WO2013014445A1

WO2013014445A1 - Derivatives of phenyl (thio) urea deoxythymidine and use thereof as antimalarials

Info

Publication number: WO2013014445A1
Application number: PCT/GB2012/051780
Authority: WO
Inventors: Ian Gilbert; Huaqing CUI
Original assignee: University Of Dundee
Priority date: 2011-07-25
Filing date: 2012-07-25
Publication date: 2013-01-31
Also published as: GB201112721D0

Abstract

Deoxythymidine derivatives according to formula (I) are disclosed. wherein: X may be O or S; and R¹, R², R³, R⁴ and R⁵ may each be independently selected from H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, nitro, phenyl, heteroaryl, substituted heteroaryl wherein the substituents may be C₁-C₆ alkyl or C₁-C₆ haloalkyl, benzyl, -CH₂OAr, -OR⁶ and six-membered ring heterocyclic groups containing 1 or more O and/or N heteroatoms wherein any N heteroatom may be C₁-C₆ alkyl-substituted; and R⁶ may be selected from C₁-C₆ alkyl, phenyl, six-membered ring heterocyclic groups containing at least one O heteroatom, benzyl and substituted benzyl wherein the substituents may be halo, C₁-C₆ alkyl or C₁-C₆ alkoxy; R⁷ may be H or C₁-C₆ alkyl; and the stereochemistry of the bond depicted as 〰 is either α or β. Such derivatives have shown good inhibitory activity against malaria-causing parasites, e.g. Plasmodium falciparum, but have shown low levels of toxicity to human cells.

Description

DERIVATIVES OF PHENYL (THIO) UREA DEOXYTHYMIDINE AND USE THEREOF AS

ANTIMALARIALS

Field of Invention

The present invention relates to compounds for use in the treatment of malaria and also to methods for making such compounds.

Introduction

Malaria is an infectious disease which is prevalent in tropical and sub-tropical regions of the world. It is transmitted from human to human by mosquitoes and has potentially fatal consequences. As such, it is widely recognised as a major health problem with an estimated 300-500 million clinical cases every year. The most severe form of the disease is caused by the parasite Plasmodium falciparum. Other parasites that cause the disease include Plasmodium malariae, Plasmodium ovale, Plasmodium knowlesi and Plasmodium vivax.

Strategies to prevent the spread of malaria include the use of mosquito nets and insect repellents to reduce the risk of being infected by a disease-carrying mosquito. Prophylactic drugs are also advised for those travelling to high-risk areas as a preventative measure. Currently, malarial treatments include drugs such as chloroquine and artemisinin and their derivatives. However, an increased reliance on such drugs has given rise to resistant strains of the parasite which have to be treated with combinations of existing drugs. Whilst the development of an effective vaccine to eradicate malaria is still ongoing, there is a clear need for novel anti-malarial agents that will be effective against resistant strains of the Plasmodium parasites.

Background art in the area of anti-malarial agents includes US Patent No. 7,601 ,702 and US Patent No. 7,795,270.

Plasmodium falciparum thymidylate kinase (P TMPK) is an essential enzyme involved in the phosphorylation of nucleosides prior to DNA synthesis. Structural and kinetic studies have indicated significant differences with the human homologue and thus it represents an attractive target for antimalarial drugs. Previous studies investigated prodrug analogues of 3'-azido-2',3'-deoxythymidine (AZT) as potential anti-malarial agents but these demonstrated insufficient activity to be progressed further [Cui et al, Bioorg. and Med. Chem. 2010, 18, 7302-7309].

The use of 5'-substituted a-thymidine derivatives has previously been reported for the inhibition of Mycobacterium tuberculosis thymidylate kinase (MfTMPK) for the potential treatment of tuberculosis [Van Daele et al, J. Med. Chem. 2007, 50, 5281 - 5292. This document did not teach the use of these compounds for the treatment of other diseases.

Statement of Invention

The present invention arises from studies relating to the use of the compounds described herein in the treatment of malaria.

According to a first aspect of the present invention, there is provided a compound of formula (I) for use an anti-malarial agent:

(I)

wherein:

X may be O or S; and

R , R², R³, R⁴ and R⁵ may each be independently selected from H, halo, C C₆ alkyl, C C₆ haloalkyl, nitro, phenyl, heteroaryl, substituted heteroaryl wherein the substituents may be d-C₆ alkyl or C C₆ haloalkyl, benzyl, -CH₂OAr, -OR⁶ and six-membered ring heterocyclic groups containing 1 or more O and/or N heteroatoms wherein any N heteroatom may be C C₆ alkyl-substituted; and R⁶ may be selected from C C₆ alkyl, phenyl, six-membered ring heterocyclic groups containing at least one O heteroatom, benzyl and substituted benzyl wherein the substituents may be halo, C C₆ alkyl or C C₆ alkoxy; and

R⁷ may be H or C C₆ alkyl.

Use as an antimalarial agent includes use against any malaria-causing parasite e.g Plasmodium falciparum, Plasmodium ovale, Plasmodium malariae, Plasmodium knowlesi and Plasmodium vivax. The antimalarial agent may be effective in inhibiting the growth of the malaria-causing parasite and/or inhibiting its effects on a subject.

In use, the compounds show good inhibitory activity against the malaria-causing parasite but show relatively low toxicity to human cells. For example, the compounds of the present invention generally demonstrate good selectivity between Plasmodium falciparum and human MRC-5 cells. In use, surprisingly the compounds of the present invention were found to be only marginally effective inhibitors of Plasmodium falciparum thymidylate kinase (P TMPK). However, instead compounds of the present invention showed inhibitory activity against the whole intact parasite, especially those compounds comprising an a- stereochemistry.

Compounds of formula (I) may be ureas or thioureas. For example, X may be O or X may be S. In a preferred embodiment the compound is a urea and X is O.

"Halo" may be any suitable halogen including fluoro, chloro, bromo and iodo. Preferably, halo is fluoro, chloro or bromo.

"Ci-C₆ alkyl" may be selected from straight or branched chain hydrocarbons containing from 1 to 6 carbon atoms, or 1 to 5 carbon atoms, or preferably 1 to 4 carbon atoms. Representative examples are methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, neohexyl, etc. In particular, d-C₆ alkyl may be tert-butyl.

"C Ce haloalkyl" may be an alkyl group in which one or more or all hydrogens thereon has been replaced with a respective halogen atom. For example, CrC₆ haloalkyl may be selected from fluoroalkyl, chloroalkyl, bromoalkyl and iodoalkyl groups. In a preferred embodiment, the C C₆ haloalkyl may be a fluoroalkyl such as pentafluoroethyl or trifluoromethyl. In particular, C C₆ haloalkyl may be trifluoromethyl.

"Nitro" may be an -N0₂ group.

"Phenyl" as used herein refers to an aromatic -C₆H₅ group.

"Heteroaryl" may be a single or fused ring system having one or more aromatic rings containing 1 or more O, N and/or S heteroatoms. Representative examples of heteroaryl groups may include, but are not limited to, pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole, pyridine, pyrimidine, pyridazine, pyrazine, indole, benzofuran, benzothiazole, benzimidazole, indazole, benzoxazole, benzisoxazole etc. Preferably, the heteroaryl group may be a pyridine or a benzothiazole.

"Substituted heteroaryl" may be a heteroaryl group as defined herein which is substituted, wherein the substituents may comprise C C₆ alkyl or d-C₆ haloalkyl groups. In preferred embodiments, the heteroaryl may be a C C₆ haloakyl-substituted pyridine such as trifluoromethyl pyridine, for example 2-trifluoromethyl pyridine, or a C C₆ alkyl-substituted benzothiazole such as methyl benzothiazole, for example, 6-methyl benzothiazole. "Benzyl" as used herein refers to a -CH₂Ph group. A substituted benzyl group may comprise substituent groups on the aromatic ring. The substituent groups may be halo, Ci-C₆ alkyl or C C₆ alkoxy groups. Representative examples include, but are not limited to, fluoro, chloro, methoxy and tert-butyl groups. The substituent groups may be in ortho, meta or para substitution pattern.

"-CH₂OAr" may be aryloxymethyl. "Ar" as used herein refers to an aromatic group that may be substituted. In particular, "Ar" may refer to a substituted phenyl ring wherein the substituents may comprise C C₆ alkyl, C C₆ haloalkyi or C C₆ alkoxy groups. In a preferred embodiment, -CH₂OAr may be -CH₂OPh i.e. a phenoxymethyl group. The term phenoxylmethyl may be used interchangeably with phenoxymethyl throughout the specification.

"Heterocyclic groups" may comprise at least 1 heteroatom. Heterocyclic groups may be aliphatic heterocyclic groups. Heteroatoms may be O and/or N. Heterocyclic groups are six-membered ring heterocycles containing 1 or more heteroatoms. Any N heteroatom present in the heterocyclic group may be C C₆ alkyl-substituted. Representative examples include, but are not limited to, piperidine, piperazine, N- alkylpiperazine, morpholine, dioxane, or tetrahydropyran. In preferred embodiments, the heterocycle may be piperidine, N-methylpiperazine, morpholine or tetrahydropyran.

"Ci-C₆ alkoxy" as used herein refers to an alkyl group, as defined above, appended to the parent molecular moiety through an oxy group, -0-. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2- propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy etc.

In a preferred embodiment of the present invention, R⁷ may be C C₆ alkyl. For example, R⁷ may be methyl.

In a preferred embodiment of the present invention, a para-substituent may be present on the phenyl ring, for example, R³ may be a group other than H. In one embodiment, preferably R³ may comprise a hydrophobic substituent, such as an alkyl group, whilst each of R , R², R⁴ and R⁵ is H. In particular, R³ may comprise an aromatic group. For example, R³ may be phenyl, phenoxy or benzyloxy. R³ may also be a substituted benzyloxy group wherein the substituents comprise C C₆ alkyl, halo and Ci-C₆ alkoxy groups, for example, R³ may be a 2-chlorobenzyloxy group. The term benzyloxy may be used interchangeably with benzoxy throughout the specification.

It will be appreciated that the compounds of the present invention may exist in different stereoisomeric forms. The stereochemistry at the 2-position of the deoxythymidine ring is indicated by a wavy bond in formula (I). The wavy bond indicates that the bond may be 'down' or 'up', or, stated in a different way, a or β. The present invention includes within its scope the use of both stereoisomeric forms, or the use of a mixture of stereoisomers, including the individual enantiomers of the compounds of formulae (I) as well as wholly or partially racemic mixtures of such enantiomers.

