, 0.42 mmol), phenol (0.10 g, 1.05 mmol) and triethylamine (0.36 ml, 2.52 mmol) in 1.0 ml of pyridine was heated at 60 ° C. for 5 minutes.A fresh brightly prepared yellow solution of aldrithiol (0.33 g, 1.47 mmol) and triphenylphosphine (0.39 g, 1.47 mmol) in 1.0 ml of pyridine was added to the mixture. of reaction above The reaction was stirred at 60 ° C. overnight, cooled to room temperature Atura atmosphere, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO 4, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (7% methanol / CHC1) to give the monophosphonamidate (66 mg, 60%, diastereoisomeric mixture 1: 1) as a pale yellow foam: RM? XH (CDC13) d 7.61 (d, J = 7.2 Hz, ÍH), 7.26-7.08 (m, 5H), 5.91 (s broad, ÍH), 4.97 (broad s, 2H), 4.22-4.12 (m, 4H) , 4.01-3.81 (m, 5H), 3.03 (broad s, HI), 1.71-1.60 (m, 2H), 1.24 (m, 3H), 0.89 (m, 2H), 0.84-0.76 (m, 3H), 0.63 (m, 2H); RM? 13P (CDCl 3) d 22.15, 20.93.

Example 18 Monophosphonidate 18: A mixture of phosphonic acid 6 (1.00 g, 3.05 mmol), .. L-2-aminobutyric acid n-butyl ester hydrochloride (1.19 g, 6.09 mmol), phenol (1.43 g, 15.23 mmol) and triethylamine (5.10 mL, 36.60 mmol) in 5.0 ml of pyridine was heated at 60 aC for 5 minutes. A fresh bright yellow solution of aldrithiol was added (4.70 g, 21.32 mmol) and triphenylphosphine (5.59 g, 21.32 mmol) in 5.00 ml of pyridine were added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (5% methanol / CH2C12) to give the monophosphonamidate (0.7 g, 42%, Compound G, diastereoisomeric mixture 1: 1) as a whitish foam: RM? XH (CDC13) d 7.60 (d, J = 6.60 Hz, 1H), 7.27-7.04 (m, 5H), 5.89 (s broad, ÍH), 4.94 (s broad, 2H), 4.22 (m, 2H), 4.07 -3.99 (m, 3H), 3.91-3.84 (m, 4H), 3.03 (s broad, ÍH), 1.70-1.57 (m, 4H), 1.35 (m, 2H), 0.92-0.75 (m, 8H), 0.63 2H) RM? 13P (CDC13) d 22.21, 20.95. Example 19 Monophosphonidate 19: A mixture of phosphonic acid 6 (0.10 g, 0.30 mmol), L-2-aminobutyric n-octanilic acid ester hydrochloride (0.15 g, 0.60 mmol), phenol (0.14 g, 1.52 mmol) and triethylamine (0.51 mL, 3.60 mmol) in 1. 0 ml of pyridine was heated at 602C for 5 minutes. A fresh bright yellow solution of aldrithiol (0.47 g, 2.13 mmol) and triphenylphosphine (0.56 g, 2. 13 mmol) in 1.0 ml of pyridine to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on ISCO (2-propanol / CH2Cl2) to give monophosphonamidate (0.12 g, 64%, diastereoisomeric mixture). 1: 1) as a pale yellow foam: RM? - "? (CDC13) d 7.62 (d, J = 6.60 Hz, ÍH), 7.25-7.08 (m, 5H), 4.24-4.21 (m 2H), 4.09-4.04 (m, 2H), 4.00 (m, ÍH) ), 3.91-3.83 (m, 4H), 3.01 (broad s, ÍH), 1.70-1.58 (m, 4H), 1.27 (m, 10H), 0.89-0.76 (m, 8H), 0.62 (m, 2H); RM? 13P (CDCl 3) d 22.22, 20.92 Example 20 Monophosphonamidate 20: A mixture of phosphonic acid 6 (1.5 g, 4.57 mmol), L-phenylalanine ethyl ester hydrochloride (2.10 g, 9.14 mmol), phenol (2.15 g, 22.85 mmol) and triethylamine (7.64 ml, 54.84 mmol) in 8.0 ml of pyridine was heated at 60 ° C. for 5 minutes.A fresh brightly prepared yellow solution of aldrithiol (7.05 g, 31.99 mmol) and triphenylphosphine (8.39 g) was added. g, 31.99 mmol) in 7.0 ml of pyridine to the above reaction mixture.The reaction was stirred at 60 aC overnight, cooled to room temperature, and concentrated.The product was partitioned between EtOAc and saturated NaHCO 3. it was washed with brine, dried with Na 2 SO, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (5% methanol / CH2C12) to give a pale yellow solid 1.32 g, containing approximately 10% impurities. The yellow solid (1.32 g, 2.28 mmol) was dissolved in 10 ml of iPrOH and transferred to a warm solution of 30 ml of iPrOH of fumaric acid (0.27 g, 2.28 mmol) and stirred at 80 aC for 30 minutes. The reaction mixture was gradually cooled to room temperature and the fumarate salt was collected at 02C. The resulting fumarate salt was neutralized by cleavage from NaHCO3 (2 times) and ethyl acetate. The organic phase was washed with brine, water, dried with? A2S0, filtered, and concentrated. The product was dried under vacuum to give the monophosphonamidate (0.70 g, 26%, Compound A, diastereoisomeric mixture 1: 1) as a white foam: NMR "" "H (CDC13) d 7.54 (d, J =, 2.4 Hz, 1H), 7.27-6.98 (m, 10H), 4.35 (m, 1H), 4. 16 (m, 2H), 4.08 (m, 2H), 3.84-3.61 (, 3H), 3.33 (m, ÍH), 3. 02 (broad s, 1H), 2.95-2.87 (m, 2H), 1.17 (m, 3H), 0.87 (m, 2H), 0.61 (m, 2H); RM? 13P (CDCI3) d 21.88, 21.07.

Example 21 Monophosphonidate 21: A mixture of phosphonic acid 6 (70 mg, 0.21 mmol), n-butyl ester hydrochloride of L-phenylalanine (0.11 g, 0.42 mmol), phenol (0.10 g, 1.05 mmol) and triethylamine (0.36 g) ml, 2.52 mmol) in 1.0 ml of pyridine was heated at 602C for 5 minutes. A fresh brightly prepared yellow solution of aldrithiol (0.33 g, 1.47 mmol) and triphenylphosphine (0.39 g, 1.47 mmol) in 1.0 mL of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO 4, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (7% methanol / CH2Cl) to give the monophosphonamidate (30 mg, 23%, diastereoisomeric mixture 1: 1) as a pale yellow foam: NMR "" "H ( CDC13) d 7.55 (d, J = 2.7 Hz, 1H), 7.25-6.98 (m, 10H), 4.36 (m, ÍH), 4.17 (m, 2H), 4.02 (m, 2H), 3.83-3.35 (m , 4H), 3.02 (broad s, 1H), 2.94-2.86 (m, 2H), 1.52 (m, 2H), 1.29 (m, 2H), 0.90 (m, 3H), 0.88 (m, 2H), 0.62 (, 2H); RM? 13P (CDC13) d 21.85, 21.05.Example 22 Monophosphonamidate 22: A mixture of phosphonic acid 6 (70 mg, 0.21 mmol), isobutyl ester hydrochloride of L-phenylalanine (0.11 g, 0.42 mmol) , phenol (0.10 g, 1.05 mmol) and triethylamine (0.36 ml, 2.52 mmol) in 1.0 ml of pyridine was heated at 60 ° C. for 5 minutes.A fresh brightly prepared yellow solution of aldrithiol (0.33 g, 1.47 mmol) and triphenylphosphine was added. (0.39 g, mmol) in 1.0 ml of pyridine was added to the above reaction mixture, the reaction was stirred at 602. C all night, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (7% methanol / CH2Cl) to give the monophosphonamidate (65 mg, 50%, diastereoisomeric mixture 1: 1) as a pale yellow foam: 1H-NMR (CDC13) d 7.56 (d, J = 3.6 Hz, HH), 7.26-6.98 (m, 10H), 4.40 (m, 1H), 4.17 (m, 2H), 3.82 (m, 2H), 3.75-3.62 (m, 3H) , 3.35 (m, ÍH), 3.04 (s broad, ÍH), 2.96-2.87 (m, 2H), 1.83 (m, ÍH), 0.90 (m, 2H), 0.86 (, 6H), 0.63 (m, 2H) ); 13P NMR (CDC13) d 21.82, 21.03. Example 23 Bisphosphonidate 23: A mixture of phosphonic acid 6 (0.10 g, 0.30 mmol), L-alanine ethyl ester hydrochloride (0.28 g, 1.80 mmol), and triethylamine (0.51 ml, 3.60 mmol) in 1.0 ml of pyridine were added. heated to 602C for 5 minutes. A fresh brightly prepared yellow solution of aldrithiol (0.47 g, 2.10 mmol) and triphenylphosphine (0.56 g, 2.10 mmol) in 1.0 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (10% methanol / CH2Cl) to give the bisphosphonamidate (80 mg, 50%) as a pale yellow foam: XH NMR (CDC13) d 7.63 (s, ), 5.88 (s broad, 1H), 4.96 (broad s, 2H), 4.24-4.16 (m, 6H), 4.00 (m, 2H), 3.86 (m, 2H), 3.72 (m, 2H), 3.01 ( s broad, ÍH), 1.36 (m, 6H), 1.26 (m, 6H), 0.86 (m, 2H), 0.61 (m, 2H); 13P NMR (CDC13) d 20.63. Example 24 Bisphosphonidate 24: A mixture of phosphonic acid 6 (1.00 g, 3.05 mmol), L-alanine n-propyl ester hydrochloride (3.06 g, 18.30 mmol) and triethylamine (5.10 ml, 36.50 mmol) in 5.0 ml of pyridine it was heated to 602C for 5 minutes. A fresh bright yellow solution of aldrithiol (4.70 g, 21.32 mmol) and triphenylphosphine (5.59 g, 21.32 mmol) in pyridine (5.0 mL) was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCC. The organic phase was washed with brine, dried with Na 2 SO 4, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (10% to give bisphosphonamidate (1.13 g, 71%, Compound F) as a pale yellow foam: E NMR (CDC13) d 7.65 (s, ÍH), . 92 (broad s, ÍH), 5.03 (broad s, 4.24 (m, 2H), 4.10-4.02 (m, 6H), 3.87 (m, 2H), 3.73 (m, 2H), 3.03 (broad s, 1H), 1.65 (m, 4H), 1.37 (, 6H), 0.93 (, 6H), 0.88 (m , 2H), 0.63 (m, 2H); 13 P NMR (CDCl 3) d 20.61. Example 25 Bisphosphonidate: A mixture of phosphonic acid 6 (0.60 g, 1.83 mmol), isopropyl ester hydrochloride of L-alanine (1.84 g, 10.98 mmol), and triethylamine (3.06 ml, 21.96 mmol) in 3.0 ml of pyridine was heated at 602C for 5 minutes. A fresh bright yellow solution of aldrithiol (2.82 g, 12.80 mmol) and triphenylphosphine (3.36 g, 12.80 mmol) in pyridine (3.0 ml) was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (10% to give bisphosphonamidate (0.53 g, 52%, Compound B) as a pale yellow foam: 1 H NMR (CDCl 3) d 7.65 (s, 1 H), 5.00 (, 2H), 4.24 (m, 3.97 (m, 2H), 3.87 (, 2H), 3.71 (m, 2H), 3.01 (broad s, 1H), 1.34 (m, 6H), 1.23 (m, 12H) 0.86 (m, 2H), 0.62 (m, 2H); 13P NMR (CDC13) d 20.59.

Example 26 Bisphosphonidate 26: A mixture of phosphonic acid 6 (0.10 g, 0.30 mmol), N-butyl ester hydrochloride of L-alanine (0.33 g, 1.82 mmol), and triethylamine (0.51 ml, 3.60 mmol) in 1.0 ml of pyridine was heated at 602C for 5 minutes. A fresh brightly prepared yellow solution of aldrithiol (0.47 g, 2.10 mmol) and triphenylphosphine (0.56 g, 2.10 mmol) in 1.0 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic was washed with brine, dried with? A2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (10% methanol / CH2C12) to give the bisphosphonamidate (97 mg, 55%) as a yellow foam. pale: RM? XH (CDC13) d 7.63 (s, ÍH), 4.24 (m, 2H), 4.09 (m, 4H), 4.01 (m, 2H), 3.86 (, 2H), 3.72 (m, 2H), 3.01 (s broad) , ÍH), 1.61 (m, 4H), 1.37 (m, 10H), 0.93 (m, 6H), 0.88 (m, 2H), 0.61 (m, 2H); RM? 13P (CDC13) d 20.59. Example 27 Bisphosphonidate 27: A mixture of phosphonic acid 6 10 g, 0.30 hydrochloride of the n-hexyl ester of L-alanine (0.38 g, 1.80 mmol), and triethylamine (0.51 ml, 3.60 mmol) in 1.0 ml of pyridine was heated to 602C for 5 minutes. A fresh brightly prepared yellow solution of aldrithiol (0.47 g, 2.10 mmol) and triphenylphosphine (0.56 g, 2.10 mmol) in 1.0 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on ISCO (2-propanol / CH2C12) to give bisphosphonamidate (0.13 g, 65%) as a pale yellow foam: NMR ^ H (CDC13) d 7.62 (s, ÍH), 4.23 (m , 2H), 4.09 (m, 4H), 4.01 (m, 2H), 3.86 (m, 2H), 3.72 (m, 2H), 2.99 (broad s, ÍH), 1.61 (m, 4H), 1.36-1.29 (m, 18H), 0.88 (, 6H), 0.84 (m, 2H), 0.60 (m, 2H); 13P NMR (CDC13) d 20.61. Example 28 Bisphosphonamidate 28: A mixture of phosphonic acid 6 (0.10 g, 0.30 mmol), n-octanil ester hydrochloride of L-alanine (0.43 g, 1.80 mmol), and triethylamine (0.51 ml, 3.60 mmol) in 1.0 ml of pyridine was heated at 602C for 5 minutes. A fresh brightly prepared yellow solution of aldrithiol (0.47 g, 2.10 mmol) and triphenylphosphine (0.56 g, 2.10 mmol) in 1.0 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated aHC03. The organic phase was washed with brine, dried with NaS0, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on ISCO (2-propanol / CHCl2) to give the bisphosphonamidate (0.13 g, 61%) as a pale yellow foam: XH NMR (CDC13) d 7.61 (s, 1H), 4.21 (, 2H ), 4.07-4.00 (m, 6H), 3.84-3.70 (m, 4H), 2.98 (s broad, ÍH), 1.60 (m, 4H), 1.34 (m, 1.27 (m, 20H), 0.87 (m, 6H), 0.83 (m, 2H), 0.58 (m, 2H); 13P NMR (CDC13) d 20.63. Example 29 Bisphosphonidate 29: A mixture of phosphonic acid 6 (0.70 g, 2.13 mmol), acid ethyl ester hydrochloride L-2-aminobutyric (2.15 g, 12.80 mmol), and triethylamine (3.57 mL, 25.56 mmol) in 3.0 mL of pyridine was heated at 602C for 5 minutes. A fresh bright yellow solution of aldrithiol (3.29 g, 14.91 mmol) and triphenylphosphine (3.92 g, 91 mmol) in pyridine (3.0 mL) was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO 4, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (10% methanol / CH2C12) to give bisphosphonamidate (0.71 g, 60%, Compound D) as a pale yellow foam: R NMR (CDCl3) d 7.64 (s) , ÍH), 4.24 (m, 2H), 4.16 (m, 4H), 3.89-3.87 (m, 4H), 3.72 (d, J = 9.0 Hz, 2H), 3. 01 (broad s, ÍH), 1.78-1.64 (m, 4H), 1.26 (m, 6H), 0.91 (m, 6H), 0.87 (m, 2H), 0.61 (m, 2H); 13P NMR (CDC13) d 21.23.

Example 30 Bisphosphonamidate 30: A mixture of phosphonic acid 6 (0.70 g, 21.32 L-2-aminobutyric acid n-butyl ester hydrochloride (2.50 g, 12.80 mmol), and triethylamine (3.57 ml, 25.56 mmol) in 3.0 ml of pyridine was heated at 602C for 5 minutes. a freshly prepared bright yellow solution of aldrithiol (3.29 g, 14.91 mmol) and triphenylphosphine (3.92 g, 14.91 mmol) in 3.0 mL of pyridine to the above reaction mixture.The reaction was stirred at 60 ° C overnight, cooled to room temperature The product was partitioned between EtOAc and saturated NaHCO 3 The organic phase was washed with brine, dried over Na 2 SO, filtered and evaporated under reduced pressure The crude product was purified by gel column chromatography of silica (10% methanol / CH2C12) to give the bisphosphonamidate (0.40 g, 31%, Compound C) as a pale yellow foam: RM? XH (CDCl3) d 7.64 (s, ÍH), 4.24 (m, 2H) , 4.11 (m, 4H), 3.91 (m, 2H), 3.87 (m, 2H), 3.71 (d, J = 9.0 Hz, 2H), 3.03 (s broad, ÍH), 1. 79-1.64 (m, 4H), 1.60 (m, 4H), 1.37 (, 4H), 0.94 (m, 6H), 0.90 (, 6H), 0.86 (m, 2H), 0. 62 (m, 2H); 13P NMR (CDC13) d 21.25.

Example 31 Bisphosphonidate 31: A mixture of phosphonic acid 6 (0.10 g, 0.30 mmol), n-octanilic acid hydrochloride of L-2-aminobutyric acid (0.33 g, 1.82 mmol), and triethylamine (0.51 ml, 3.60 mmol) in 1.0 ml of pyridine was heated at 602C for 5 minutes. A fresh brightly prepared yellow solution of aldrithiol (0.47 g, 2.10 mmol) and triphenylphosphine (0.56 g, 2.10 mmol) in 1.0 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO 4, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on ISCO (2-propanol / CH2Cl2) to give the bisphosphonamidate (0.12 g, 55%) as a pale yellow foam: RM? X ?. (CDC13) d 7.64 (s, 1H), 4.24 (m, 2H), 4.13-4.05 (m, 4H), 3.91 (m, 2H), 3.87-3.72 (m, 4H), 3.01 (s broad, ÍH) , 78-1.65 (m, 4H), 61-1.29 (m, 24H), 0.91 (m, 6H), 0.89 (m, 6H), 0.86 (, 2H), (m, 2H); RM? 13P (CDC13) d 21.20. Example 32 Bisphosphonidate 32: A mixture of phosphonic acid 6 (0.60 g, 1.82 mmol), L-phenylalanine ethyl ester hydrochloride (2.51 g, 10.96 mmol), and triethylamine (3.06 ml, 21.84 mol) in 3.0 ml of pyridine were added. heated to 602C for 5 minutes. A fresh brightly prepared yellow solution of aldrithiol (2.82 g, 12.74 mmol) and triphenylphosphine (3.36 g, 12.74 mmol) in 3.0 mL of pyridine was added to the above reaction mixture. The reaction was stirred at 602C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO 4, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on ISCO (2-propanol / CH2C12) to give bisphosphonamidate (0.53 g, 43%) as a pale yellow foam: 1 H NMR (CDC13) d 7.48 (s, 7.22-7.06 (, 10H) , 4.20 (m, ÍH), 4.12 (m, 4H), 4.09 (m, 2H), 4.04 (m, 3.63 (m, 2H), 3.33-3.21 (m, 2H), 3.04-2.78 (m, 5H) , 1.20 (m, 6H), 0.83 (m, 2H), 0.58 (m, 2H); 13 P NMR (CDCl 3) d 20.38. Example 33 Bisphosphonamidate 33: A mixture of phosphonic acid 6 (70 mg, 0.21 mmol), n-butyl ester hydrochloride of L-phenylalanine (0.33 g, 1.26 mmol), and triethylamine (0.36 ml, 2.52 mmol) in 1.0 ml of pyridine was heated at 602C for 5 minutes. A fresh bright yellow solution of aldrithiol (0.33 g, 1.47 mmol) and triphenylphosphine was added. (0.39 g, 1.47 mmol) in 1.0 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO 4, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (10% methanol / CH2C12) to give the bisphosphonamidate (0.11 g, 70%) as a pale yellow foam: RM? R (CDCl3) d 7.51 (s, 1H), 7.23-7.06 (m, 10H), 4.23 (m, ÍH), 4.11-4.05 (m, 7H), 3.65 (m, 2H), 3.35-3.23 '(m , 2H), 3.01 (m, 1H), 3.04-2.78 (m, 4H), 1.57 (m, 4H), 1.33 (m, 4H), 0.92 (m, 6H), 0.86 (m, 2H) 0.61 (m, '2H); RM? 13P (CDC13) d 20.35. Example 34 Bisphosphonidate 34: A mixture of phosphonic acid 6 (70 mg, 0.21 mmol), isobutyl ester hydrochloride of L-phenylalanine (0.33 g, 1.26 mmol), and triethylamine (0.36 ml, 2.52 mmol) in 1.0 ml of pyridine were added. heated to 602C for 5 minutes. A fresh bright yellow solution of aldrithiol (0.33 g, 1.47 mmol) and triphenylphosphine was added. (0.39 g, 1.47 mmol) in 1.0 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated aHCÜ3. The organic phase was washed with brine, dried with? A2SO4 / filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (10% MeOH / CH2Cl2) to give bisphosphonamidate (78 mg, 50%) as a pale yellow foam: 2H NMR (CDCl3) d 7.52 (s, 1H), 7.24-7.07 (m, 10H), 4.26 (m, ÍH), 4.11 (m, 2H), 4.01 (m, ÍH), 3.85 (m, 4H), 3.66 (m, 2H), 3.35-3.25 (m, 2H), 3.07- 2.85 (m, 3H), 2.97-2.79 (m, 2H), 1.89 (m , 2H), 0.90 (m, 12H), 0.89 (m, 2H), 0.62 (m, 2H); 13 P NMR (CDCl 3) d 20.31. EXAMPLE 35 BisPOC from cPrPMEDAP 35: A mixture of phosphonic acid 6 (0.20 g, 0.61 mmol) and triethylamine (0.42 ml, 3.01 mmol) in 2.0 ml of 1-methyl-2-pyrrolidinone was heated at 602C for 30 minutes. P0CC1 (0.45 g, 2.92 mmol) was added. The reaction mixture was stirred at 60 ° C for 3 hours, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO 4, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on ISCO (2-propanol / CH2Cl2) to give the bisPCC of cPrPMEDAP (0.13 g, 39%) as a solid: RM? XH (CDCl 3) d 7.58 (s, ÍH), 5.66 (m, 4H), 4.92 (m, 2H), 4.22 (m, 2H), 3.90-3.88 (m, 4H), 3.01 (s broad, ÍH), 1.81 (m, 12H), 0.86 (m, 2H), 0.62 (m, 2H); RM? 13P (CDCl 3) d 20.93. Examples 36 to 38 refer to the Esguema de Reaction 10. Example 36 Bisphosphonidate 37: A mixture of phosphonic acid 36 (0.32 g, 1.00 mmol), L-alanine butyl ester hydrochloride (0.47 g, 2.60 mmol), and triethylamine (0.27 g, 2.60 mmol) in pyridine (5.0 mL) was heated at 602C for 5 minutes. A fresh bright yellow solution of aldrithiol (0.77 g, 3.50 mmol) and triphenylphosphine (0.92 g, 3.50 mmol) in 2.0 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (10% methanol / CH2Cl2) to give the bisphosphonamidate (0.43 g, 75%) as a pale yellow foam. Example 37 Monophosphoric acid 38: A mixture of diacid 36 (1.30 g, 4.10 mmol) and 0.1 ml of DMF in 35 ml of sulfolane was heated to 70 ° C. Thionyl chloride (0.54 ml, 7.38 mmol) was added dropwise over a period of 1 hour. The temperature was increased to 90 ° C and TMSOPh (0.75 g, 4.51 mmol) was added and stirred for 1 hour. The reaction mixture was cooled to room temperature overnight. The reaction mixture was added dropwise of stirred well cooled acetone(100 ml). The product was precipitated. The solid was filtered and dissolved in 40 ml of methanol and the pH was adjusted to 3 with 45% KOH. The solid was collected by filtration. The product was further purified by dissolving in methanol, adjusting the pH to 6 with 45% KOH, and crystallizing from ice-cold acetone to give the monophosphonic acid (0.20 g, 12%) as a whitish solid. Example 38 Monophosphonidate 39: A mixture of monophosphonic acid 38 (0.20 g, 0.50 mmol), L-alanine isopropyl ester hydrochloride (0.17 g, 1.00 mmol) and triethylamine (0.10 g, 1.00 mmol) in 2.0 ml of pyridine was heated at 602C for 5 minutes. A fresh brightly prepared yellow solution of aldrithiol (0.39 g, 1.75 mmol) and triphenylphosphine (0.46 g, 1.75 mmol) in 2.0 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHC 3. The organic phase was washed with brine, dried with Na 2 SO 4 / filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (7% methanol / CH2C12) to give the monophosphonamidate (0.14 g, 54%, diastereomeric mixture 1: 1) as a pale yellow foam. Example 39 refers to Reaction Scheme 11 Example 39 Bisphosphonidate 41: A mixture of phosphonic acid 40 (0.36 g, 1.00 mmol), n-butyl ester hydrochloride of L-alanine (0.47 g, 2.60 mmol), and triethylamine ( 0.27 g, 2.60 mmol) in 5.0 ml of pyridine was heated at 602C for 5 minutes. A fresh bright yellow solution of aldrithiol (0.77 g, 3.50 mmol) and triphenylphosphine (0.92 g, 3.50 mm? L) in pyridine (2.0 ml) was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with? A2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (10% MeOH / CH2Cl2) to give the bisphosphonamidate (0.32 g, 35%) as a pale yellow foam. Examples 40 to 56 refer to Reaction Schemes 12 to 16. Example 40 Bisphosphonamidate 43: A mixture of phosphonic acid 42 (0.37 g, 1.00 mmol), n-butyl ester hydrochloride of L-alanine (0.47 g, 2.60 mmol), and triethylamine (0.27 g, 2.60 mmol) in 5.0 ml of pyridine was heated at 602C for 5 minutes. A fresh bright yellow solution of aldrithiol (0.77 g, 3.50 mmol) and triphenylphosphine (0.92 g, 3.50 mmol) in 2.0 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (10% methanol / CH 2 Cl 2) to give the bisphosphonamidate (0.53 g, 85%) as a pale yellow foam. Example 41 Bisphosphonamidate 45: A mixture of phosphonic acid 44 (0.55 g, 2.00 mmol), L-alanine butyl ester hydrochloride (0.94 g, 5.20 mmol), and triethylamine (0.54 g, 5.20 mmol) in 5.0 ml of pyridine were added. heated to 602C for 5 minutes. A fresh bright yellow solution of aldrithiol (1.54 g, 7.00 mmol) and triphenylphosphine (1.84 g, 7.00 mmol) in 5.0 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with? A2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (10% methanol / CH 2 Cl 2) to give the bisphosphonamidate (0.48 g, 45%) as a pale yellow foam. Example 42 Monophosphonic acid 46: A mixture of diacid 44 (10.00 g, 36.30 mmol) and 0.2 ml of DMF in 50 ml of sulfolane was heated to 70 ° C. Thionyl chloride (4.72 ml, 70 mmol) was added dropwise over a period of 1 hour. The temperature was increased to 90 ° C and TMSOPh (6.65 g, 40.00 mmol) was added and stirred for 1 hour. The reaction mixture was cooled to room temperature overnight. The reaction mixture was added dropwise to 100 ml "of ice-cold acetone.It was well stirred. The product was precipitated. The solid was filtered and dissolved in 40 ml of methanol and the pH was adjusted to 3 with 45% KOH '. The solid was collected by filtration and dried in vacuo to give the monophosphonic acid (12.40 g, 97%) as a solid. Example 43 Monophosphonidate 47: A mixture of monophosphonic acid 46 (1.00 g, 2.86 mmol), L-alanine methyl ester hydrochloride (0.80 g, 5.73 mmol) and triethylamine (0.58 g, 5.73 mmol) in 5.0 ml of pyridine was heated at 602C for 5 minutes. A freshly prepared bright yellow solution of aldrithiol (2.21 g, 10.00 rrmol) and triphenylphosphine (2.63 g, 10.00 mmol) in 5.0 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCCg. The organic phase was washed with brine, dried with Na 2 SO 4, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (7% methanol / CH2Cl2) to give the monophosphonamidate (0.80 g, 64%, diastereomeric mixture 1: 1) as a pale yellow oil.