Compounds of formula (I) may be selected from 5'-phenylurea α-2'- deoxythymidine derivatives, 5'-phenylthiourea a-2'-deoxythymidine derivatives, 5'- phenylurea 3-2'-deoxythymidine derivatives and 5'-phenylthiourea 3-2'-deoxythymidine derivatives i.e. the relative stereochemistry around the deoxythymidine ring may be a or β. Preferably, the relative stereochemistry around the deoxythymidine ring is a. The preferred stereochemistry is illustrated in formula (II) below.

wherein:

X may be O or S; and

R , R², R³, R⁴ and R⁵ may each be independently selected from H, halo, C C₆ alkyl, C C₆ haloalkyl, nitro, phenyl, heteroaryl, substituted heteroaryl wherein the substituents may be C C₆ alkyl or C C₆ haloalkyl, benzyl, -CH₂OAr, -OR⁶ and six-membered ring heterocyclic groups containing 1 or more O and/or N heteroatoms wherein any N heteroatom may be C C₆ alkyl-substituted; and R⁶ may be selected from C C₆ alkyl, phenyl, six-membered ring heterocyclic groups containing at least one O heteroatom, benzyl and substituted benzyl wherein the substituents may be halo, C C₆ alkyl or C C₆ alkoxy; and

R⁷ may be H or C C₆ alkyl.

Alternatively the relative stereochemistry around the deoxythymidine ring is β and thus the compound may comprise a stereochemistry according to formula (III).

wherein:

X may be O or S; and

R⁷ may be H or C C₆ alkyl.

In preferred embodiments of the present invention, the compounds of formula (I) may be selected from A/-(5'-deoxy-a-thymidin-5'-yl)-/V'-(4-(2- chlorobenzyloxy)phenyl)urea, A/-(5'-deoxy-a-thymidin-5'-yl)-A/'-(4-phenylphenyl)urea, N- (5'-deoxy-a-thymidin-5'-yl)-Ay-(4-piperdin-1 -ylphenyl)urea, A/-(5'-deoxy-a-thymidin-5'-yl)- A/'-(4-benzyloxyphenyl)urea and A/-(5'-deoxy-a-thymidin-5'-yl)-/V'-(4-phenyloxyphenyl) urea.

According to a second aspect of the present invention, there are provided novel compounds of formula (IV

(IV)

wherein:

X may be O or S; and

R , R², R³, R⁴ and R⁵ may each be independently selected from H, halo, C C₆ alkyl, C C₆ haloalkyl, nitro, phenyl, heteroaryl, substituted heteroaryl wherein the substituents may be C C₆ alkyl or C C₆ haloalkyl, benzyl, -CH₂OAr, -OR⁶ and six-membered ring heterocyclic groups containing 1 or more O and/or N heteroatoms wherein any N heteroatom may be C C₆ alkyl-substituted; and R⁶ may be selected from C C₆ alkyl, phenyl, six membered ring heterocyclic groups containing at least one O heteroatom, benzyl and substituted benzyl groups wherein the substituents may be halo, C C₆ alkyl or C C₆ alkoxy; and R⁷ may be H or C C₆ alkyl.

subject to the proviso that when R and R⁵ are each H and either R² or R⁴ is halo or C C₆ haloalkyl, R³ may not be halo; or

subject to the proviso that when X is S, then R , R², R³, R⁴ and R⁵ may not each be H; or when X is S and R\ R², R⁴ and R⁵ are each H, then R³ may not be C C₆ alkoxy, C C₆ alkyl, halo or morpholino.

It is to be appreciated that the terms used in the description of formula (IV) are to be taken as defined previously in formula (I).

According to a third aspect of the present invention, there is provided a method for making compounds according to formula (I). Compounds of the present invention may be synthesised as described in the Schemes and in the Examples. It is to be appreciated that modifications thereof will be apparent to those skilled in the art.

Formula (I) does not define the stereochemistry at the 2'-position of the thymidine ring and formula (I) may thus comprise a-derivatives (II), β-derivatives (III) and mixtures thereof. Different synthetic routes are employed to produce the thymidine core scaffold (VI) according to the desired stereochemistry, as is described in the Examples section.

Compounds according to formula (I) may be made as outlined in Scheme 1 below.

Scheme 1 : Synthesis of 5'-substituted 2'-deoxythymid ine derivatives, a) DM F, rt

Isocyanate and/or thioisocyanate derivatives (V) may be coupled with an amine according to formula (VI). Conditions may comprise the use of an organic solvent. Representative solvents include, but are not limited to DMF, DMSO, dioxane, NMP, THF, EtOAc, DCM. Preferably, the solvent may be DMF. The reaction may take place at a range of temperatures, for example the reaction may take place between 0 °C and 50 °C, or 5 °C and 30 °C. Preferably, the reaction takes place at room temperature.

According to a fourth aspect of the present invention, there is provided a pharmaceutical formulation comprising a compound of formula (I), or physiologically acceptable salt, solvate, amide or ester, or other physiologically functional derivative thereof and a pharmaceutically acceptable carrier for the treatment of malaria.

The use of the term "treatment" herein may mean an amelioration of a condition suffered by a patient; the treatment may be curative (i.e. resulting in obviation of the condition) or it may not be curative. Treatment may refer to a prophylactic treatment wherein the condition may be prevented, or wherein manifestation of the condition may be reduced or delayed.

Pharmaceutical formulations may present in any form typical for the administration of a pharmaceutical compound to a subject. Representative examples of typical formulations include, but are not limited to, capsules, granules, tablets, powders, lozenges, suppositories, pessaries, nasal sprays, gels, creams, ointments, sterile aqueous preparations, sterile solutions, aerosols, implants etc.

Representative examples of physiologically acceptable salts of the compounds according to the invention may include, but are not limited to, acid addition salts formed with organic carboxylic acids such as acetic, lactic, tartaric, maleic, citric, pyruvic, oxalic, fumaric, oxaloacetic, 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.

Physiologically functional derivatives of compounds of the present invention are derivatives, which may be converted in the body into the parent compound. Such physiologically functional derivatives may also be referred to as "pro-drugs" or

"bioprecursors". Physiologically functional derivatives of compounds of the present invention may include hydrolysable esters or amides, particularly esters, in vivo.

Determination of suitable physiologically acceptable esters and amides is well within the skills of those skilled in the art.

It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the compounds described herein, which may be used in the any one of the uses/methods described. The term solvate is used herein to refer to a complex of solute, such as a compound or salt of the compound, and a solvent. If the solvent is water, the solvate may be termed a hydrate, for example a mono-hydrate, di- hydrate, tri-hydrate etc, depending on the number of water molecules present per molecule of substrate.

Pharmaceutical formulations may include those suitable for oral, parenteral

(including subcutaneous, intradermal, intramuscular and intravenous), topical (including dermal, buccal and sublingual), rectal, nasal and pulmonary administration e.g., by inhalation. Preferably, the formulation is suitable for oral or parenteral administration. The formulation may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. Methods typically include the step of bringing into association an active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

Pharmaceutical formulations suitable for oral administration wherein the carrier is a solid are most preferably presented as unit dose formulations such as boluses, capsules or tablets each containing a predetermined amount of active compound. A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine an active compound in a free-flowing form such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, lubricating agent, surface-active agent or dispersing agent. Moulded tablets may be made by moulding an active compound with an inert liquid diluent. Tablets may be optionally coated and, if uncoated, may optionally be scored. Capsules may be prepared by filling an active compound, either alone or in admixture with one or more accessory ingredients, into the capsule shells and then sealing them in the usual manner. Cachets are analogous to capsules wherein an active compound together with any accessory ingredient(s) is sealed in a rice paper envelope. An active compound may also be formulated as dispersible granules, which may for example be suspended in water before administration, or sprinkled on food. The granules may be packaged, e.g., in a sachet. Formulations suitable for oral administration wherein the carrier is a liquid may be presented as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water liquid emulsion.

Formulations for oral administration include controlled release dosage forms, e.g., tablets wherein an active compound is formulated in an appropriate release-controlling matrix, or is coated with a suitable release-controlling film. Such formulations may be particularly convenient for prophylactic use.

Pharmaceutical formulations suitable for parenteral administration include sterile solutions or suspensions of an active compound in aqueous or oleaginous vehicles.

Injectible preparations may be adapted for bolus injection or continuous infusion. Such preparations are conveniently presented in unit dose or multi-dose containers which are sealed after introduction of the formulation until required for use. Alternatively, an active compound may be in powder form which is constituted with a suitable vehicle, such as sterile, pyrogen-free water, before use.

An active compound may also be formulated as long-acting depot preparations, which may be administered by intramuscular injection or by implantation, e.g., subcutaneously or intramuscularly. Depot preparations may include, for example, suitable polymeric or hydrophobic materials, or ion-exchange resins. Such long-acting formulations are particularly convenient for prophylactic use.

It should be understood that in addition to the aforementioned carrier ingredients the pharmaceutical formulations described above may include, an appropriate one or more additional carrier ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.

Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, 0.1 M and preferably 0.05 M phosphate buffer or 0.8% saline. Additionally, pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.

Formulations suitable for topical formulation may be provided for example as gels, creams or ointments.

Therapeutic formulations for veterinary use may conveniently be in either powder or liquid concentrate form. In accordance with standard veterinary formulation practice, conventional water soluble excipients, such as lactose or sucrose, may be incorporated in the powders to improve their physical properties. Thus particularly suitable powders of this invention comprise 50 to 100% w/w and preferably 60 to 80% w/w of the active ingredient(s) and 0 to 50% w/w and preferably 20 to 40% w/w of conventional veterinary excipients. These powders may either be added to animal feedstuffs, for example by way of an intermediate premix, or diluted in animal drinking water. Liquid concentrates of this invention suitably contain the compound or a derivative or salt thereof and may optionally include a veterinarily acceptable water- miscible solvent, for example polyethylene glycol, propylene glycol, glycerol, glycerol formal or such a solvent mixed with up to 30% v/v of ethanol. The liquid concentrates may be administered to the drinking water of animals.

According to a fifth aspect of the present invention, there is provided a method of inhibiting a malaria-causing parasite comprising administering a composition comprising a compound of the invention. The composition may be administered to an individual or to an environment.

The method may comprise a method of treatment of malaria, said method comprising administering a therapeutically useful amount of a compound of the invention, or physiologically acceptable salt, solvate, ester, amide or other physiologically functional derivative thereof, to a subject in need thereof.