Example 44 Monophosphonidate 48: A mixture of monophosphonic acid 46 (0.35 g, 1.00 mmol), L-alanine isopropyl ester hydrochloride (0.34 g, 2.00 mmol) and triethylamine (0.20 g, 2.00 mmol) in 2.0 ml of pyridine was heated at 602C for 5 minutes. A fresh bright yellow solution of aldrithiol (0.77 g, 3.50 mmol) and triphenylphosphine (0.92 g, 3.50 mmol) in 2.0 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with? A2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (7% methanol / CH2C12) to give the monophosphonamidate containing some impurities. The resulting compound was treated with fumaric acid (77 mg) in 10 ml of CH3C? hot and cooled to room temperature. The product was precipitated and dried in vacuo to give the monophosphonamide fumarate salt (0.13 g, 22%, diastereoisomeric mixture 1: 1) as a solid. Example 45: Benzyl ether of PMEG 50: A mixture of diacid 49 (0.62 g, 2.00 mmol) and 10 ml of benzyl alcohol was cooled to 0 ° C with stirring. Sodium hydride (0.24 g, 10.00 mmol) was added in portions and the reaction mixture was heated to 100 ° C in 1 hour. 20 ml of additional benzyl alcohol and sodium hydride (0.12 g, 5.00 mmol) were added. The reaction was stirred at 140 aC for 1 hour and cooled to room temperature. The volatile materials were evaporated under reduced pressure, 50 ml of water was added, and the pH was adjusted to 11 with NaOH. The product was divided between toluene (3 times) and water. The aqueous phase was acidified with HCl until pH = 3 and maintained at 0SC overnight. The product was collected and dried under vacuum to give the benzyl ether (0.18 g, 22%) as a tan solid. Example 46 Monophosphonidate 51: A mixture of phosphonic acid 50 (0.13 g, 0.34 mmol), L-alanine isopropyl ester hydrochloride (0.11 g, 0.68 mmol), phenol (0.16 g, 1.69 mmol) and triethylamine (0.28 mL, 2.03 mmol) in 2.0 mL of pyridine was heated to 602C. for 5 minutes. A fresh bright yellow solution of aldrithiol (0.52 g, 2.37 mmol) and triphenylphosphine (0.62 2.37 mmol) in pyridine (2.0 ml) was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO 4, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (5% methanol / CHC12) to give the monophosphonamidate (50 mg, 26%, diastereoisomeric mixture 1: 1) as a thick oil. Example 47 Monophosphonidate 52: A mixture of monophosphonamidate 51 (50 mg, 0.09 mmol) and 50 mg of Pd (0H) 2 / C in iPrOH (3 ml) was stirred at room temperature under 1 atmosphere of hydrogen (balloon) overnight . The reaction mixture was filtered through a plug of celite and the solvent was removed on a rotary evaporator under reduced pressure. The crude product was purified by column chromatography on silica gel (5-15% methanol / CHC13) to give the monophosphonamidate (40 mg, 95%, diastereomeric mixture 1: 1) as a whitish foam. Example 48 Bisphosphonamidate 54: A mixture of phosphonic acid 53 (0.10 g, 0.35 mmol), L-alanine butyl ester hydrochloride (0.38 g, 2.10 mmol), and triethylamine (0.58 ml, 4.20 mmol) in 1.0 ml of pyridine was heated at 602C for 5 minutes.

A fresh brightly prepared yellow solution of aldrithiol (0.53 g, 2.45 mmol) and triphenylphosphine (0.64 g, 2.45 mmol) in 1.0 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was divided between? TOAc and saturated NaHCO3. The organic was washed with brine, dried with Na 2 SO 4, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (15% to give bisphosphonamidate (25 mg, 13%) as a pale yellow foam: XH NMR (CD3OD) d 7.82 (s, ÍH), 4.26 (m , 2H), 4.11 (m, 4H), 3.94 (m, 2H), 3.88 (m, 2H), 3.78 (m, 2H), 1.61 (, 4H), 1.39 (m, 4H), 1.34 (m, 6H) ), 0.95 (m, 6H); 13P NMR (CDC13) d 23.39. Example 49 Diisopropyl Phosphonate 55: A mixture of 4 (3.00 g, 7.66 mmol) and 10% Pd / C (0.60 g) in 30 ml of methanol was stirred at room temperature under a hydrogen atmosphere (balloon) overnight. The reaction mixture was filtered through a plug of celite and the solvent was removed on a rotary evaporator. The crude product was purified by column chromatography on silica gel (5% methanol / CHCl3) to give the diisopropyl phosphonate (2.08 g, 76%) as a thick oil which solidified upon standing: XH NMR (CDCl3) d 8.72 (s, 1H), 7.94 (s, 1H), 4.73 (m, 2H), 4.33 (m, 2H), 3.97 (m, 2H), 3.73 (d, J = 8.1 Hz, 2H), 1.31 ( m, 12H); 13 P NMR (CDCl 3) d 18.47. Example 50 Phosphonic acid 56: Diisopropylphosphonate 55 (0.10 g, 0.28 mmol) was dissolved in 1.5 ml of CH3CN and cooled to 02C. Bromotrimethylsilane (0.18 ml, 1.40 mmol) was added. The reaction mixture was stirred at 02C for 2 hours and warmed to room temperature overnight. 0.5 ml of DMF was added to form a solution and stirred for 2 hours. Methanol was added and stirred for 2 hours. The volatile materials were evaporated under reduced pressure. The remaining DMF solution was slowly added to CH3CN cooled with ice and the product precipitated. The solid was collected and dried in vacuo to give the phosphonic acid (74 mg, 95%) as a white solid. Example 51 Bisphosphonidate 57: A mixture of phosphonic acid 56 (23 g, 0.08 mmol), n-butyl ester hydrochloride of L-alanine (91 mg, 0.50 mmol), and triethylamine (0.14 ml, 0.96 mmol) in 0.5 ml of pyridine was heated at 602C for 5 minutes. A freshly prepared bright yellow solution of aldrithiol (0.11 g, 0.56 mmol) and triphenylphosphine (0.12 g, 0.56 mmol) in 0.5 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 aC overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with? A2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on ISCO (2-propanol / CH2Cl2) to give bisphosphonamidate (17 mg, 38%) as a pale yellow foam: 2 H NMR (CDCl 3) d 8.65 (s, 1 H), 7.94 (s, ÍH) 5.20 (s broad, 2H), 4.35 (m, -2H), 4.20-3.92 (m, 6H), 3.89 (, 2H), 3.72 (m, 2H), 3.42-3.19 (m, 2H), 1.61 (m, 4H), 1.32 (m, 8H), 0.96 (, 6H); 13P NMR (CDC13) d 20.70. Example 52 Monophosphonidate 58: A mixture of phosphonic acid 56 (20 mg, 0.07 mmol), L-phenylalanine ethyl ester hydrochloride (33 mg, 0.14 mmol), phenol (33 mg, 0.35 mmol) and triethylamine (0.12 ml, 0.84 mmol) in 0.5 ml of pyridine was heated at 602C for 5 minutes. A freshly prepared bright yellow solution of aldrithiol (0.11 g, 0.56 mmol) and triphenylphosphine (0.12 g, 0.56 mmol) in 0.5 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na S0, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on ISCO (2-propanol / CH2Cl2) to give the monophosphonamidate (13 mg, 34%, diastereoisomeric mixture 1: 1) as a whitish foam: NMR (CDC13) d 8.69 (d, J = 15.0 Hz, 1H), 7.84 (d, J = 4.2 Hz, 1H), 7.25-6.97 (m, 4.35 (m, HH), 4.23 (m, 2H), 4.08 (m, 2H), 3.85 (, 1H), 3.72 (m, HH), 3.62 ( m, HH), 3.38 (m, 1H), 2.95-2.86 (m, 2H), 1.17 (m, 3H); RM? 13P (CDC13) d 21.67, 20.84.

Example 53 Diisopropyl Phosphonate 59: A mixture of Compound 4 (1.00 g, 2.56 mmol) and 3 ml of allylamine in 3.0 ml of CH3CN was placed in a scintillation flask and heated at 65 ° C for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The product was partitioned between EtOAc and brine, dried with Na 2 SO, filtered, and concentrated. The product was dissolved in minimal CH3CN and water was added, and lyophilized to give the diisopropyl phosphonate (1.00 g, 95%). Example 54 Phosphonic acid 60: Diisopropylphosphonate 59 (1.00 g, 2.43 mmol) was dissolved in 1.5 ml of CH3CN and cooled to 02C. Bromine trimethylsilane (0.31 ml, 12.15 mmol) was added. The reaction mixture was stirred at 0 ° C for 2 hours and was warmed to room temperature overnight, 0.5 ml of DMF was added to form a solution and stirred for 2 hours, methanol was added and stirred for 2 hours. Volatile materials were evaporated under reduced pressure The remaining DMF solution was added slowly to ice-cold CH 3 CN and the product was precipitated.The solid was collected and dried in vacuo to give the phosphonic acid (0.48 g, 60%) as a solid Example 55 Monophosphonamidate 61 and Bisphosphonamidate 62: A mixture of diacid 60 (0.40 g, 1.20 mmol), isopropyl ester hydrochloride of L-alanine (0.49 g, 2.40 mmol), phenol (0.68 7.20 mmol), and triethylamine (1.0 ml, 7.20 mmol) in 3.0 ml of pyridine was heated at 60 ° C. for 5 minutes.A fresh brightly prepared yellow solution of aldrithiol (1.84 g, 8.40 mmol) and triphenylphosphine (2.20 g, 8.40 mmol) in 3.0 ml of pyridine was added. to the previous reaction mixture. n was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with? A2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (5-10% methanol / CH2Cl2) to give monophosphonamidate 61 (0.52 g, 37%, diastereoisomeric mixture 1: 1) and bisphosphonamidate 62 (0.13 g, 20%) . Example 56 Bisphosphonamidate 63: A mixture of phosphonic acid 60 (0.33 g, 1.00 mmol), L-alanine butyl ester hydrochloride (0.47 g, 2.60 mmol), and triethylamine (0.27 g, 2.60 mmol) in 5.0 ml of pyridine were added. heated to 602C for 5 minutes. A fresh bright yellow solution of aldrithiol (0.77 g, 3.50 mmol) and triphenylphosphine (0.92 g, 3.50 mmol) in 2.0 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated aHC03. The organic phase was washed with brine, dried with? A2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (10% methanol / CH 2 Cl 2) to give bisphosphonamidate (0.32 g, 55%) as a pale yellow foam. Example 57 refers to Reaction Scheme 17. Example 57 BisPOC of 6.alile PMEDAP 64: A mixture of phosphonic acid 60 (0.20 g, 0.61 mmol) and triethylamine (0.42 ml, 3.01 mmol) in 2.0 ml of l-methyl- 2-pyrrolidinone was heated at 602C for 30 min. POCCl (0.45 g, 2.92 mmol) was added. The reaction mixture was stirred at 60 ° C for 3 hours, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with? A2S0 / filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on ISCO (2-propanol / CH2C12) to give the bisPOC of 6-allyl PMEDAP 64 (0.11 g, GS 192727) as a solid: X H NMR (CDCl 3) d 7.60 (s, 1 H), 6.00 (m, 1 H), 5.66 (m, 4 H), . 30 (dd, ÍH), 5.17 (dd, 1H), 4.92 (m, 2H), 4.80 (s, 2), 4.22 (m, 4H), 3.95 (m, 4H), 1.35 (m, 12H); RM? 13P (CDC13) d 20.94. Examples 58 to 61 refer to the Scheme of Reaction 18. Example 58 Biphosphoa idato 65: A mixture of phosphonic acid 60 (35 mg, 0.11 mmol), L-alanine ethyl ester hydrochloride (0.1 g, 0.65 mmol), and triethylamine (0.2 ml, 1.43 mmol) in 0.5 ml of pyridine was heated at 602C 'for 5 minutes. A fresh bright yellow solution of aldrithiol (0.16 g, 0.74 mmol) and triphenylphosphine (0.20 g, 0.75 mmol) in 0.5 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on ISCO (2-propanol / CH2C12) to give the bisphosphoamidate (23 mg, 41%) as a pale yellow foam: NMR ^ H (CDC13) d 7.70 (s, ÍH), 6.00 (m , 1H), 5.30 (dd, 1H), 5.17 (dd, ÍH), 4.30 (m, 4H), 4.20-4.00 (m, 6H), 3.89 (m, 2H), 3.72 (m, 3.42 (m, ÍH ), 3.22 (m, 1H), 1.45-1.25 (m, 12H); 13P NMR (CDCl3) d 20.77 Example 59 Biphosphoamidate 66: A mixture of phosphonic acid 60 (0.10 g, 0.30 mmol), cyclobutyl ester hydrochloride L-alanine (0.33 g, 0.91 mmol), and triethylamine (0.50 mL, 3.59 mmol) in 2.0 mL of pyridine was heated at 60 ° C. for 5 minutes.A fresh brightly prepared yellow solution of aldrithiol (0.47 g, 2.12 mmol) was added. and triphenylphosphine (0.56 g, 2.14 mmol) in 1.0 ml of pyridine to the above reaction mixture.The reaction was stirred at 60 aC overnight, cooled to room temperature, and concentrated.The product was divided between? tOAc and NaHCO 3 The organic phase was washed with brine, dried with Na 2 SO 4, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on ISCO (2-propanol / CH2Cl2) to give the bisphosphoamidate (45 mg, 26%) as a pale yellow foam: XH NMR (CDC13) d 7.60 H), 6.00 (m, H), 5.30 (dd, 1H), 5.18 (dd, 5.00 (m, 2H), 4.78 (s, 2H), 4.30 (m, 4H), 4.00 (, 2H), 3.89 (m, 2H), 3.72 (m, 2H) ), 3.38 (m, ÍH), 3.19 (m, 1H), 2.38 (m, 4H), 2.10 4H), 1.85-1.60 (m, 4H), 1.45 (m, 6H); 13P NMR (CDC13) d 20.61. Example 60 Biphosphoamidate 67: A mixture of phosphonic acid 60 (0.10 g, 0.30 mmol), hydrochloride of the n-hexyl ester of L-alanine (0.25 g, 1.21 mmol), and triethylamine (0.7 ml, 5.02 mmol) in 2.0 ml of pyridine was heated at 60 aC for 5 minutes. A fresh bright yellow solution of aldrithiol (0.47 g, 2.12 mmol) and triphenylphosphine (0.56 2.14 mmol) in 1.0 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO 4, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on ISCO (2-propanol / CH2Cl2) to give the bisphosphoamidate (80 mg, 41%) as a pale yellow foam: NMR XH (CDCl 3) d 7.65 (s, HH), 6.00 (m, HH), 5.30 (dd, HH), 5.17 (d, ÍH), 4.80 (s, 2H), 4.25 (m, 4H), 4.20- 4.00 (m, 6H), 3.85 (m, 2H), 3.72 (m, 2H), 3.42 (, 3.20 (m, 1H), 1.70 (m, 4H), 1.32 (, 18H), 0.96 (, 6H) NMR XE (CDC13) d 20.61 Example 61 Biphosphoamidate: A mixture of phosphonic acid 60 (35 mg, 0.11 mmol), L-2-aminobutyric acid n-butyl ester hydrochloride (0.13 g, 0.64 and triethylamine (0.2 1.43 mmol ) in 0.5 ml of pyridine was heated to 602C for 5 minutes.A fresh brightly prepared yellow solution of aldrithiol (0.16 g, 0.74 mmol) and triphenylphosphine (0.20 g, 75 mmol) in 0.5 ml of pyridine was added to the reaction mixture. The reaction was stirred at 60 aC overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO 4, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on ISCO (2-propanol / CH2Cl2) to give bisphosphoamidate (32 mg, 49%) as a pale yellow foam: XR NMR (CDC13) d 7.68 (H), 6.00 (m, 1H), 5.70 (s broad, ÍH), 5.30 (dd, ÍH), 5.18 (dd, 4.80 (s, 2H), 4.25 (m, 4H), 4.20-4.05 (m, 6H), 3.89 (m, 2H), 3.72 (m, 2H), 3.35 (m, 1H), 3.15 1.60 (m, 8H), 1.40 (m, 4H), 0.96 (m, 12H); 13P NMR (CDC13) d 21.25.

Examples 62 to 71 relate to the "Reaction Scheme 19." EXAMPLE 62 Biphosphoamidate 69: A mixture of phosphonic acid 60 (35 mg, 0.11 mmol), L-phenylalanine ethyl ester hydrochloride (0.15 g, 0.65 mmol), and 0.2 ml of triethylamine (0.2 ml, 1.43 mmol) in 0.5 ml of pyridine was heated at 602C for 5 min.A fresh brightly prepared yellow solution of aldrithiol (0.16 g, 0.74 mmol) and triphenylphosphine (0.20 g, 0.75 mmol) was added. in pyridine (0.5 ml) to the above reaction mixture.The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated.The product was partitioned between EtOAc and saturated NaHCO 3. - washed with brine, dried with Na 2 SO 4, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on ISCO (2-propanol / CH2C12) to give bisphosphoamidate (28 mg, 39%) as a pale yellow foam: RM? XH (CDC13) d 7.58 (s, 1H), 7.28-7.03 (m, 10H), 6.00 (m, 5.30 (dd, ÍH), 5.17 (dd, 1H), 4.25-4.00 (m, 8H), 3.65 ( m, 2H), 3.42-3.19 (m, 2H), 3.15-2.77 (m, 6H), 1.23 (, 6H), RM? 13P (CDCl3) d (CDCls) 20.34 Example 63 Biphosphoamidate 70: A mixture of acid phosphonic 60 (35 mg, 0.11 mmol), L-phenylalanine n-butyl ester hydrochloride (0.15 g, 58 mmol), and triethylamine (0.2 mL, 1.43 mmol) in 0.5 mL pyridine was heated at 602C for 5 min. A freshly prepared bright yellow solution of aldrithiol (0.16 g, 0.74 mmol) and triphenylphosphine (0.20 g, 0.75 mmol) in 0.5 ml of pyridine was added to the above reaction mixture.The reaction was stirred at 60 ° C overnight, cooled The product was partitioned between EtOAc and saturated NaHCO 3 The organic phase was washed with brine, dried over Na 2 SO 4, filtered, and evaporated under reduced pressure The crude product was purified by chromatography on ISCO (2-propanol / CH2C1 2) to give bisphosphoamidate (49 mg, 63%) as a pale yellow foam: NMR X (CDC13) d 7.58 (s, ÍH), 7.28-7.03 (m, 10H), 6.00 (m, ÍH), 5.70 ( s broad, 1H), 5.30 (dd, 1H), 5.17 (dd, 1H), 4.78 (s, 2H), 4.25-4.03 (m, 8H), 3.65 2H), 3.19 (m, 2H), 3.17-2.78 (m, 6H), 1.61 (m, 4H), 1.32 (m, 4H), 0.96 (m, 6H); RM? 13P (CDC13) d 20.35. Example 64 Biphosphoamidate 71: A mixture of phosphonic acid 60 (0.10 g, 0.30 mmol), isobutyl ester hydrochloride of L-phenylalanine (0.31 g, 1.20 mmol), and triethylamine (0.7 ml, . 02 mmol) in 2.0 ml of pyridine was heated at 602C for 5 minutes. A fresh bright yellow solution of aldrithiol (0.44 g, 2.00 mmol) and triphenylphosphine was added. (0.53 g, 2.00 mmol) in 1.0 ml of pyridine to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO. The organic phase was washed with brine, dried with Na 2 SO, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on ISCO (2-propanol / CH2Cl2) to give bisphosphoamidate (94 mg, 42%) as a pale yellow foam: E NMR (CDC13) d 7.55 (s, 1H), 7.27-7.03 ( m, 10H), 6.00 (m, ÍH), 5.70 (broad s, 1H), 5.25 (dd, 1H), 5.17 (dd, 1H), 4.78 (s, 2H), 4.25-4.08 (m, 4H), 3.87 (m, 4H), 3.65 (m, 2H), 3.42-3.19 (m, 2H), 3.17-2.78 (m, 6H), 1.97 (m, 2H), 0.96 (m, 12H); RM? 13P (CDCl3) d 20.31. Example 65 Monophosphamidat9 72: A mixture of phosphonic acid 60 (35 mg, 0.11 mmol), L-alanine ethyl ester hydrochloride (32 mg, 0.20 mmol), phenol (50 mg, 0.53 mmol) and triethylamine (0.2 ml, 1.43 mmol) in 0.5 ml of pyridine was heated at 602C for 5 minutes. A fresh bright yellow solution of aldrithiol (0.16 g, 0.74 mmol) and triphenylphosphine (0.20 g, 0.75 mmol) in 0.5 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated aHC03. The organic phase was washed with brine, dried with? A2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on ISCO (2-propanol / CH2Cl2) to give the monophosphamidate (12 mg, 22%: diastereoisomeric mixture 1: 1) as a whitish foam: RMN ^? (CDC13) d 7.62 (d, ÍH), 7.30-7.04 (, 5H), 6.00 (m, ÍH), 5.30 (dd, ÍH), 5.18 (dd, ÍH), 4.30-4.05 (m, 7H), 3.90 -3.80 (, 4H), 1.23 (m, 6H); I3P NMR (CDCl3) d 21.89, 20.65. Example 66 Monophosphamidate 73: A mixture of phosphonic acid 60 (35 mg, 0.11 mmol), N-butyl ester hydrochloride of L-alanine (39 mg, 0.21 mmol), phenol (50 mg, 0.53 mmol) and triethylamine (0.2 mL, 1.43 mmol) in 0.5 mL of pyridine was heated at 602C for 5 minutes. A fresh bright yellow solution of aldrithiol (0.16 g, 0.74 mmol) and triphenylphosphine (0.20 g, 0.75 mmol) in 0.5 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHC 3. The organic phase was washed with brine, dried with Na 2 SO 4, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on ISCO (2 -propanol / CH2Cl2) to give the monophosphamidate (16 mg, 28%, diastereoisomeric mixture 1: 1) as a whitish foam: 1H-NMR (CDC13) d 7.61 (d, 1H) , 7.32-7.06 (m, 5H), 6.00 (m, ÍH), 5.80 (broad s, 1H), 5.30 (dd, ÍH), 5.20 (dd, 1H), 4.80 (m, 2H), 4.30-4.05 ( , 7H), 3.90-3.80 (m, 4H), 3.90-3.60 (m, 2H), 1.60 (m, 2H), 1.32 (m, 5H), 0.96 (m, 3H); XR NMR (CDC13) d 21.96, 20.70.