Methods of administration to an individual may comprise any method typically employed in the administration of a pharmaceutical formulation to a patient. Methods of administration to an individual may include, but are not limited to, oral, rectal, ocular, topical, buccal (for example, sub-lingual), parenteral (for example, sub-cutaneous, intramuscular, intradermal, intravenous), inhalation and transdermal etc.). Preferably, methods of administration may comprise oral administration, for example by ingestion.

The method may comprise a method of inhibiting the activity and/or growth of a malaria-causing parasite by administering a composition comprising a compound of the invention to the environment or to a mosquito. Such methods may inhibit the spread of malaria-causing parasites, such as Plasmodium falciparum, in the wild and/or in the mosquito population and so reduce incidence of malaria.

Administering a composition to the environment may comprise spraying or spreading the composition on an area or space. In these and other embodiments, the compositions may be used as parasiticides.

The environment may be an open or enclosed space wherein malaria-causing parasites may be found. For instance, the environment may be an area of land and/or water or it may be within a building, such as a hospital. The environment may be an area where mosquitoes may be found, for example, where they live, breed, lay their eggs or where mosquito larvae develop.

According to a sixth aspect of the present invention, there is provided a composition comprising a compound of the invention suitable for application to an environment. Such compositions may be in a form that enables them to be applied easily to an environment, for example in a form that allows them to be sprayed and/or spread on an environment. For instance, such compositions may be in the form of emulsions, emulsifiable concentrates, suspensions, foamable preparations, granules, microcapsules, solutions, powders or aerosols.

When in the form of an aerosol, compositions may comprise a gas propellant, such as n-butane, iso-butane, propane or dimethylether. Typically, the gas propellant will be present in an amount between 10% and 80% by weight based on the total weight of the composition. In these and other embodiments, compositions may be provided in an aerosol can for ease of application to the environment.

Compositions may be in the form of a sprayable solution. Sprayable solutions may comprise one or more of the following: mineral oil fractions, animal or vegetable oils, aliphatic hydrocarbons, aromatic hydrocarbons such as alkylated naphthalenes and tetranaphthalene, which may be mixed with xylenes, cyclohexanols, ketones, halogenated hydrocarbons such as tri- and tetrachloroethane, trichloroethylene, or tri- and tetrachlorobenzene.

Aqueous preparations may be used, such as emulsions, pastes or powders that may be moistened with water.

Compositions may comprise dispersing agents such as nonionic compounds. Dispersing agents may be condensation products of aliphatic alcohol, carboxylic acids or amines having a long-chain hydrocarbons.

Compositions may further comprise anionic and/or cationic dispersants. Anionic dispersants may be sodium salts of the sulfuric ester of dodecylic alcohol or of dodecylbenzenesulfonic acid, or potassium or triethanolamine salts of oleic or abietic acid, or the sodium salt of a sulfonic acid of petroleum, or mixtures thereof. Cationic dispersants may comprise quaternary ammonium compounds. For example, cetyl pyridinium bromide or dioxyethylbenzyl-dodecylammonium chloride.

Compositions may comprise powders or dusting agents which may act as a vehicle to carry compounds of the invention. For example, talc, kaolin, bentonite, calcium carbonate, cork dust or wood dust.

According to a further aspect of the present invention, there is provided a use of a compound of the invention in the manufacture of a medicament for use in the treatment of malaria.

Detailed Description of the Invention Embodiments of the present invention are described in more detail in the following, non-limiting examples.

Examples

Chemistry

A summary of the various synthetic routes used to synthesise compounds of the present invention have been illustrated in Schemes 2, 3, 4 and 5 below. Experimental details and characterisation data follow the summary of the routes employed.

The preparation of 5'-phenyl(thio)urea a-2'-deoxythymidine derivatives (II) first involved the synthesis of a-2'-deoxythymidine 5, as shown in Scheme 2.

Scheme 2 : Synthesis of alpha-2'-deoxythymidine. a) diphenylacetyl chloride, pyridine, 0 °C, 50%; b) p- toluoyl chloride, pyridine, rt, 56%; c) acetic anhydride, H₂S0₄, CH₃CN , 51 %; d) NaOMe, MeOH , 90%.

3-2'-deoxythymidine 1 was selectively protected with diphenylacetyl chloride. The 3'-position was then protected with p-toluoyl chloride to give compound 3. Epimerisation of the base 3 using acetic anhydride/sulphuric acid [Ward et al, Tetrahedron Lett. 1993, 34(42), 6779-6782]. gave a ratio of α:β derivatives of approximately 3:1 . The mixture was readily separated by crystallization to yield compound 4. Identification of the a- and β- 2'-deoxythymidine derivatives (3 and 4) was carried out by H NMR. The two acyl groups were removed from compound 4 by sodium methoxide to give a-2'-deoxythymidine 5.

a-2'-deoxythymidine 5 was then converted into 5'-amino substituted α-2'- deoxythymidine 8 in several steps [Cui et al, Bioorg. and Med. Chem. 2010, 18, 7302- 7309], before undergoing the coupling step with various isocyanate and thioisocyanate derivatives (V) to give compounds according to formula (II) wherein R⁷ is methyl, as is best illustrated in Scheme 3.

wherein R = Me

Scheme 3: Synthesis of 5'-substituted alpha-2'deoxythymidine derivatives, a) methanesulfo nyl chlo ride, pyridine, -38 °C, 43%; b) sodiu m azide, DM F, 60 °C, 43%; c) 1 0% Pd/C, MeO H, 95%; d) (th io)isocyanates (V), DM F, rt a-2'-Deoxythymidine 5 was sulfonated and was then reacted with sodium azide to give compound 7. Hydrogenation of the azido group gave amine 8. Amine 8 could then be coupled with either thioisocyanate derivatives or with isocyanate derivatives (V) to give the thiourea and urea compounds according to formula (II) wherein R⁷ is methyl.

The preparation of 5'-phenyl(thio)urea 3-2'-deoxythymidine derivatives according to formula (III), wherein R⁷ is methyl, is illustrated in Scheme 4.

wherein R = Me

Scheme 4: Synthesis of 5'-substituted beta-2'deoxythymidine derivatives, a) methanesulfo nyl chlo ride, pyridine, -38 °C, 50%; b) sod iu m azide, DMF , 60 °C, 64%; c) 1 0% Pd/C, MeO H, 98%; d) (th io)isocyanates (V), DM F, rt

3-2'-Deoxythymidine 1 was sulfonated and then reacted with sodium azide to give compound 30. Hydrogenation of the azido group gave amine 31 . Amine 31 could then be coupled with either thioisocyanate derivatives or with isocyanate derivatives (V) to give the thiourea and urea compounds according to formula (III), wherein R⁷ is methyl.

The isocyanate and thioisocyanate derivatives (V) employed in step 'd' of Schemes 3 and 4 may be obtained commercially or may be prepared according to any method commonly used for the preparation of such compounds. The preparation of a series of 4-benzyloxyphenyl isocyanates used in this coupling step is outlined in Scheme 5 below.

Scheme 5: Synthesis of 4-benzyloxyphenyl isocyanate derivatives, a) NaH , N-Boc protected 4-aminophenol, DM F; b) TFA, DCM; c) Et₃N , triphosgene, EtOAc.

A variety of substituted benzyl bromides 7a-7e were reacted with N-Boc- protected aminophenol under basic conditions to give the derivatives 8a-8e. Removal of the Boc-protecting group using TFA gave the TFA salt of amine derivatives 9a-9e. The isocyanate derivatives 10a-10e could then be prepared using triphosgene according to the conditions reported in the literature. [Knaggs et al. Org. Biomol. Chem. 2005, 3, 4002].

General : Chemical and solvents were purchased from the Sigma-Aldrich Chemical Company, Fluka, VWR, Acros, Fisher Chemicals and Alfa Aesar. H NMR, ³C NMR and COSY NMR were recorded on a Bruker Avance DPX 500 spectrometer ( H at 500.1 MHz and ³C at 125.8 MHz). Chemical shift (<5) are expressed in ppm. Signalsplitting patters are described as singlet (s), broad singlet (bs), double (d), triplet (t), quarter (q), multiplet (m). Low resolution electrospray (ES) mass spectra were recorded either on a Applied Biosystem Mariner API-TOF biospectrometry Workstation spectrometer or on a Bruker MicroTof mass spectrometer, run in a positive ion mode, using either methanol, methanol/water (95:5), or water/acetonitrile (1 :1 ) + 0.2% formic acid as the mobile phase. High resolution electrospray measurements were performed on a Bruker Daltonics MicrOTOF mass spectrometer. Column-chromatography was carried out using Silica gel 60 from Fluka. Thin layer chromatography (TLC) was carried out on Merck silica gel 60 F254 plates using UV light or PMA for visualization. TLC data are given as the R value with the corresponding eluent system specified in brackets.