Example 67 Monophosphamidate: A mixture of phosphonic acid 60 (0.10 g, 0.30 mmol), cyclobutyl ester hydrochloride of L-alanine (0.11 g, 0.61 mmol), phenol (0.13 g, 1.39 mmol) and triethylamine (0.5 ml, 3.59 mmol) ) in 2.0 ml of pyridine was heated at 602C for 5 minutes. A freshly prepared bright yellow solution of aldrithiol (0.47 g, 2.12 mmol) and triphenylphosphine (0.56 g, 2.14 mmol) in 1.0 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on ISCO (2-propane / CH2C12), to give monophosphamidate (28 mg, 17%, diastereoisomeric mixture 1: 1) as a whitish :: RM foam? XH (CDC13) d 7.60 (d, 1H), 7.25-7.03 (m, 5H), 6.00 (m, HH), 5.30 (d, ÍH), 5.18 (dd, HH), 5.00 (m, 2H), 4.79 (d, 2H), 4.28-4.05 (m, 4H), 3.90 (m, 4H), 3.70 (m, ÍH), 3.57 (m, 1H), 2.30 2H), 2.00-1.60 (m, 4H), 1.25 (m, 3H); RM? 13P (CDC13) d 21.91, 20.64. Example 68 Monophosphamidate 75: A mixture of phosphonic acid 60 (0.10 g, 0.30 mmol), N-hexyl ester hydrochloride of L-alanine (0.13 g, 0.61 mmol), phenol (0.14 g, 1.52 mmol) and triethylamine (0.7 ml) , 5.02 mmol) in 2.0 ml of pyridine was heated at 602C for 5 minutes. A freshly prepared bright yellow solution of aldrithiol (0.47 g, 2.12 mmol) and triphenylphosphine (0.56 g, 2.14 mmol) in 1.0 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on ISCO (2-propanol / CH2Cl2) to give the monophosphoamidate (28 mg, 16%, diastereoisomeric mixture 1: 1) as a whitish foam: RM? XH (CDC13) d 7.60 (d, ÍH), 7.25-7.03 (m, 5H), 6.00 (m, . 85 (s, ÍH), 5.30 (dd, ÍH), 5.17 (dd, ÍH), (d, 2H), 4.35-4.05 (m, 7H), 3.90 (, 4H), 3.70 (m, ÍH), 1.60 (m, 2H), 1.30 (, 9H), 0.96 (m, 3H); RM? 13P (CDC13) d 21.97, 20.69. Examples 69 to 72 refer to Reaction Scheme 21. Example 69 Monophosphamidate 76: A mixture of phosphonic acid 60 (35 mg, 0.11 mmol), L-2-aminobutyric acid n-butyl ester hydrochloride (42 mg, 0.21 mmol), phenol (50 mg, 0. 53 mmol) and triethylamine (0.2 ml, 1.43 mmol) in 0.5 ml of pyridine was heated at 602C for 5 minutes. A fresh bright yellow solution of aldrithiol (0.16 g) was added, 0.74 mmol) and triphenylphosphine (0.20 g, 0.75 mmol) in 0.5 ml of pyridine were added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO 4, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on ISCO (2-propanol / CH2C12) to give the monophosphamidate (17 mg, 29%, diastereoisomeric mixture 1: 1) as a white foam: NMR ^? (CDC13) d 7.60 (d, ÍH), 7.25-7.03 (m, 5H), 6.00 (, 1H), 5.30 (dd, ÍH), 5.17 (dd, 1H), 4.78 (d, 2H), 4.30-4.03 (m, 7H), 3.95-3.80 (m, 4H), 3.62 (m, ÍH), 3.40 (m, 1H), 60 (m, 4H), 1.38 (m, 2H), 0.98-0.75 (m, 6H) ); 13 P NMR (CDCl 3) d 22.26, 20.95. Example 70 Monophosphamidate: A mixture of phosphonic acid 60 (35 mg, 0.11 mmol), L-phenylalanine ethyl ester hydrochloride (48 mg, 0.21 mmol), phenol (50 mg, 0.53 mmol) and triethylamine (0.2 ml, 1.43 mmol) ) in 0.5 ml of pyridine was heated at 602C for 5 minutes. A fresh bright yellow solution of aldrithiol (0.16 g, 0.74 mmol) and triphenylphosphine (0.20 g, 0.75 mmol) in 0.5 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO 4, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on ISCO (2-propanol / CH2Cl2) to give the monophosphoamidate (14 mg, 23%, diastereoisomeric mixture 1: 1) as a whitish foam: RM? XE (CDCl 3) d 7.60 (d, 1H), 7. 25-7.03 (m, 10H), 6.00 (m, 1H), 5.30 (dd, 1H), 5.17 (dd, ÍH), 4.80 (m, 2H), 4.40-4.08 (, 7H), 3.85-3.65 (m, 4H), 3.25 (m, 2H), 2.95-2.86 (m, 2H), 1. 20 (m, 3H); RM? 13P (CDCl3) d 21.86, 21.06. Example 71 Monophosphamidate 78: A mixture of phosphonic acid 60 (35 mg, 0.11 mmol), n-butyl ester hydrochloride of L- 'phenylalanine (55 mg, 0.21 phenol (50 mg, 0.53 mmol) and triethylamine (0.2 ml, 1.43 mmol) in 0.5 ml of pyridine was heated to 602C. A fresh brightly prepared yellow solution of aldrithiol (0.16 g, 0.74 mmol) and triphenylphosphine (0.20 g, 0.75 mmol) in 0.5 ml of pyridine was added to the above reaction mixture, and the reaction was stirred at 60 ° C. overnight, cooled to room temperature, and concentrated.The product was partitioned between EtOAc and saturated aHC03 The organic phase was washed with brine, dried with α2S04, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on ISCO (2-propanol / CH2Cl2) to give the monophosphoamidate (18 mg, 28%, diastereoisomeric mixture 1: 1) as a whitish foam: 2 H NMR (CDCl 3) d 7.60 (d, 1H), 7.25-6.97 (m, 10H), 6.00 (, HH), 5.80 (s broad, HH), 5.30 (dd, 1H), 5.17 (dd, 1H), 4.78 (d, 2H), 4.03 (, 7H), 3.85-3.65 (, 4H), 3.45-3.25 (, 2H), 2.95-2.86 (m, 2H), 1.57 (m, 2H), 1.30 (m, 2H) ), 0.96 (m, 3H); 13P NMR (CDC13) d 21.89, 21.09. Example 72 Monophosphamidate 79: A mixture of phosphonic acid 60 (0.10 g, 0.30 mmol), isobutyl ester hydrochloride of L-phenylalanine (0.16 g, 0.61 mmol), phenol (0.14 g, 1.52 mmol) and triethylamine (0.7 5.02 mmol) 2.0 ml of pyridine was heated at 60 aC for 5 minutes. A freshly prepared bright yellow solution of aldrithiol (0.47 g, 2.12 mmol) and triphenylphosphine (0.56 g, 2.14 mmol) in 1.0 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO 4, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on ISCO (2-propanol / CH2Cl2) to give the monophosphamidate (19 mg, 10%, diastereoisomeric mixture 1: 1) as a whitish foam: XH NMR (CDC13) d 7.60 (d, 1H) , 7.25-7.03 (m, 10H), 6.00 (m, 1H), 5.30 (dd, ÍH), 5.17 (dd, ÍH), 4.78 (d, 2H), 4.45 (m, ÍH), 4.35-4.18 (m , 4H), 3.95-3.60 (m, 1H), 3.35 (m, HH), 3.00-2.83 (m, 2H), 1.85 (m, HH), 0.96 (m, 6H); 13P NMR (CDC13) d 21.90, 21.07. Examples 73 to 76 are related to Reaction Scheme 22. Example 73 Monophosphamidate 80: A mixture of mohophosphonic acid 6 (0.10 g, 0.30 mmol), cyclobutyl ester hydrochloride of L-alanine (0.11 g, 0.61 mmol), phenol ( 0.13 g, 1.4 mmol), and triethylamine (0.51 ml, 3.67 mmol) in 2 ml of pyridine was heated at 602C for 5 minutes. A freshly prepared bright yellow solution of aldrithiol (0.47 g, 2.12 mmol) and triphenylphosphine (0.56 g, 2.14 mmol) in 1.0 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO 4 / filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on ISCO (2-propanol / CH2Cl2) followed by purification followed by purification by Gilson HPLC to give the monophosphamidate (33 mg, 20%, diastereoisomeric mixture 1: 1) as a whitish foam: XH NMR ( CDC13) d 7.60 (m, ÍH), 7.30-7.03 (m, 5H), 5.80 (s broad, 1H), 5.00 (m, ÍH), 4.80 (d, 2H), 4.05 (m, 3.90 (, 4H) , 3.03 (broad s, ÍH), 2.35 (m, 2H), 2.05 (m, 1.80 (m, 2H), 1.30 (m, 3H), 0.90 (m, 2H), 0.62 (m, 2H); 13P NMR (CDCI3) d 21.91, 20.61.

Example 74 Biphosphoamidate 81: A mixture of phosphonic acid 6 (60 mg, 0.18 mmol), cyclobutyl ester hydrochloride of L-alanine (0.13 g, 0.72 mmol), and triethylamine (0.31 ml, 2.16 mmol) in 1 ml of pyridine were added. heated to 602C for 5 minutes. A freshly prepared bright yellow solution of aldrithiol (0.28 g, 1.26 mmol) and triphenylphosphine (0.34 g, 1.26 mmol) in 0.5 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO 4, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (5% methanol / CH2Cl2) to give the bisphosphoamidate (30 mg, 28%) as a pale yellow foam: XR NMR (CDCl3) d 7.60 (s, ÍH), 5.70 (s, ÍH), 5.00 2H), 4.90 (s, 2H), 4.25 (m, 2H), 4.00 (m, 2H), 3.90 (m, 2H), 3.78 (m, 2H), 3.40 (m, ÍH) ), 3.21 (, ÍH), 3.03 (s broad, ÍH), 2.35 (m, 4H), 2.05 (m, 4H), 1.90-1.65 (m, 4H), 1.32 (, 6H), 0.90 (m, 2H) ), 0.60 (m, 2H); 13P NMR (CDCl 3) d 20.70. Example 75 Biphosphoamidate 82: A mixture of phosphonic acid 6 (60 mg, 18 mmol), cyclopentyl ester hydrochloride of L-alanine (0.13 g, 0.72 mmol), and triethylamine (0.31 ml, 2.16 mmol) in 1.0 ml of pyridine was heated at 602C for 5 minutes. A fresh bright yellow solution of aldrithiol (0.28 g, 1.26 mmol) and triphenylphosphine (0.34 g, 1.26 mmol) in 0.5 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (5% methanol / CH2C12) to give bisphosphoamidate (30 mg, 27%) as a pale yellow foam: RM? XH (CDC13) d 7.62 (s, ÍH), 5.72 (s, ÍH), 5.20 (m, 2H), 4.80 (s, 2H), 4.25 (m, 2H), 4.04-3.88 (m, 4H), 3.74 (m, 2H), 3.40 (m, ÍH), 3.23 (m, ÍH), 3.03 (s broad, ÍH), 1.58 (, 16H), 1.37 (, 6H), 0.90 (m, 2H), 0.60 (m 2H); RM? 13P (CDC13) d 20.64. Example 76 Biphosphoamidate 83: A mixture of phosphonic acid 6 (40 mg, 0.12 mmol), cyclobutyl ester hydrochloride of L-ferylalanine (0.13 g, 0.48 mmol), and triethylamine (0.20 ml, 1.44 mmol) in 0.5 ml of pyridine was heated at 602C for 5 minutes. A fresh bright yellow solution of aldrithiol (0.19 g, 0.85 mmol) and triphenylphosphine (0.22 g, 0.85 mmol) was added in 0. 5 ml of pyridine to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO 4, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (5% methanol / CH 2 Cl 2) to give the bisphosphoamidate (20 mg, 22%) as a pale yellow foam: XR NMR (CDCl 3) d 7.50 (s, ÍH), 7.28-7.05 (m, 10H), 5.72 (s, ÍH), 5.00 (m, 2H), 4.90 (s, 2H), 4.23-4.03 (m, 4H), 3.68 (m, 2H), 3.42-3.19 ( m, 2H), 3.15-2.82 (m, 7H), 2.38 (m, 4H), 2.00 (, 4H), 1.85-1.55 (m, 4H), 0.90 (m, 2H), 0.60 (m, 2H), 13P NMR (CDC13) d 20.31. Examples 77 and 78 refer to Reaction Scheme 23.

Example 77 Diisopropyl Phosphonate 84: A mixture of 4 (5.0 g, 12.82 mol) and -trifluoroethylamine (6.35 g, 64.10 mmol) in 40 ml of CH 3 CN was placed in a reaction pump and heated at 80 ° C for 4 hours . The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The product was divided between 15% (3 x) and brine, dried with Na 2 SO 4, filtered, and concentrated. The crude product was purified by chromatography on ISCO (2 -propanol / CH2C12) followed by purification by Gilson HPLC to give 84 (3.26 g., 56%) as a pale yellow foam. Example 78 Biphosphoamidate 85: A mixture of phosphonic acid 42 (0.11 g, 0.29 mmol), cyclobutyl ester hydrochloride of L-alanine (0.31 g, 1.75 mmol), and triethylamine (0.52 3.67 mmol) in 2.0 ml of pyridine was heated to 602C for 5 minutes. A fresh brightly prepared yellow solution of aldrithiol (0.47 g, 2.12 mmol) and triphenylphosphine (0.56 g, 2.12 mmol) in 1.0 ml of pyridine was added to the above reaction mixture. The reaction was stirred at 60 ° C overnight, cooled to room temperature, and concentrated. The product was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with brine, dried with Na 2 SO, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on ISCO (2-propanol / CHC12) to give bisphosphoamidate (97 mg, 54%) as a pale yellow foam: XR NMR (CDC13) d 7.65 (s, 1H), 5.90 (broad s) , ÍH), . 00 (m, 2H), 4.80 (s, 2H), 4.35-4.20 (m, 4H), 4.00 (m, 2H), 3. 87 (m, 2H), 3.70 (d, 2H), 3.38 (, ÍH), 3.20 (m, ÍH), 2.30 (m, 4H), 2.00 (m, 4H), 1.90-1.60 (m, 4H), 1.35 (m, 6H); 13P NMR (CDC13) d 20.61. Example 79 This Example teaches the assays used to demonstrate antiproliferative activity. Cell type used for anti-proliferation assays Human cancer cell lines used in anti-proliferation assays included six cervical carcinoma cell lines with three types of HPV (HPV-16, HPV-18, HPV-39), a cell line of cervical carcinoma negative to HPV, and two carcinomas similar to keratinocytes from the tongue. The normal human cells tested included skin keratinocytes, cervical keratinocytes and lung fibroblasts. Skin keratinocytes and cervical keratinocytes were obtained from Cambrex (East Rutherford, NJ) and all other cells were obtained from the American Type Culture Collection (Manassas, VA). Table 79-1 summarizes the characteristics of each cell type and culture conditions. Anti-proliferation assay procedure - 1. Cell culture The cells were detached from the culture flasks using trypsin, counted, and seeded in 96-well culture plates (250-1000 cells per well, depending on cell type). The next day (defined as day 0), after the cells were coupled to the bottom of the plates, serial dilutions were added in duplicate to one fifth of the compounds. Zero compound and 10 μM colchicine (inhibitor of cell division) were added to the control wells, which could represent 100% proliferation and 0% proliferation, respectively. 2 . Staining of the cells with sulfonamide B Seven days after the addition of the compounds, the culture plates were treated with trichloroacetic acid? 10% at 4 ° C for 1 hour, then washed with water. This procedure allows proteins derived from the cell to bind to the lower surface of the plates. The proteins were stained with 0.4% sulforrodamine B in 1% acetic acid for 10 minutes, followed by intensive washing with 1% acetic acid. The remaining dye bound to the bottom of the plates was dissolved in 10 mM Trizma base. This generated purple color that was quantified by measuring the absorbance at a wavelength of 510 nm, using the spectrophotometer. 3. Data analysis From the experimental data, the sigmoidal curve of dose response was generated and the 50% effective concentration (EC50) was calculated using GraphPad Prism version 4.01 for Windows (Software GraphPad, San Diego, California USA). Table 79-1. Cell types used in anti-proliferation assays Culture medium The cells were maintained in humidified incubators at 37 ° C with 5% C02, in the following culture media. Al: Culture maintenance medium: Eagle MEM with BSS from Earle (Cambrex, East Rutherford, NJ), supplemented with 10% fetal bovine serum, 2 mM glutamine, 100 units / ml penicillin, and 100 μg / ml streptomycin . A2: Medium for antiproliferation assays: Eagle MEM with Earle BSS, supplemented with 5% fetal bovine serum, 2 mM glutamine, 100 units / ml penicillin and 100 μg / ml streptomycin. Bl: Medium for culture maintenance: keratinocyte-SFM (Invitrogen, Carisbad, C?), Supplemented with 0. 01 mg / ml of bovine pituitary extract, 0. 001 μg / ml of recombinant epidermal growth factor, 100 units / ml of penicillin and 100 μg / ml of streptomycin. B2: Medium for antiproliferation assays: 4: 1 mixture of Bl and A2. Results 1. The activity of selective antiproliferation of the amidate prodrugs in HPV-positive SiHa cells was compared with normal fibroblasts. The goal was to discover a compound that inhibits the development of the lesion transformed by HPV without affecting normal cells in the epidermis and dermis (such as keratinocytes and fibroblasts). Antiproliferation assays were established in vi tro using SiHa cells and HEL cells, which model the lesion transformed by HPV and normal fibroblasts, respectively. The SiHa cells are derived from squamous cell carcinoma in the cervix, caused by infection with HPV-16 and HEL fibroblasts are derived from normal human embryonic lung (Table 79-1). As shown in Table 79.2, the 50% effective concentration (EC50) of the seven amidate prodrugs in SiHa cells that were in the range of 0.13-3.2 nM, while EC50 in HEL cells was in the range of 12 -727 nM, indicating that these compounds inhibited the proliferation of SiHa cells more efficiently than HEL cells. The selectivity index of HEL / SiHa (EC50 of HEL divided between EC50 of SiHa) was in the range of 72-559 (Table 79-2). The seven amidate prodrugs produce the same metabolite, cprPMEDAP. cprPMEDAP is also metabolized to PMEG [Compton et al., 1999; Haste et al., 1999]. The EC50 antiproliferation of these compounds in SiHa cells was much higher than those of the prodr(Table 79-2), indicating that the coupling of the amidate portions improved potency. In addition, the selectivity indexes HEL / SiHa of cprPMEDAP and PMEG were 17 and 4.1, respectively (Table 79-2), indicating that prodrugs have better selectivity than cprPMEDAP, and cprPMEDAP has better selectivity than PMEG.