5'-0-diphenylacetyl-thymidine (2): To a solution of thymidine (1 g, 4.38 mmol) in dry pyridine (32 ml) under Ar at 0°C, was added dropwise to a solution of 2, 2- diphenylacetyl chloride (1 g, 4.38 mmol) dissolved in 3 ml DCM. The mixture was left under stirring for 1 .5 h and the reaction was allowed to warm to room temperature. After that, water (50 ml) was added then extracted with DCM (2 x 50 ml). The organic phase was washed with 3N HCI (50 ml, 50 ml) and with a saturated solution of NaHC0₃ (2 x 50 ml) to neutralize. The organic layer was then dried with MgS0₄ and the solvent was evaporated. The residue was purified by chromatography using 2% MeOH/DCM to yield compound 2 886 mg (50%) as a solid. TLC (10%MeOH/DCM) R = 0.56; 1 H-NMR (500MHz, CDCI₃): 5 7.22-7.30 (m, 10H, H-Ph), 7.1 1 (s, 1 H, H6), 6.15 (t, J = 5.96 Hz, 1 H, H1 ), 5.02 (s, 1 H, CH-Ph), 4.47 (dd, J1 = 12.21 Hz, J2 = 4.84 Hz, 1 H, H5), 4.30 (dd, J1 = 12.20 Hz, J2 = 3.10 Hz, 1 H, H5), 4.12-4.17 (m, 2H, H3' and H4), 2.20 (m, 1 H, H2), 1 .82 (s, 3H, H7), 1 .68 (m, 1 H, H2); 13C-NMR (125MHz, CDCI₃): δ 176.3 {C6), 168.1 (C4), 154.4 (C2), 141 .9 (C-Ph), 139.1 (C6), 132.7, 132.6, 132.4, 131 .5, 131 .4 (C-Ph), 1 14.9 (C5), 89.0 (C7 ), 88.3 (C4), 75.1 (C3), 68.5 (C5), 61 .1 (C-C-Ph), 43.9 (C2), 16.3 (C7); LCMS (ES+): m/z (%) 437 (100) [M+H]+; HRMS (ES+): calcd for C24H25N206 [M+H]+ 437.1707 m/z, found 437.171 1 m/z (-0.91 ppm). 3'-0-p-toluoyl-5'-0-diphenylacetyl-thymidine (3): To a solution of 2 (1 .143 g, 2.6 mmol) in dry pyridine/DCM (18 ml / 3 ml), was added dropwise a solution of p-toluoyl chloride (616 mg, 4 mmol) liquid. The mixture was left under Ar and stirring for 3 h. After this, water (50 ml) was added, then extracted with DCM (2 x 50 ml). The organic phase was washed with 3N HCI (2 x 50 ml), and then washed with saturated solution of NaHC0₃ (2 x 50 ml). The organic phase was then dried with MgS0₄ and the solvent was evaporated. The residue was purified by chromatography. The final product 3 was obtained as a solid (0.8 g, 55.6 %). TLC (10%MeOH/DCM) Rf = 0.67; 1 H-NMR (500MHz, CDCI₃): δ 8.36 (s, 1 H, NH), 7.39 (d, J=8.28 Hz, 2H, H-Ph), 7.27-7.37 (m, 10H, H-Ph), 7.14 (s, 1 H, H6), 6.32 (dd, J=9.25 Hz, J =5.28Hz, 1 H, H1 ), 5.26 (d, J =6.64 Hz, H3), 5.1 1 (s, 1 H, CH-Ph), 4.74 (dd, J =12.13 Hz, J =4.01 Hz, 1 H, H4), 4.39- 4.43 (m, 2H, H5), 2.45 (s, 3H, CHS), 2.40 (dd, J =14.28 Hz, J =6.47 Hz, 1 H, H2), 1 .88 (s, 3H, H7), 1 .64 (m, 1 H, H2); 13C-NMR (125MHz, CDCI₃): δ 171 .9 (CO), 166.1 (CO), 163.0 (C4), 149.9 (C2), 144.7, 138.1 , 129.8, 129.3, 128.9, 128.8, 128.5, 128.5, 127.7, 127.6, 126.3 (C-Ph), 134.6 (C6), 1 1 1 .3 (C5), 84.8 (C7 ), 82.5 (C4), 74.7 (C3), 64.5 (C5), 57.4 (C-C-Ph), 37.2 (C2), 21 .7 (CH3), 12.6 (C7); LCMS (ES+): m/z (%) 555 (100) [M+H]+; HRMS (ES+): calcd for C32H31 N207 [M+H]+ 555.2126 m/z, found 555.2104 m/z (4.00 ppm).

3'-0-p-toluoyl-5'-0-diphenylacetyl-a-thymidine (4): To a solution of 3 (440 mg, 0.8 mmol) in 2 ml dry CH₃CN was added the freshly prepared solution containing H₂S0₄ (1 .66 mmol, 0.088 ml) and acetic anhydride (5.5 mmol, 0.519 ml) in 2 ml dry CH₃CN. After 1 .5-2 h, the mixture was quenched with saturated NaHC0₃ solution, and extracted with EtOAC for three times. The alpha-anomer was easily crystallized from the ethanol solution of the mixture, giving compound 4 a-anomer 160 mg (51 %) as a solid. TLC (10% MeOH/DCM) R = 0.58; 1 H-NMR (500MHz, CDCI₃): δ 7.99 (s, 1 H, NH), 7.69 (d, J = 8.21 Hz, 2H, H-Ph), 7.14-7.30 (m, 8H, H-Ph and H6), 5.99 (dd, J = 7.21 Hz, J = 1 .89 Hz, 1 H, H1 ), 5.25 (d, J = 6.48 Hz, 1 H, H3), 5.03 (s, 1 H, CH-Ph), 4.63 (t, J = 3.60, 1 H, H4), 4.32 (m, 2H, H5), 2.34 (s, 3H, CH3), 2.23 (m, 1 H, H2); 2.09 (d, J = 15.45 Hz, 1 H, H2), 1 .77 (s, 3H, CH3); 13C-NMR (125MHz, CDCI3): δ 171 .9 (CO), 166.1 (CO), 163.5 (C4), 150.2 (C2), 144.6, 138.04, 138.02, 129.8, 129.3, 129.0, 128.8, 128.54, 128.5, 127.8, 127.6, 126.2 (C-Ph), 134.6 (C6), 1 1 1 .4 (C5), 84.7 (C7 ), 82.5 (C4), 74.8 (C3), 64.6 (C5), 57.4 (C-C-Ph), 37.1 (C2), 21 .8 (CH3), 12.7 (CH3); LCMS (ES+): m/z (%) 555 (100) [M+H]+; HRMS (ES+): calcd for C32H31 N207 [M+H]+ 555.2126 m/z, found 555.21 12 m/z (2.41 ppm). a-2'-deoxythymidine (5): Compound 4 (2mmol) was dissolved in a solution of 0.2 M NaOMe in 40 ml Methanol. The reaction was stirred at room temperature until the disappearance of the starting material (around 3 h) was observed by TLC. The solution was neutralized by Dowex ion exchanged resin (washed by methanol before use) to be pH 6.0. The resin was filtered and washed twice with methanol, water and

some DCM too. The methanol and DCM was evaporated and the precipitation was formed and filtered to get rid of them. The water was evaporated to get the pure final product 5 436 mg (90%) as a solid. TLC (10%MeOH/DCM) Rf = 0.13; 1 H-NMR (500MHz, D₂0): 5 8.32 (s, 1 H, HH), 7.62 (s, 1 H, H6), 6.04 (s, 1 H, H1 ), 4.26, 4.30 (s, 2H, H3' and H4), 3.58 (d, J = 12.35 Hz, H5), 3.49 (d, J = 1 1 .73 Hz, H5), 2.59 (m, 1 H, H2), 2.04 (d, J = 14.82 Hz, H2), 1 .77 (s, 3H, CH3); 13C-NMR (125MHz, D20): δ 170.9 (C4), 166.7 (C2), 151 .5 {C6), 138.0 (C5), 1 10.5 (C7 ), 88.5 (C4), 70.5 (C3), 61 .4 (C5), 39.4 (C2), 1 1 .5 (CH3); LCMS (ES+): m/z (%) 243 (100) [M+H]+, 485 (52) [2M+H]+; HRMS (ES+): calcd for doH^Os [M+H]+ 243.0975 m/z, found 243.0982 m/z (-2.77 ppm).

5'-0-methanesulfonyl-a-thymidine (6): To a solution of a-thymidine (484 mg, 2 mmol) in pyridine (8 ml) and DCM (1 ml) at -38 °C (dry ice in ethanol), methanesulfonyl chloride (154 μΙ, 2 mmol) in 1 ml dry DCM was added dropwise. The reaction mixture was stirred 1 h at -38 'C, then stirred for another 2 h at 0 °C. The reaction was quenched by adding 10 ml H₂0. The product was transferred to a flask to evaporate the water, DCM and pyridine. Toluene was added to co-evaporate to remove pyridine. The residue was purified by column chromatography to yield a pure product 6 272.2 mg (42.5%) as a solid. TLC (10%MeOH/DCM) R = 0.51 ; 1 H-NMR (500MHz, MeOD): δ 7.75 (s, 1 H, H6), 6.19 (m, 1 H, H1 ), 4.45 (m, 1 H, H4), 4.35 (m, 1 H, H5'), 4.26 (m, 1 H, H5), 4.19 (m, 1 H, H3), 3.27 (s, 3H, CHS), 2.67 (m, 1 H, H2), 2.06 (m, 1 H, H2), 1 .86 (s, 3H, CH3); 13C-NMR (125MHz, MeOD): δ 162.8 (C4), 152.4 (C2), 138.7 (C6), 1 1 1 .1 (C5), 72.5 (C7 ), 72.2 (C4), 70.7 (C3), 64.4 (C5), 41 .1 (C2), 37.3 (CH3), 12.6 (CH3); LCMS (ES+): m/z (%) 321 (100) [M+H]+; HRMS (ES+): calcd for Cn

[M+H]+ 321 .0751 m/z, found 321 .0766 m/z (-4.55 ppm). 5'- azido-5'-deoxy-a-thymidine (7): A solution of compound 6 (3 mmol) and NaN₃ (6 mmol) in 30 ml dry DMF was heated to 60 'C overnight. The reaction mixture was evaporated in vacuum and can coevaporate with ethanol and toluene (temperature not above 60 'C). Then the solution was cooled and get rid of the insoluble, this is the waste need to neutralize with 20% NaN0₂ solution to pH 6. Then the soluble solution was co-evaporated with ethanol and toluene again. The solution was put to high vacuum to evaporate the left DMF overnight. The crude product was purified by column chromatography to yield compound 7 344 mg (43.1 %) as a solid; TLC (10%MeOH/DCM) R = 0.33; H-NMR (500MHz, DMSO): δ 1 1 .30 (s, 1 H, H), 7.76 (s, 1 H, H6), 6.16 (m, 1 H, H1 ), 5.53 (d, J=3.07 Hz, 1 H, OH), 4.28 (m, 1 H, H4), 4.17 (m, 1 H, H3), 3.40 (m, 2H, H5), 2.61 (m, 1 H, H2), 1 .96 (m, 1 H, H2), 1 .79 (s, 1 H, CH₃); ³C- NMR (125MHz, DMSO): δ 163.8 (C4), 150.5 (C2), 136.8 (C6), 109.0 (C5), 85.9 (C7 ), 84.7 (C4), 70.7 (C3), 51 .5 (C5), 39.1 (C2), 12.3 (CH₃); LCMS (ES+): m/z (%) 268 (100) [M+H]+; HRMS (ES+): calcd for C^HUNsC [M+H]+ 268.1040 m/z, found 268.1029 m/z (3.99 ppm).

5'-amino-5'-deoxy-a-thymidine (8): A solution of azide 7 (515 mg, 2 mmol) in 50ml methanol was hydrogenated under atmospheric pressure for 3 h in the presence of 10% Pd/C (100 mg, 5%mol). After 3 h, TLC checked the disappearance of compound 7. Then the catalyst was removed by filtration through celite and the filtrate was evaporated to yield pure compound 8 457 mg (94.8%) as a solid. TLC (10% MeOH/DCM) R = 0.001 ; H-NMR (500MHz, DMSO): 5 7.74 (s, 1 H, H6), 6.09 (m, 1 H, H1 ), 5.31 (s, 1 H, OH), 4.19 (m, 1 H, H4), 4.07 (m, 1 H, H3), 3.35 (m, 1 H, H5), 3.17 (s, 1 H, H5), 2.54 (m, 1 H, H2), 1 .90 (m, 1 H, H2), 1 .78 (s, 3H, CH₃); LCMS (ES+): m/z (%) 242 (100) [M+H]+; HRMS (ES+): calcd for C₁₀H₁₆N₃O4 [M+H]+ 242.1 135 m/z, found 242.1 132 m/z (1 .09 ppm).

5'-0-methanesulfonyl-thymidine (29): Thymidine (484 mg, 2 mmol) was reacted with methanesulfonyl chloride (154 μΙ, 2 mmol) following the procedure of compound 6 to yield compound 29 320mg (49.8 %) as a solid. TLC (10%MeOH/DCM) Rf = 0.65; 1 H- NMR (500MHz, DMSO): δ 1 1 .37 (s, 1 H, NH), 7.49 (s, 1 H, H6), 6.23 (t, J = 7.65 Hz, 1 H, H1 ), 5.51 (d, J = 4.00 Hz, 1 H, H4), 4.25-4.41 (m, 3H, H3' and H5), 3.95-3.98 (m, 1 H, OH), 3.23 (s, 3H, CHS), 2.07-2.21 (m, 2H, H2), 1 .77 (s, 3H, CH3); 13C-NMR (125MHz, DMSO): δ 163.6 (C4), 150.4 (C2), 135.8 {C6), 109.9 (C5), 83.9 (C7 ), 83.3 (C4'), 70.1 (C3), 69.6 (C5), 38.3 (C2), 36.7 (CH3), 12.0 (CH3); LCMS (ES+): m/z (%) 321 (100) [M+H]+; HRMS (ES+): calcd for C1 1 H17N207S1 [M+H]+ 321 .0751 mlz, found 321 .0754 m/z (-0.98 ppm).

5'- azido-5'-deoxy-thymidine (30): Compound 29 (3 mmol) was reacted with NaN3 (6 mmol) following the procedure of preparation compound 7 to yield compound 30 516 mg (64 %) as a solid. TLC (10% MeOH/DCM) R = 0.40; 1 H-NMR (500MHz, MeOD): δ 7.56 (s, 1 H, H6), 6.28 (t, J=6.80 Hz, 1 H, H1 ), 4.36 (m, 1 H, H4), 3.97 (dd, J=8.70, J=3.98, 1 H, H3), 3.57-3.67 (m, 2H, H5), 2.25-2.35 (m, 2H, H2), 1 .91 (s, 3H, CH3); 13C-NMR (125MHz, MeOD): δ 166.3 (C4), 152.3 (C2), 137.8 {C6), 1 1 1 .9 (C5), 86.4 (C7 ), 86.3 (C4), 72.5 (C3), 53.4 (C5), 40.2 (C2), 12.5 (CH3); LCMS (ES+): m/z (%) 268 (100) [M+H]+; HRMS (ES+): calcd for C10H14N5O4 [M+H]+ 268.1040 mlz, found 268.1038 mlz (0.88 ppm).

5'-amino-5'-deoxy-thymidine (31): Compound 30 (268 mg, 1 mmol) was hydrogenated to give compound 31 237 mg (98.3 %) as a solid. TLC (10%MeOH/DCM) R = 0.001 ; 1 H-NMR (500MHz, MeOD): δ 7.37 (s, 1 H, H6), 6.1 1 (t, J = 6.84 Hz, 1 H, H1 ), AA A (m, 1 H, H3), 3.17 (m, 1 H, H4), 3.20-3.24 (m, 2H, NH2), 2.72-2.83 (m, 2H, H5), 2.10-2.20 (m, 2H, H2), 1 .79 (s, 3H, CH3); 13C-NMR (125MHz, MeOD): δ 166.6 (C4), 152.5 (C2), 138.1 (C6), 1 1 1 .9 (C5), 88.5 (C7 ), 86.2 (C4), 72.9 (C3), 44.7 (C5), 40.2 (C2), 12.5 (CH3); LCMS (ES+): m/z (%) 242 (100) [M+H]+; HRMS (ES+): calcd for C10H16N3O4 [M+H]+ 242.1 135 mlz, found 242.1 131 mlz (1 .98ppm).

General Procedure for compounds 8a - 8e

A suspension of 60% sodium hydride in mineral oil (2 mmol) was added to a suspension of 4-((pivaloyloxy)amino)phenol in 5 ml DMF under Ar and cooled with ice bath. Then different substituted benzyl bromide (7a - 7b) was added to the mixture. The reaction was left under RT for 3 h. The reaction mixture was removed DMF and purified by chromatography by Hexane/EtOAC (7/3) to give the compounds 8a - 8e.

A/-(4-((2-chlorobenzyl)oxy)phenyl)-0-pivaloylhydroxylamine (8a): 2-Chlorobenzyl bromide reacted with 4-((pivaloyloxy)amino)phenol to yield compound 8a as a solid; TLC (10% MeOH/DCM) R = 0.91 ; 1 H-NMR (500MHz, CDCI3): 5 7.55-7.57, 7.40-7.42, 7.26-7.32, 6.93-6.96 (m, 8H, H-Ph), 6.35 (s, 1 H, NH), 5.16 (s, 2H, CH2), 1 .53 (s, 9H, CH3); 13C-NMR (125MHz, CDCI3): δ 154.6 (CO), 134.8, 132.6, 131 .9, 129.4, 128.9, 128.8, 127.0, 1 15.3 (C-Ph), 76.8 (C(CH3)3), 67.5 (CH2), 28.4 (CH3); LCMS (ES+): m/z (%) 278 (100) [M+H]+.

A/-(4-((2-chlorobenzyl)oxy)phenyl)-0-pivaloylhydroxylamine (8b): 3-Chlorobenzyl bromide reacted with 4-((pivaloyloxy)amino)phenol to yield compound 8b as a solid; TLC (10% MeOH/DCM) R = 0.91 ; 1 H-NMR (500MHz, DMSO): δ 9.17 (s, 1 H, NH), 7.34-7.50, 6.90-6.93 (m, 8H, H-Ph), 5.06 (s, 2H, CH2), 2.30 (s, 3H, CHS), 1 .46 (s, 9H, CH3); 13C-NMR (125MHz, DMSO): δ 153.2 (CO), 152.9, 139.9, 133.0, 133.0, 130.3, 127.6, 127.2, 1 19.5, 1 14.8 (C-Ph), 78.7 (C(CH3)3), 68.4 (CH2), 28.1 (CH3); LCMS (ES+): m/z (%) 278 (100) [M+H]+.

A/-(4-((4-chlorobenzyl)oxy)phenyl)-0-pivaloylhydroxylamine (8c): 4-Chlorobenzyl bromide reacted with 4-((pivaloyloxy)amino)phenol to yield compound 8c as a solid; TLC (10% MeOH/DCM) R = 0.92; 1 H-NMR (500MHz, CDCI3): δ 7.37, 7.28-7.29, 6.90- 6.92 (m, 8H, H-Ph), 6.37 (s, 1 H, NH), 5.01 (s, 2H, CH2), 3.83 (s, 3H, CHS), 1 .53 (s, 9H, CHS); 13C-NMR (125MHz, CDCI3): δ 154.5 (CO), 135.6, 133.7, 131 .9, 128.8, 128.7, 120.4, 1 15.3 (C-Ph), 76.8 (C(CH3)3), 69.6 (CH2), 28.4 (CH3); LCMS (ES+): m/z (%) 278 (100) [M+H]+. A/-(4-((4-methoxybenzyl)oxy)phenyl)-0-pivaloylhydroxylamine (8d): 4-

Methoxybenzyl bromide reacted with 4-((pivaloyloxy)amino)phenol to yield compound 8c as a solid; TLC (10% MeOH/DCM) R = 0.75; 1 H-NMR (500MHz, CDCI3): δ 7.27- 7.32, 7.00-7.02, 6.87-6.94 (m, 8H, H-Ph), 6.37 (s, 1 H, NH), 5.03 (s, 2H, CH2), 3.83 (s, 3H, CH3), 1 .53 (s, 9H, CH3); 13C-NMR (125MHz, CDCI3): δ 159.8 (CO), 154.8, 138.7, 131 .7, 129.6, 120.5, 1 19.6, 1 15.3, 1 13.5, 1 12.8 (C-Ph), 70.2 (CH2), 55.3 (CH3), 28.4 (CH3); LCMS (ES+): m/z (%) 274 (100) [M+H]+.

A/-(4-((4-tertbutylbenzyl)oxy)phenyl)-0-pivaloylhydroxylamine (8e): 4- tertbutylbenzyl bromide reacted with 4-((pivaloyloxy)amino)phenol to yield compound 8c as a solid; TLC (10% MeOH/DCM) R = 0.93; 1 H-NMR (500MHz, CDCI3): δ 7.36- 7.43, 7.27-7.28, 6.92-6.95 (m, 8H, H-Ph), 6.35 (s, 1 H, NH), 5.01 (s, 2H, CH2), 1 .53 (s, 9H, CH3), 1 .34 (s, 9H, CH3); 13C-NMR (125MHz, CDCI3): δ 151 .0 (CO), 134.0, 127.5, 125.8, 125.5, 1 15.2 (C-Ph), 76.8 (C(CH3)3), 70.2 (CH2), 34.6 (C(CH3)3), 31 .4 (CH3), 28.4 (CH3); LCMS (ES+): m/z (%) 300 (100) [M+H]+. General Procedure for compounds 9a - 9e

The Boc group protected 8a - 8e (1 .4 mmol) was dissolved in 40 ml DCM and stirred at RT for few minutes. TFA (2 ml) was added with a syringe. The solution changed from colorless to a slight yellow. After 3 h, the reaction was evaporated under reduced pressure and purified by chromatography to get a brown to grey color solid.