It is known that PMEG is phosphorylated to PMEGpp which acts as a chain-terminator inhibitor of cellular DNA polymerase [Compton et al. , 1999; Haste et al. , 1999] . Four known DNA polymerase inhibitors (Cidofovir, Ara C, 5 doxifluiridine and aphidicolin) and other anticancer drugs with different mechanisms of action, including, DNA-topoisomerase inhibitors (dacarbazine, ellipticine), DNA alkylating agents (doxorubicin,. mitoxantrone, bleomycin, ireclorethamine), and tubulin inhibitors (vincristine, vihblastine, etoposide, and indanocin) were -0 tested in SiHa and HEL cells (Table 79-2). The EC50 of antiproliferation of these compounds in SiHa cells varied, and some were equally or more potent than the seven amidate prodrugs. However, all of them showed poor selectivity index HEL / SiHa (0.01-3.98), in comparison with the seven amidate prodrugs. Taken together, a single group of compounds were shown, which show the EC50 antiproliferation of sub-baj or nM in the SiHa carcinoma cells positive to HPV-16, and a selectivity greater than 50 times when compared with the HEL fibroblasts. 2 . Selective proliferation activity of amidate prodrugs in HPV-positive SiHa cells compared to normal keratinocytes In order to test the effect of the compounds on 5 normal cells from the epidermis, anti-proliferation assays were performed using primary human keratinocytes , isolated skin (PHK) and cervix (CK). The antiproliferative EC50 values obtained with seven prodrugs in PHC and CK were lower than those in HEL, indicating that keratinocytes are more susceptible than fibroblasts (Table 79-2 and 79-3). However, the selectivity indices of PHK / SiHa and CK / SiHa of these prodrugs and cprPMEDAP were still better than the PMEG control compounds and a DNA polymerase inhibitor, AraC (Table 79-3). Thus, the prodrugs preferably inhibited the proliferation of HPV-16 positive SiHa cells, compared to normal skin and cervical keratinocytes. 3. Anti-proliferation activities in other HPV-positive cells The seven prodrugs were then tested in five additional cell lines derived from HPV-induced cervical carcinoma (listed in Table 79-1) in antiproliferation assays, and the data is shown in the Table 4 together with the data of SiHa. In the SiHa, C-4I and MS751 cells, all compounds, except Compound C, showed EC50 antiproliferation of sub-low nM. In CaSki, HeLa and ME-180 cells, however, all compounds were significantly less potent, with EC50 in the range of 7.8-410 nM. There seems to be no correlation between the resistance and the type of HPV (16, 18 or 39), or resistance and metastasis (CaSki, MS751, and ME180 are derived from the site with metastasis). The control compound AraC (DNA-polymerase inhibitor) uniformly inhibited all cell lines with EC50 values in the range of 94-257 nM. 4. Anti-proliferation activities in HPV-negative carcinoma cells To investigate the effect of the compounds on HPV-negative carcinoma cell lines, three cell lines (HT-3, SCC4, SCC9, Table 79-1) were tested in antiproliferation assays. . As shown in Table 79-4, the seven prodrugs were equally or more potent than the control AraC compound. Table 79-2. Selective inhibition of HPV16 + SiHa cells compared to HEL fibroblasts Table 79-3. Selective inhibition of HPV16 + SiHa cells compared to primary keratinocytes Table 79-4. Anti-proliferation activities in other positive and HPV-negative carcinoma cells Example 80 Antiproliferation Assay Antiproliferation assays measure the effect of the compounds on the proliferation of cultured cells. The active compounds in antiproliferation assays can be cytostatic (inhibit cell division) and / or cytocidal (kill cells). By performing antiproliferation assays using HPV-positive carcinoma cells and normal cells, compounds were identified that selectively inhibit the proliferation of HPV-positive carcinoma cells compared to normal human tissue cells. Table 80-1 summarizes the characteristics of each cell type, including six cervical carcinoma cell lines transformed by HPV, normal human skin keratinocytes (PHK), and normal lung fibroblasts (HEL). Skin keratinocytes were obtained from Cambrex (East Rotherford, NJ). All other cells were obtained from the American Type Culture Collection (Manassas, VA). The cells were detached from the culture flasks using trypsin, counted and seeded in 96-well culture plates (250-100 cells per well, depending on cell type). The next day (defined as day 0), serial dilutions were added to a fifth, of the compounds, in duplicate. Seven days after the addition of the compounds, the culture plates were treated with 10% trichloroacetic acid at 4 ° C for 1 hour and washed with water. This procedure allows the cellular proteins to bind to the lower surface of the plates. The proteins were stained with 0.4% sulforhodamine B in 1% acetic acid for 10 minutes, followed by intensive washing with 1% acetic acid. The remaining dye bound to the bottom of the plates was solubilized on 10 mM Trizma base, generating a purple color. The intensity of the color (proportional to the number of cells) was quantified by measuring the absorbance at 510 nm wavelength, using a spectrophotometer. Cells without drug treatment (= 100% proliferation) and cells treated with 10 μM colchicine (inhibitor of cell division) (= 0% proliferation) were used as controls to determine the percentage of inhibition. The percentage inhibition values were graphically plotted against the concentrations of the compound, adjusted to a sigmoidal dose response curve, from which the concentration of the compound that reduced the cell proliferation rate or rate by 50% was determined. (= EC50). GraphPad Prism version 4.00 for Windows (GraphPad Software, San Diego, California, USA) was used to adjust the curve and calculate the EC50. Apoptosis assay (caspase 3 induction method) Induction of caspases is one of the early events associated with apoptosis or programmed cell death. The caspase activity can be quantitatively detected using the fluorescent substrate. Compounds that act directly from the apoptotic pathway can induce caspase in a relatively short incubation period (<24 hours). Compounds that disrupt other cell physiology, which eventually causes apoptosis, may require a longer incubation period (> 48 hours) for the induction of caspase. 10,000 cells were seeded in 96-well culture plates and incubated with serial dilutions to one-fifth of the compounds for 24, 48 and 72 hours. The cells were used and caspase activity was measured in the cell lysates using the fluorescent substrate, according to the manufacturer's instructions (caspase test kit, Roche, Indianapolis, IN). Apoptosis assay (Annexin V staining method) ü The translocation of phosphatidylserine from the inner part of the cell membrane to the outer part is one of the early / intermediate events associated with apoptosis with programmed cell death. Translocated phosphatidylserine can be detected by incubating the cells with Annexin V labeled with FITC, which is a desired phospholipid binding protein, dependent. When the cells are stained with annexin-FITC and propidium iodide (which stains the dead cells) the living cells are negative for both dyes, the dead cells are positive for both, while the apoptotic cells are sensitive only for annexin FITC. SiHa HPV-16 cells were cultured with three different concentrations of the compounds for 3 or 7 days and simultaneously stained with annexin FITC and propidium iodide. The staining of each individual cell was examined by flow cytometry. Results Selective antiproliferation activity The purpose of this procedure was to identify compounds that inhibit the development of the lesion transformed by HPV without affecting normal cells in the epidermis and dermis (such as keratinocytes and fibroblasts). Therefore, the compounds were tested on SiHa, PHK and HEL cells, which are models of cells transformed with HPV, normal keratinocytes, and normal fibroblasts, respectively. Representative compounds of the present invention, such as those listed in Table 80-2, showed detectable levels of antiproliferative activity in SiHa cells, with an effective concentration of 50% (EC50) of less than 25,000 nM. The active compounds were also tested in HEL cells. In all cases, the EC50 in the HEL cells were greater than the EC50 in the SiHa cells, indicating that the active compounds inhibited the proliferation of the SiHa cells, more efficiently than the HEL cells. Other nucleotide / nucleoside analogs, such as PMEG (2-phosphonomethoxyethylguanine), Ara-C (cytarabine, CASE # 147-94-3), and gencitabine (CASE # 95058-81-4) did not show such selectivity. Podofilox (CASE # 518-28-5), the active ingredient of the anti-wrinkle drug Condilox, also showed no selectivity. Representative prodrug compounds of the present invention, such as those listed in Table 80-3, show activities. In most cases, the prodrugs were more potent and in some cases, more selective than their respective parent compounds. Most of the phosphoamidate prodrugs were more active and selective than podofilox. Taken together, the compounds were identified, which possess EC50 subnM antiproliferation in HPV-16 positive SiHa cells, and a greater than 50 fold selectivity as compared to PHK keratinocytes or HEL fibroblasts. Anti-proliferation activity in other HPV + cell lines The selected compounds were also tested on five additional cell lines derived from cervical carcinoma induced by HPV (see example 79 and table 80-4). Each compound showed different levels of activities in the HPV + cell lines, despite the type of HPV present. In general, compounds were more potent in SiHa (HPV-16), C-41 (HPV-18), and MS751 (HPV-18) cells, than in CaSki (HPV-16), HeLa (HpV-18) cells ), and ME-180 (HPV-39).

Induction of apoptosis (caspase induction method 3) A representative compound of the present invention was tested for the induction of apoptosis in SiHa cells. When the cells were incubated for 72 hours (solid bar), a significant, dose-responsive induction of caspase was observed, indicating that the compound induces apoptosis (Figure 80-1). Induction of caspase was less obvious with incubation for 48 hours (shaded bars) and was not observed with incubation at 24 hours (data not shown). Induction of apoptosis (Annexin V staining method> PMEG, N6-cyclopropyl PMEDAP, and a representative compound of the present invention were tested at three different concentrations, for the induction of apoptosis in SiHa cells, using the double staining method with annexin V-propidium With the three compounds, a higher percentage of apoptotic cells was observed on day 7 than on day 3. The aforementioned representative compound of the present invention was the most active in the induction of apoptosis; On day 7, 63.8% of the cells in the cultures treated with 0.2 μg / m of this compound were apoptotic, In contrast, the cultures treated with 0.2 μg / ml of PMEG and 0.5 μg / ml of N6-cyclopropyl PMEDAP only had 1.2% and 15.9% of apoptotic cells, respectively.

Table 80-1. Cell types used in antiproliferation assays * The subtype of HPV DNA integrated into cellular DNA ** Culture media The cells were maintained in humidified incubators at 372C with 5% C02, in the following culture media: Al: Culture maintenance medium: Eagle MEM with BSS from Earle (Cambrex, East Rutherford, NJ), supplemented with 10% fetal bovine serum, 2 mM glutamine, 100 units / ml penicillin, and 100 μg / ml streptomycin. A2: Medium for antiproliferation ass Eagle MEM with Earle BSS, supplemented with 5% fetal bovine serum, 2 mM glutamine, 100 units / ml penicillin, and 100 μg / ml streptomycin. Bl: Culture maintenance medium: keratinocyte-SFM (Invitrogen, Carisbad, CA), supplemented with 0.01 mg / ml of bovine pituitary extract, 0.001 μg / ml of recombinant epidermal growth factor, 100 units / ml of penicillin, and 100 μg / ml streptomycin. B2: Means for antiproliferation assay: 4: 1 mixture of Bl and A2. Table 80-2. Anti-proliferation activity of PMEDAP substituted with N6 in SiHa HPV-16 + cells and HEL fibroblasts Where Rxl is hydrogen, and Rx2 is one of the following substituents, except in the indicated instances (*), where Rxl and R together form an N-heterocyclic ring Methylamine 1-propylamine 1-butylamine Dimethylamine Methylethylamine 2-methyIpropan-1 -amine Allylamine 2-propylamine 2-butyleneamine 2-isobuty1enamine Cyclopropylamine Cyclopropylmethanamine 1-cyclopropylethanamine Dicyclopropylamine Cyclobutylamine Cyclopentanamine Cyclohexaneamine Cycloheptamine Cyclooctamine Dietanolamine 2-ethanolamine 2-propanolamine l-amino-2-propanolamine 2-methoxyethylamine 6-aminohexanamine 3-aminopropylamine 2-dimethylaminoethylamine 6-hexanatoamine Benzylamine Methylbenzylamine 4-aminobenzylamine 2-phenylethanamine 2-pyridinyl-2-methanamine 3-pyridinyl-l-methanamine 4-pyridinyl-l-methanamine 1-naphthylamine * pyrrolidine (N6 makes to pyrrolidine) * piperidine (? 6 makes piperidine) * morpholine (? 6 makes morpholine) 2,2, 2-trifluoroethanamine Table 80-3. Anti-proliferation activity of phosphoramidate prodrugs of PMEDAP substituted with N6 in SiHa cells, HPV16 +, PHK keratinocytes, and HEL fibroblasts Table 80-4. Antiproliferation activities of N6-cyclopropyl-PMEDAP and its phosphoamidate prodrugs in six different HPV-positive cells EXAMPLE 81 Rabbit Skin Irritation Study of Compounds A and B A study was conducted to evaluate the potential of two compounds of the present invention to produce irritation when administered via dermal application to male rabbits for seven consecutive d A total of six males were assigned to the study as presented in the following table.

The vehicle, positive control articles and test items were administered dermally once a day for seven days during the study. The test articles were administered at concentrations of 0.01, 0.03 and 0.1%. Positive control articles were administered at 0.1% (PMEG) or 1% concentrations (Cidofovir®). The dose volume for all formulations was a fixed volume of 100 μl. The test sites for each animal were shaved before the initial administration and as necessary during the study. The two sites were pinched on the left dorsal side, and three were pinched on the right dorsal side. The profile of each dosage (approximately 6.45 cm2 (1 square inch) each) was marked with indelible ink. The total pinched area comprised less than 10% of the total body surface area of each animal. The vehicle and the appropriate positive control and test article were administered to each animal within a dosing site of approximately 6.45 cm2 (1 square inch). The vehicle was administered over the left rostral site (Dose Site 1), and the appropriate "positive control" article was administered to the left caudal site (Dosage Site 2) The appropriate test article was administered as follows: 0.01% at right rostral site (Dosage site 3), 0.03% to the right intermediate site (Dosage site 4), and 0.1% to the right caudal site (Dosage site 5) Collars were placed on the animals immediately after dosing by 1 The sites were evaluated for erythema and edema before dosing on day 1 and daily after this, approximately 24 hours after each dose and before the next dose, each site was assigned an irritation rating with Based on the Draize scale for the skin irritation score (Draize JH, Woodard G, Calvery HO, Me thods for the s tudy of irri ta ti on and toxi ci t and of sub tances' appli ed topi cally to the skin to nd mucous membranes. J Pharmacol Exp Ther 1944; 82: 377-90). Observations for mortality, morbidity and availability of food and water were conducted twice a day for all animals. Detailed clinical examinations were conducted before randomization, before dosing on day 1, and daily after this. Body weights were measured and recorded the day after arrival, before randomization, and before dosing on days 1, 3 and 7. Euthanasia was by intravenous anesthesia of overdose with euthanasia solution based on pentobarbital sodium and Bleeding through vision of the femoral vessels. The animals were carefully examined for external abnormalities including masses. The skin was reflected from a ventral midline incision and any abnormalities were identified and correlated with ante-ortem findings. Abdominal, thoracic and cranial cavities were examined for abnormalities and organs removed, examined, and, where required, placed in neutral buffered formalin. Dosage sites, kidneys and any gross lesions of each animal were collected and preserved. Microscopic examinations of sections with paraffin stained with fixed hematoxylin and eosin were made for each dosing site for all animals. The slides were examined by a veterinary pathologist. A four-step grading system was used to define the adjustable lesions for comparison between the dose groups. Conclusions The two test articles produced no remarkable clinical findings, skin irritation, changes in body weight or macroscopic and microscopic observations at any dose concentrations. One of the positive controls was associated with clinical findings and light to moderate macroscopic and microscopic observations.

Example 82 Irritation Study of the Rabbit Fur of the Compounds B and H A study was conducted to evaluate the potential of two compounds of the present invention to produce irritation when administered via dermal application to male rabbits for seven consecutive days. A total of 24 males were assigned to the study.