4-(2-Chlorobenzoxy)phenyl amine (9a): Compound 8a was removed the Boc group to give compound 9a as a solid; TLC (10% MeOH/DCM) R = 0.21 ; 1 H-NMR (500MHz, DMSO): δ 9.37 (s, 2H, NH2), 7.57-7.60, 7.51 -7.54, 7.37-7.43, 7.19-7.34, 7.08-7.14 (m, 8H, H-Ph), 5.16 (s, 2H, CH2); 13C-NMR (125MHz, DMSO): δ 134.0, 132.6, 130.2, 130.0, 129.4, 127.4, 123.0, 1 15.8 (C-Ph), 67.2 (CH2); LCMS (ES+): m/z (%) 234 (100) [M+H]+.

4-(3-Chlorobenzoxy)phenyl amine (9b): Compound 8b was removed the Boc group to give compound 9b as a solid; TLC (10% MeOH/DCM) R = 0.23; 1 H-NMR (500MHz, DMSO): 5 9.28 (s, 1 H, NH), 7.39-7.51 , 7.17-7.19, 7.06-7.08 (m, 8H, H-Ph), 5.13 (s, 2H, CH2); 13C-NMR (125MHz, DMSO): δ 133.1 , 130.4, 127.8, 127.3, 126.2, 1 15.8 (C-Ph),

68.5 (CH2); LCMS (ES+): m/z (%) 234 (100) [M+H]+. 4-(4-Chlorobenzoxy)phenyl amine (9c): Compound 8c was removed the Boc group to give compound 9c as a solid; TLC (10% MeOH/DCM) R = 0.21 ; 1 H-NMR (500MHz, DMSO): δ 9.49 (s, 2H, NH2), 7.47, 7.20-7.22, 7.07-7.08 (m, 8H, H-Ph), 5.1 1 (s, 2H, CH2); 13C-NMR (125MHz, DMSO): δ 135.8, 132.5, 129.5, 128.4, 123.3, 1 15.8 (C-Ph),

68.6 (CH2); LCMS (ES+): m/z (%) 234 (100) [M+H]+.

4-(4-Methoxybenzoxy)phenyl amine (9d): Compound 8d was removed the Boc group to give compound 9d as a solid; TLC (10% MeOH/DCM) R = 0.24; 1 H-NMR (500MHz, DMSO): δ 9.48 (s, 2H, NH2), 7.29-7.32, 7.19-7.22, 7.06-7.09, 7.00-7.01 , 6.89-6.91 (m, 8H, H-Ph), 5.09 (s, 2H, CH2), 3.76 (s, 3H, CH3); 13C-NMR (125MHz, DMSO): δ 159.3, 138.3, 129.6, 123.3, 1 19.7, 1 15.8, 1 13.2, 1 13.2 (C-Ph), 69.3 (CH2), 55.0 (CH3); LCMS (ES+): m/z (%) 230 (100) [M+H]+.

4-(4-ierfbutylbenzoxy)phenyl amine (9e): Compound 8e was removed the Boc group to give compound 9e as a solid; TLC (10% MeOH/DCM) R = 0.23; 1 H-NMR (500MHz, DMSO): δ 9.37 (s, 2H, NH2), 7.42-7.36, 7.25-7.27, 7.08-7.10, (m, 8H, H-Ph), 5.07 (s, 2H, CH2), 1 .28 (s, 9H, CH3); 13C-NMR (125MHz, DMSO): δ 157.4, 150.4, 133.7, 127.6, 125.6, 125.4, 125.2, 123.8, 1 15.7 (C-Ph), 69.3 (CH2), 34.3 (C(CH3)3), 31 .1 (CH3); LCMS (ES+): m/z (%) 256 (100) [M+H]+. General Procedure for compounds 10a - 10e

Et₃N (0.5 mmol) was added to a solution of the amines 9a - 9e in 10 ml EtOAC. The mixture was kept at 0 - 5 °C and trisphogene (2 mmol) was added. The reaction mixture was gradually brought to reflux at 77 ^<C for 2 h. The progression of the reaction was monitored by TLC. Excess solvent was removed in vacuoand the crude product was flashed by a short pad of Si0₂ to yield the isocyanates (10a - 10e). Because the isocyanates were very active, they were directly use for the next step.

General Coupling Procedure for amine 8 and (thio)isocyanate derivatives to give compounds according to formula (II)

A compound of amine 8 (1 eq.) was dissolved in DMF at 0 °C. The coupling reagents (1 .1 eq.) were added and the reaction mixture was allowed to stir at room temperature for 3 h. After the completion of the reaction, the reaction mixture was evaporated to dry (ethanol and toluene were used to co-evaporate) and the residue was purified by column chromatography to yield the compounds as a solid.

A/-(5'-deoxy-a-thymidin-5'-yl)-A '-(2-methyoxylphenyl)urea (13): 2-Methoxyphenyl isocyanate reacted with amine 8 to yield compound 13 as a solid; TLC (10% MeOH/DCM) R = 0.18; H-NMR (500MHz, DMSO): δ 1 1 .29 (s, 1 H, H), 8.07-8.09 (m, 1 H, NH and HH), 7.78 (s, 1 H, H6), 6.82-7.02 (m, 4H, H-Ph), 6.19 (qt, J=3.66 Hz, 1 H, H1 ), 5.46 (s, 1 H, OH), 4.12-4.18 (m, 2H, H3' and H4), 3.83 (s, 3H, CH₃), 3.23-3.27, 3.1 1 -3.17 (m, 2H, H5), 2.55-2.60 (m, 1 H, H2), 1 .94 (d, J=14.20 Hz, 1 H, H2), 1 .78 (s, 3H, CH₃); ³C-NMR (125MHz, DMSO): δ 163.8 (C4), 155.2 (CO), 150.5 (C2), 136.9 {C6), 147.3, 129.3, 121 .0, 120.4, 1 18.0, 1 10.5 (C-Ph), 108.8 (C5), 87.0 (C7 ), 84.7 (C4), 70.8 (C3), 55.6 (CH₃), 41 .0 (C5), 39.0 (C2), 12.3 (CH₃); LCMS (ES+): m/z (%) 391 (100) [M+H]+; HRMS (ES+): calcd for C^H^Oe [M+H]+ 391 .1612 m/z, found 391 .1615 m/z (-0.61 ppm). A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(3-methyoxylphenyl)urea (14): 3-Methoxyphenyl isocyanate reacted with amine 8 to yield compound 14 as a solid; TLC (10% MeOH/DCM) R = 0.28; H-NMR (500MHz, DMSO): δ 11.24 (s, 1H, NH), 8.54 (s, 1H, NH), 7.77 (d, J=1.05 Hz, 1H, H6), 7.10-7.14 (m, 2H, H-Ph), 6.85 (qt, J=3.05 Hz, 1H, H- Ph), 6.48 (qt, J=3.36 Hz, 1H, H-Ph), 6.24 (t, J=5.77 Hz, 1H, NH), 6.18 (qt, J=3.71 Hz, 1H, H7), 5.43 (d, J=3.25 Hz, 1H, OH), 4.16-4.21 (m, 2H, H3' and H4), 3.71 (s, 3H, CHS), 3.23-3.28, 3.09-3.18 (m, 2H, H5), 2.55-2.61 , 1.92-1.96 (m, 2H, H2), 1.78 (s, 3H, CHS); ³C NMR (125MHz, DMSO): δ 163.8 (C4), 159.6 (CO), 155.1 (C2), 136.9 (C6), 150.5, 141.6, 129.4, 109.0, 106.5, 103.4 (C-Ph), 110.0 (C5), 86.8 (C7), 84.7 (C4), 70.9 (C3), 54.8 (CH3), 41.0 (C5), 39.0 (C2), 12.3 (CH3); LCMS (ES+): m/z (%) 391 (100) [M+H]+; HRMS (ES+): calcd for C^H^Oe [M+H]+ 391.1612 m/z, found 391.1629 m/z (-4.33 ppm).

A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(4-methyoxylphenyl)urea (15): 4-Methoxyphenyl isocyanate reacted with amine 8 to yield compound 15 as a solid; TLC (10% MeOH/DCM) R = 0.38; H-NMR (500MHz, DMSO): δ 11.28 (s, 1H, NH), 8.34 (s, 1H, NH), 7.78 (s, 1H, H6), 7.28 (d, J=8.75 Hz, 2H, HPh), 6.81 (d, J=8.75 Hz, 2H, H-Ph),

6.14- 6.18 (m, 2H, H7'and NH), 5.44 (d, J=2.45 Hz, 1H, OH), 4.18 (d, J=4.50 Hz, 2H, HS' and H4), 3.69 (s, 3H, CH₃), 3.16-3.24 (m, 1H, H5), 3.07-3.12 (m, 1H, H5), 2.54- 2.60 (m, 1H, H2), 1.93 (d, J=14.20 Hz, 1H, H2), 1.78 (s, 3H, CH₃); ³C-NMR (125MHz, DMSO): δ 163.8 (C4), 155.4 (CO), 153.9, 133.7, 119.3, 113.9 (C-Ph), 150.5 (C2), 136.9 (C6), 108.8 (C5), 87.0 (C7), 84.7 (C4), 79.1 (C3), 70.8 (C5), 55.1 (CH₃), 41.0 (C2), 12.2 (CH₃); LCMS (ES+): m/z (%) 391 (100) [M+H]+; HRMS (ES+): calcd for C₁₈H₂₃N₄0₆ [M+H]+ 391.1612 m/z, found 391.1613 m/z (-0.27 ppm).

A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(2-chlorophenyl)urea (16): 2-Chlorophenyl isocyanate reacted with amine 8 to yield compound 16 as a solid; TLC (10% MeOH/DCM) R = 0.43; H-NMR (500MHz, DMSO): δ 11.29 (s, 1H, NH), 8.16 (s, 1H, NH), 7.79 (d, J=1.2 Hz, H6), 7.39 (qt, J=3.16 Hz, 1H, H-Ph), 7.17-7.26 (m, 2H, H-Ph), 6.94-6.97 (m, 1H, H-Ph), 6.20 (qt, J=3.78 Hz, 1H, H7), 5.48 (d, J=3.30 Hz, 1H, OH),

4.15- 4.21 (m, 2H, H3' and H4), 3.28-3.33 (m, 1H, H5), 3.12-3.17 (m, 1H, H5), 2.56- 2.62 (m, 1H, H2), 1.93-1.97 (m, 1H, H2), 1.79 (s, 3H, CH₃); ³C-NMR (125MHz, DMSO): δ 163.8 (C4), 154.8 (CO), 150.5 (C2), 136.6 (C6), 136.9, 129.1, 127.4, 122.5, 121.1, 120.8 (C-Ph), 108.9 (C5), 86.7 (C7), 84.6 (C4), 70.9 (C3), 41.1 (C5), 39.0 {C2), 12.3 (CH₃); LCMS (ES+): m/z (%) 395 (100) [M+H]+; HRMS (ES+): calcd for C17H20CI1N4O5 [M+H]+ 395.1117 m/z, found 395.1112 m/z(1.13 ppm).

A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(3-chlorophenyl)urea (17): 3-Chlorophenyl isocyanate reacted with amine 8 to yield compound 17 as a solid; TLC (10% MeOH/DCM) Rf = 0.25; H-NMR (500MHz, DMSO): δ 11.25 (s, 1H, NH), 8.77 (s, 1H, NH), 7.77 (d, J=1.00 Hz, 1H, H6), 7.67 (t, J=2.00 Hz, 1H, HPh), 7.16-7.26 (m, 2H, H- Ph), 6.93-6.95 (m, 1H, H-Ph), 6.35 (t, J=5.77 Hz, 1H, NH), 6.18 (qt, J=3.75 Hz, 1H, H1), 5.43 (d, J=3.25 Hz, 1H, OH), 4.16-4.21 (m, 2H, H3' and H4), 3.23-3.28 (m, 1H, H5), 3.09-3.15 (m, 1H, H5), 2.55-2.61 (m, 1H, H2), 1.92-1.96 (m, 1H, H2), 1.78 (s, 3H, CH₃); ³C-NMR (125MHz, DMSO): δ 163.8 (C4), 154.9 (CO), 150.5 (C2), 136.9 (C6), 141.9, 133.1, 130.2, 120.7, 116.9, 116.0 (C-Ph), 108.8 (C5), 86.7 (C7), 84.6 (C4), 70.9 (C3), 41.0 (C5), 39.0 (C2), 12.3 (CH₃); LCMS (ES+): m/z (%) 395 (100) [M+H]+; HRMS (ES+): calcd for C„H₂₀C N₄O₅ [M+H]+ 395.1117 m/z, found 395.1108 m/z (2.21 ppm).

A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(4-nitrophenyl)urea (23): 4-Nitrophenyl isocyanate reacted with amine 8 to yield compound 23 as a solid; TLC (10%MeOH/DCM) Rf = 0.31; H-NMR (500MHz, DMSO): 511.29 (s, 1H, NH), 9.36 (s, 1H, NH), 8.15 (d, J=9.27 Hz, 1H, 2H, H-Ph), 7.78 (s, 1H, H6),7.62 (d, J=9.25 Hz, 2H, H-Ph), 6.57 (t, J=5.71 Hz, 1H, NH), 6.19 (m, 1H, H1), 5.48 (d, J=3.34 Hz, 1H, OH), 4.17, 4.22 (m, 2H, H3' and H4); 3.14, 3.29 (m, 2H, H5), 2.59, 1.95 (m, 2H, H2); 1.78 (s, 3H, CH₃); ³C-NMR (125MHz, DMSO): δ 163.8 (C4), 154.4 (CO), 150.5 (C2), 136.9 (C6), 147.0, 140.4, 125.2, 116.8 (C-Ph), 108.9 (C5), 86.4 (C7), 84.6 (C4), 79.1 (C3), 70.8 (C5), 41.0 (C2), 12.3 (CH₃); LCMS (ES+): m/z (%) 406 (100) [M+H]+; HRMS (ES+): calcd for C₁₇H₂oN₅0₇ [M+H]+ 406.1357 m/z, found 406.1372 m/z (-3.75 ppm).

A/-(5'-deoxy-a-thymidin-5'-yl)-A'-phenylurea (4a): Phenyl isocyanate reacted with amine 8 to yield compound 4a as a solid; TLC (10% MeOH/DCM) Rf = 0.44; H-NMR (500MHz, DMSO): δ 11.24 (s, 1H, NH), 8.52 (s, 1H, NH), 7.77 (d, J = 1.20 Hz, 1H, H6), 7.37-7.39 (m, 2H, H-Ph), 7.20-7.24 (m, 2H, H-Ph), 6.88-6.91 (m, 1H, H-Ph), 6.25 (t, J = 5.85 Hz, 1H, NH), 6.19 (qt, J = 3.75 Hz, 1H, H1), 5.43 (d, J = 3.25 Hz, 1H, OH), 4.17- 4.21 (m, 2H, H3' and H4), 3.24-3.29, 3.10-3.15 (m, 2H, H5), 2.57-2.61 (m, 1H, H2), 1.92-1.96 (m, 1H, H2), 1.78 (s, 3H, CH₃); ³C-NMR (125 MHz, DMSO): δ 163.8 (C4), 155.2 (CO), 150.5 (C2), 136.9 (C6), 140.3, 128.6, 121.1, 117.6 (C-Ph), 108.8 (C5), 86.9 (C7), 84.7 (C4), 70.9 (C3), 56.0 (C5), 41.0 {C2), 12.3 (CH₃); LCMS (ES+): m/z (%) 361 (100) [M+H]+; HRMS (ES+): calcd for C₁₇H₂₁N₄0₅ [M+H]+ 361.1506 m/z, found 361.1496 m/z (2.85 ppm). A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(4-chlorophenyl)urea (4b): 4-Chlorophenyl isocyanate reacted with amine 8 to yield compound 4b as a solid; TLC (10% MeOH/DCM) R = 0.14; 1H-NMR (500MHz, DMSO): δ 11.28 (s, 1H, NH), 8.71 (s, 1H, NH), 7.77 (d, J= 1.10 Hz, 1H, H6), 7.40-7.43 (m, 2H, H-Ph), 7.25-7.28 (m, 2H, H-Ph), 6.31 (t, J= 5.82 Hz, 1H, NH), 6.18 (qt, J= 3.75 Hz, 1H, H7), 5.45 (d, J= 3.25 Hz, 1H, OH), 4.15-4.21 (m, 2H, H3' and H4), 3.23-3.28 (m, 1H, H5), 3.08-3.14 (m, 1H, H5), 2.55-2.60 (m, 1H, H2), 1.92-1.96 (m, 1H, H2), 1.78 (s, 3H, CH3); 13C-NMR (125MHz, DMSO): δ 163.8 (C4), 155.0 (CO), 150.5 (C2), 139.3 (C-Ph), 136.9 (C6), 128.5, 124.5, 119.0 (C-Ph), 108.8 (C5), 86.7 (C7), 84.6 (C4), 70.8 (C3), 48.6 (C5), 41.0 (C2), 12.3 (CH3); LCMS (ES+): m/z (%) 395 (100) [M+H]+; HRMS (ES+): calcd for C17H20CI1N4O5 [M+H]+ 395.1117 m/z, found 395.1115 m/z (0.47 ppm).

A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(4-chlorophenyl)thiourea (4c): 4-Chlorophenyl isothiocyanate reacted with amine 8 to yield compound 4c as a solid; TLC (10% MeOH/DCM) R = 0.16; 1H-NMR (500MHz, DMSO): δ 11.26 (s, 1H, NH), 9.71 (s, 1H, NH), 7.86 (s, 1H, NH), 7.79 (d, J= 1.20 Hz, 1H, H6), 7.48-7.51, 7.35-7.38 (m, 4H, H- Ph), 6.21 (qt, J = 3.73 Hz, 1H, H1), 5.48 (d, J = 3.35 Hz, 1H, OH), 4.34-4.37 (m, 1H, H3), 4.22-4.25 (m, 1H, H4), 3.67-3.69, 3.48-3.53 (m, 2H, H5), 2.57-2.63 (m, 1H, H2), 1,92-1.96 (m, 1H, H2), 1.79 (s, 3H, CH3); 13C-NMR (125MHz, DMSO): δ 180.8 (CS), 163.8 (C4), 150.5 (C2), 136.9 (C6), 128.4, 124.6 (C-Ph), 108.8 (C5), 85.7 (C7), 84.6 (C4), 70.9 (C3), 45.5 (C5), 39.0 (C2), 12.2 (CH3); LCMS (ES+): m/z (%) 411 (100) [M+H]+; HRMS (ES+): calcd for C17H20CI1 N404S1 [M+H]+ 411.0888 m/z, found 411.0883 m/z (1.23 ppm).

A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(4-bromophenyl)urea (4d): 4-Bromophenyl isocyanate reacted with amine 8 to yield compound 4d as a solid; TLC (10% MeOH/DCM) R = 0.42; 1H-NMR (500MHz, DMSO): δ 11.26 (s, 1H, H), 9.71 (s, 1H, HH), 7.88 (s, 1H, HH), 7.79 (d, J = 1.20 Hz, 1H, H6), 7.44-7.50 (m, 4H, H-Ph), 6.21 (qt, J = 3.73 Hz, 1H, H7), 5.48 (d, J = 3.35 Hz, 1H, OH), 4.34-4.37 (m, 1H, H3), 4.22-4.25 (m, 1 H, H4), 3.67-3.69, 3.48-3.53 (m, 2H, H5), 2.57-2.63 (m, 1 H, H2), 1.93-1.96 (m, 1H, H2), 1.78 (s, 3H, OH 3); 13C-NMR (125MHz, DMSO): δ 180.7 (CS), 163.8 (C4), 150.5 (C2), 136.9 {C6), 138.7, 131.3, 124.8 (C-Ph), 108.8 (C5), 85.7 (C7), 84.6 (C4), 79.2 (C3), 70.9 (C5), 45.5 (C2), 12.3 (CH3); LCMS (ES+): m/z (%) 455 (100) [M+H]+; HRMS (ES+): calcd for C17H20BM N404S1 [M+H]+ 455.0383 m/z, found 455.0373 m/z (2.33 ppm).

A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(4-bromophenyl)thiourea (4e): 4-Bromophenyl isocyanate reacted with amine 8 to yield compound 4e as a solid; TLC (10% MeOH/DCM) R = 0.42; H-NMR (500MHz, DMSO): δ 11.26 (s, 1H, H), 9.71 (s, 1H, HH), 7.88 (s, 1H, HH), 7.79 (d, J = 1.20 Hz, 1H, H6), 7.44-7.50 (m, 4H, H-Ph), 6.21 (qt, J = 3.73 Hz, 1 H, H7 ), 5.48 (d, J = 3.35 Hz, 1 H, OH), 4.34-4.37 (m, 1 H, H3), 4.22-4.25 (m, 1H, H4), 3.67-3.69, 3.48-3.53 (m, 2H, H5), 2.57-2.63 (m, 1H, H2), 1.93-1.96 (m, 1H, H2), 1.78 (s, 3H, 0H₃); ³C-NMR (125MHz, DMSO): δ 180.7 (CS), 163.8 (C4), 150.5 (C2), 136.9 {C6), 138.7, 131.3, 124.8 (C-Ph), 108.8 (C5), 85.7 (C7), 84.6 (C4), 79.2 (C3), 70.9 (C5), 45.5 (C2), 12.2 (CH₃); LCMS (ES+): m/z (%) 455 (100) and 457 (100) [M+H]+; HRMS (ES+): calcd for C₁₇H₂oBr₁N₄0₄S₁ [M+H]+ 455.0383 m/z, found 455.0373 m/z (2.33 ppm).