The test and control articles were administered dermally once a day for 7 consecutive days during the study. The dose levels for Compound B were 0.03, 0.1 and 0.3%. The dose levels for Compound H were 0.03, 0.1 and 0.3%. The dose level for PMEG (positive control) was 0.1%. The dose level for cPrPMEDAP (positive control) was 1.0%. The dose level for vehicle control was 0.0% (this was dosed as gel and ointment formulations). The dose volume for all sites was a constant volume of 100 μl.

Less than 24 hours before the first administration, the hair of the animal's back was clamped. This pinched area comprised no less than 10% of the total body surface area. Care was taken to avoid abrading the skin. The test, positive control and vehicle control articles were administered within a dosing site of approximately 2.54 x 2.54 cm (1 x 1 inch). Two dosing sites were placed along the left dorsal surface. The positive control article or vehicle was administered to the rostral site, and the low dose of the test article was administered to the caudal site. The two dosing sites were placed along the right dorsal surface. The average dose of the test article was administered to the rostral site, and the high dose of the test article was administered to the caudal site. Collars were placed on the animals for approximately two hours immediately after dosing. The duration of the carrying of the collars was documented in the raw data. Observations for mortality, morbidity and the availability of food and water were conducted twice a day for all animals. Test sites were evaluated for erythema and edema before the first administration, and approximately 24 hours after each administration (before the next scheduled dose) and daily during the 7-day registration period. The observations for the clinical signs were conducted daily during the study at the same time as the dermal observations. The body weights were measured and recorded the day after the reception, before the random distribution, before the administration of the test article on day 1, and on days 7 and 14, and at necropsy (days 8 and 15). ). The body weights taken at reception and before the random distribution are not reported, but are kept in the study file. Blood samples will be collected from 4 to 6 ml of 6 animals / group at the end, and 3 animals / group to the recovery of the jugular vein or other suitable vein for the evaluation of the parameters of clinical pathology. Additional blood samples (approximately 1 ml) of all the jugular animals and another suitable vein were taken for the determination of plasma concentrations of the test article at approximately 2 hours after the dose on day 7. The samples were placed in tubes containing potassium EDTA and stored on a block of ice until they were centrifuged. The animals were not fasted before the blood was collected. The samples were stored at -70 ° C before the test. Complete necropsy tests were performed under procedures approved by a veterinary pathologist on all animals. The euthanasia was through an overdose of anesthesia with euthanasia solution based on sodium pentobarbital via the vein / artery of the ear or other suitable vein and the bleeding was by cutting the femoral vessels. The animals were carefully examined for external abnormalities including masses. The skin was reflected from the ventral midline incision and any abnormalities were identified and correlated with the antemortem findings. The abdominal cavities, thoracic and cranial were examined for abnormalities and organs removed, examined and, where required, placed in neutral buffered formalin. Microscopic examination of the paraffin sections stained with hematoxylin and eosin, fixed, was performed on the tissue sections from the dosing sites (4 per animal), the kidneys, and any gross lesions.At the time of the necropsy, the On day 8 for the animals in the main study and on day 15 for the animals in recovery, the four dosing sites per animal were identified Approximately half of each dosing site was removed and then harvested and preserved as mentioned above for processing While the other approximate half of each dosing site was still intact on the animal, the following procedures were performed: The dosing sites were rubbed with three gauze of ethanol (95%) and allowed to dry completely. (3M® packing tape or equivalent) to each dosing site ten times. The tape was used for each application. The remaining portions of the dosing sites were then excised with scissors. The scissors were washed between each dose site and each animal with acetone and ethanol. The order of removal from the dose site was the vehicle or positive control site, low dose site, medium dose site, and high dose site. 1 cm2 of tissue was excised from each dose site. The tissue sample was weighed and recorded. The skin punches were shredded with clean scissors in individual sized scintillation jars. 5 ml of buffered saline, with phosphate, was added to the flask. The tissue was then homogenized with pulses of 20 seconds using a mechanical homogenizer. The homogenates were rapidly frozen at approximately -20 ° C. Conclusions Based on skin irritation scores and microscopic findings, one of the test items was non-irritating in the vehicle gel, but was a mild to moderate irritant in the vehicle ointment. The second test article was a very light irritant in the vehicle gel and a mild irritant when formulated in the vehicle ointment.

Example 83 Preparation of the Topical Gel Pharmaceutical Composition This example illustrates the preparation of a representative topical gel composition containing an active compound of Formula I. A topical gel composition is prepared having the following composition: * X = compound in the range of 0.01% to 1.0% Other compounds of Formula I, such as those prepared in accordance with the present specification, can be used as the active compound in the preparation of the gel formulations of this example. .

The following ingredients have been evaluated for the suitability during the development of this formulation: Isopropyl myristate (solvent / cosolvent / penetration enhancer), polyethylene glycols, triacetin (solvents), cetyl alcohol and stearyl alcohol (stiffening agents), carbomer ( viscosity enhancer), and Tweens, Spans (emulsifiers). Example 84 Preparation of the Topical Ointment Pharmaceutical Composition This example illustrates the preparation of a representative topical ointment composition containing an active compound of Formula I. A topical ointment composition having the following composition is prepared: * X = Compound in the range of 0.01% to 1.0% Other compounds of Formula I, such as those prepared according to the present specification, can be used as the active compound in the preparation of the gel formulations of this example . The following ingredients have been evaluated for the adequacy during the development of this formulation: Isopropyl myristate (solvent / cosolvent / penetration enhancer), Polyethylene glycols, triacetin (solvents), "Cetyl alcohol and stearyl alcohol (stiffening agents), Carbomer (viscosity enhancer), and Tweens, Spans (emulsifiers).

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Claims (59)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A compound of Formula I, characterized in that:? iA e? iB SQn j_n¿epen- ementely Y1; Rxl is H and Rx2 is W5; es = 0, -0 (RX), = S, -? (RX), -? (0) (Rx), -N (0Rx) -? (0) (0RX), -? (? (RX) ( Rx)); with the proviso that at least one of Y1 is -? (R) X; R x is independently R 1, R 2, R 4, W 3 or a protecting group; R1 is independently -H or alkyl of 1 to 18 carbon atoms; R 2 is independently R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups, or taken together at a carbon atom, two R 2 groups form a ring of 3 to 8 carbon atoms and the ring may be substituted with 0 to 3 groups R3; R3 is R3a, R3b, R3c or R3d, with the proviso that when R3 is linked to a heteroatom, then R3 is R3c or R3d; R3a is -H, -F, -C1, -Br, -I-, -CF3, -CN, -N3, -? O2, or -OR4; R3b is -0; -0 (R4), = S, -? (R4), -N (0) (R4), -N (0R4), -N (0) (OR4), or -? (? (R4) (R4); R3c is -R4, -? (R) (R4), SR4, S (0) R4, -S (0) 2R4, -S (0) (0R4), -S (0) 2 (0R4), - OC (R3b) R4, CC (R3b) R4, -OC (R3b) (? (R4) (R4)), SC (R3b) R4, -SC (R3b) OR4, -SC (R3b) N (R4) ( R4)), - (R4) C (R3b) R4, -? (R4) C (R3b) OR4,? (R4) C (R3b) (? (R4) (R4)), W3 or -R5W3; R3d is -C (R3b) R4, -C (R3b) OR4, C (R3b) W3, C (R3b) OW3, or C (R3) (? (R4) (R4)); R 4 is -H, or an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms; R 5 is alkylene of 1 to 18 carbon atoms, alkenylene of 2 to 18 carbon atoms, or alkynylene of 2 to 18 carbon atoms; W3 is W4 or W5; W4 is R6, -C (R3b) R6, -C (R3) W5, -SOM2R6 or -SOMW5, wherein R6 is R4, wherein each R4 is substituted with 0 to 3 R3 groups; W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 groups R2; and M2 is 0, 1 or 2; and the pharmaceutically acceptable salts thereof.
2. 2. The compound according to claim 1, characterized in that Y1A and Y1B are -N (RX).
3. 3. The compound according to claim 2, characterized in that Rx is R2.
4. 4. The compound according to claim 3, characterized in that R2 is R4 substituted with R3d.
5. 5. The compound according to claim 4, characterized in that R4 is ethyl substituted with R3d.
6. 6. The compound according to claim 5, characterized in that R3d is -C (R3b) OR4.
7. 7. The compound according to claim 6, characterized in that R3b is = 0.
8. 8. The compound according to claim 7, characterized in that R4 is alkyl of 1 to 18 carbon atoms.
9. 9. The compound according to claim 1, characterized in that R3d is -C (R3b) OW3.
10. 10. The compound according to claim 1, characterized in that R4 is propyl substituted with R3d.
11. 11. The compound according to claim 1, characterized in that R3d is -C (R3) OR4.
12. 12. The compound according to claim 3, characterized in that R2 is R4 independently substituted with two R3 groups.
13. 13. The compound according to claim 12, characterized in that R4 is methyl substituted with two R3 groups. The compound according to claim 13, characterized in that one group R3 is R3c. 15. The compound according to claim 1, characterized in that R5 is methylene. 16. The compound according to claim 1, characterized in that W3 is W5. 17. The compound according to claim 14, characterized in that a group R3 is R3d. 18. The compound according to claim 1, characterized in that R3c is W3. 19. The compound according to claim 1, characterized in that Y1A is -N (RX) and W5 is a carbocycle. 20. The compound according to claim 1, characterized in that Y1B is -N (RX). 21. The compound according to claim 1, characterized in that R3c is -R5W3. 22. The compound according to claim 16, characterized in that W5 is a carbocycle. 23. The compound according to claim 1, characterized in that Y1B is -0 (RX). 24 The compound according to claim 23, characterized in that Y1B is -0 (W3). 25. The compound according to claim 22, characterized in that "the carbocycle is phenyl 26. The compound according to claim 1, characterized in that R2 is R4 substituted with R3c and R3d.27 The compound according to the claim 26, characterized in that R4 is ethyl substituted with R3c and R3d 28. The compound according to claim 1, characterized in that Y1A and Y1B are -0 (RX) 29. The compound according to claim 1, characterized in that Rx2 is R4 30. The compound according to claim 1, characterized in that R2 is R4 substituted with an R3, 31. The compound according to claim 30, characterized in that R4 is methyl substituted with an R3. according to claim 31, characterized in that R3 is R3, The compound according to claim 32, characterized in that R3a is -CF3, 34. The compound according to Claim 30, characterized in that R4 is -CH2CF3. 35. The compound according to claim 1, characterized in that it is used as an antiproliferative agent. 36. The compound according to claim 1, characterized in that it is used as an apoptotic agent. 37. The compound according to claim 1, characterized in that for use as an anti-HPV agent. 38. The compound according to claim 1, characterized in that for use as a topical anti-HPV agent. 39. The compound according to claim 1, characterized in that it has Formula IA 40. The compound according to claim 1, characterized in that it has the formula 41. The compound according to claim 1, characterized in that it has the formula 42. The compound according to claim 1, characterized in that it has the formula 43. The compound according to claim 1, characterized in that it has the formula 44. The compound according to claim 1, characterized in that it has the formula 45. The compound according to claim 1, characterized in that it has the formula 46. The compound according to claim 1, characterized in that it has the formula 47. The compound according to claim 1, characterized in that it has the formula 48. The compound according to claim 1, characterized in that it has the formula 49. The compound according to claim 1, characterized in that it has the formula 50. The compound according to claim 1, characterized in that it has the formula 51. A pharmaceutical composition characterized in that it comprises an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 52. The pharmaceutical composition according to claim 51, characterized in that the composition is a gel composition. 53. The pharmaceutical composition according to claim 51, characterized in that the pharmaceutical composition is an ointment composition. 54. A pharmaceutical composition, characterized in that it comprises an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and an effective amount of at least one antiviral agent, and a pharmaceutically acceptable carrier. 55. The pharmaceutical composition according to claim 54, characterized in that the composition is a gel composition. 56. The pharmaceutical composition according to claim 54, characterized in that the composition is an ointment composition. 57. A compound of the formula characterized in that R4 is hydrogen, or an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms or alkynyl of 2 to 18 carbon atoms and pharmaceutically acceptable salts thereof. 58. A gel or ointment, characterized by comprising the compound according to claim 57. 59. The ointment or gel according to claim 58, characterized in that for use as an antiproliferative, apoptotic or anti-HPV agent.