A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(3-trifluoromethyl-4-chlorophenyl)urea (4f): 3- Trifluoromethyl-4-chlorophenyl isocyanate reacted with amine 8 to yield compound 4f as a solid; TLC (10% MeOH/DCM) R = 0.17; 1H-NMR (500MHz, DMSO): δ 11.25 (s, 1H, NH), 9.06 (s, 1H, NH), 8.06 (d, J = 1.60 Hz, 1H,H-Ph), 7.77 (d, J = 1.20 Hz, 1H, H6), l. A-l. l (m, 2H, H-Ph), 6.45 (t, J= 5.82 Hz, 1H, HH), 6.18 (qt, J = 3.75 Hz, 1H, H1), 5.44 (d, J= 3.35 Hz, 1H, OH), 4.16-4.22 (m, 2H, H3' and H4), 3.23-3.28, 3.11- 3.18 (m, 2H, H5), 2.55-2.61 (m, 1H, H2), 1.92-1.96 (m, 1H, H2), 1.78 (s, 3H, CHS); 13C-NMR (125MHz, DMSO): δ 163.8 (C4), 154.9 (CO), 150.5 (C2), 136.89 (C6), 140.0, 131.9, 126.5, 122.3, 121.5, 116.1 (C-Ph), 108.8 (C5), 86.6 (C7), 84.6 (C4), 70.8 (C3), 41.1 (C5), 39.0 (C2), 12.2 (CH3); LCMS (ES+): m/z (%) 463 (100) [M+H]+; HRMS (ES+): calcd for C18H23N405 [M+H]+ 463.0991 m/z,found 463.0989 m/z (0.35 ppm).

A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(3-trifluoromethyl-4-chlorophenyl)thiourea (4g):

3-Trifluoromethyl-4-chlorophenyl isothiocyanate reacted with amine 8 to yield compound 4g as a solid; TLC (10%MeOH/DCM) R = 0.38; 1H-NMR (500MHz, DMSO): δ 11.30 (s, 1H, NH), 10.01 (s, 1H, NH), 8.15 (m, 2H, H-Ph and NH), 7.79 (s, 1H, H6), 7.74 (d, J= 9.26 Hz, 1H, H-Ph), 7.64 (d, J = 8.74 Hz, 1H, H-Ph), 6.22 (m, 1H, H7), 5.52 (m, 1H, OH), 4.36 (m, 1H, H4), 4.24 (m, 1H, H3), 3.71 (m, 1H, H5), 3.51 (m, 1H, H5), 2.61 (m, 1H, H2), 1.95 (m, 1H, H2), 1.78 (s, 3H, CH3); 13C-NMR (125MHz, DMSO): δ 180.7 (CS), 163.8 (C4), 150.5 (C2), 139.1 (C6), 136.9, 131.6, 127.2, 124.4, 123.8 (C-Ph), 108.9 (C5), 85.5 (C7), 84.6 (C4), 70.9 (C3), 48.6 (C5), 45.5 (C2), 12.3 (CH3); 19F-NMR (470MHz, DMSO): δ 61.47; LCMS (ES+): m/z (%) 478 (100) [M+H]+; HRMS (ES+): calcd for C18H19CI1 F3N404S1 [M+H]+ 479.0762 m/z, found 479.0781 m/z (-3.93 ppm). A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(4-iert-butylphenyl)urea (4h): 4-te/t-butylphenyl isothiocyanate reacted with amine 8 to yield compound 4h as a solid; TLC (10%MeOH/DCM) R = 0.15; H-NMR (500MHz, DMSO): δ 11.28 (s, 1H, NH), 8.45 (s, 1H, NH), 7.78 (s, 1H, H6), 7.29 (d, J = 8.70 Hz, 2H, HPh), 7.23 (d, J = 8.70 Hz, 2H, H- Ph), 6.17-6.21 (m, 2H, H7'and NH), 5.45 (d, J= 3.15 Hz, 1H, OH), 4.16-4.20 (m, 2H, H3' and H4), 3.22-3.27 (m, 1H, H5), 3.09-3.14 (m, 1H, H5), 2.54-2.60 (m, 1H, H2), 1.94 (d, J = 7.12 Hz, 1H, H2), 1.78 (s, 3H, CH₃), 1.24 (s, 9H, CHS); ³C-NMR (125MHz, DMSO): δ 163.8 (C4), 155.2 (CO), 150.5 (C2), 143.3, 137.7 (C-Ph), 136.9 (C6), 125.2, 117.5 (C-Ph), 108.8 (C5), 86.9 (C7), 84.6 (C4), 79.1 (C3), 70.8 (C5), 41.0 (C2), 33.8 (C(CH₃)₃), 31.2 (CH3), 12.2 (CH₃); LCMS (ES+): m/z (%) 417 (100) [M+H]+; HRMS (ES+): calcd for C21H29N4O5 [M+H]+ 417.2106 m/z, found 417.2120 m/z (-3.37 ppm).

A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(2-phenylphenyl)urea (4i): 2-Phenylphenyl isocyanate reacted with amine 8 to yield compound 4i as a solid; TLC (10% MeOH/DCM) R = 0.32; H-NMR (500MHz, DMSO): δ 11.23 (s, 1 H, H), 7.88 (qt, J = 3.05 Hz, 1H, HH), 7.76 (d, J= 1.15 Hz, 1H, H6), 7.05-7.89 (m, 9H, H-Ph), 6.72 (t, J = 5.80 Hz, 1H, HH), 6.14 (qt, J= 3.73 Hz, 1H, H1), 5.41 (d, J= 1.85 Hz, 1H, OH), 4.15- 4.17 (m, 2H, H3' and H4), 3.20-3.25, 3.08-3.13 (m, 2H, H5), 2.52-2.57 (m, 1H, H2), 1.91-1.95 (m, 1H, H2), 1.78 (s, 3H, CH₃); ³C-NMR (125MHz, DMSO): δ 163.8 (C4), 155.6 (CO), 150.5 (C2), 136.4 (C6), 138.7, 136.9, 132.3, 130.1, 129.1, 128.7, 127.6, 127.3, 122.6, 122.5 (C-Ph), 108.8 (C5), 87.1 (C7), 84.7 (C4), 70.9 (C3), 41.2 (C5), 39.0 (C2), 12.3 (CH₃); LCMS (ES+): m/z (%) 437 (100) [M+H]+; HRMS (ES+): calcd for C₂₃H₂₅N₄0₅ [M+H]+ 437.1819 m/z, found 437.1811 m/z (1.92 ppm). A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(4-phenylphenyl)urea (4j): 4-Phenylphenyl isocyanate reacted with amine 8 to yield compound 4i as a solid; TLC (10% MeOH/DCM) R = 0.32; H-NMR (500MHz, DMSO): δ 11.25 (s, 1H, NH), 8.66 (s, 1H, NH), 7.78 (d, J= 1.15 Hz, 1H, H6), 7.28-7.62 (m, 9H, H-Ph), 6.30 (t, J = 5.85 Hz, 1H, NH), 6.20 (qt, J = 3.75 Hz, 1H, H7), 5.44 (d, J = 3.25 Hz, 1H, OH), 4.18-4.23 (m, 2H, H3' and H4), 3.26-3.30, 3.12-3.18 (m, 2H, H5), 2.57-2.62 (m, 1H, H2), 1.93-1.97 (m, 1H, H2), 1.79 (s, 3H, CH₃); ³C-NMR (125MHz, DMSO): δ 163.8 (C4), 155.1 (CO), 150.5 (C2), 136.9 (C6), 139.9, 132.8, 128.8, 126.9, 126.6, 126.0, 118.0 (C-Ph), 108.8 (C5), 86.8 (C7), 84.7 (C4), 70.9 (C3), 41.1 (C5), 39.0 (C2), 12.3 (CH₃); LCMS (ES+): m/z (%) 437 (100) [M+H]+; HRMS (ES+): calcd for C23H25N4O5 [M+H]+ 437.1819 m/z, found 437.1821 m/z (-0.35 ppm).

A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(4-piperdin-1-ylphenyl)urea (4k): 4-Piperdin-1- ylphenyl isocyanate reacted with amine 8 to yield compound 4k as a solid; TLC (10% MeOH/DCM) R = 0.30; H-NMR (500MHz, DMSO): δ 11.28 (s, 1H, NH), 8.25 (s, 1H, NH), 7.77 (d, J = 1.20 Hz, 1H, H6), 7.19-7.22 (m, 2H, H-Ph), 6.80-6.83 (m, 2H, H-Ph), 6.17 (qt, J= 3.71 Hz, 1H, H7), 6.12 (t, J= 5.90 Hz, 1H, NH), 5.44 (d, J= 3.25 Hz, 1H, OH), 4.15-4.20 (m, 2H, H3' and H4), 3.20-3.24 (m, 1H, H5), 3.07-3.12 (m, 1H, H5), 2.99 (t, J= 5.42 hz, 4H, CH₂), 2.54-2.59 (m, 1H, H2), 1.91-1.95 (m, 1H, H2), 1.78 (s, 3H,CH₃), 1.58-1.63 (m,4H,CH₂), 1.48-1.51 (m, 2H, CH₂); ³C-NMR (125MHz, DMSO): δ 163.8 (C4), 155.4 (CO), 150.5 (C2), 136.9 (C6), 146.9, 132.4, 119.0, 116.8 (C-Ph), 108.8 (C5), 87.0 (C7), 84.6 (C4), 70.8 (C3), 50.6 (CH₂), 41.0 (C5), 39.0 (C2), 25.4 (CH₂), 23.8 (CH₂), 12.3 (CH₃); LCMS (ES+): m/z (%) 444 (100) [M+H]+; HRMS (ES+): calcd for C22H30N5O5 [M+H]+ 444.2241 mlz, found 444.2231 m/z (2.31 ppm).

A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(4-(4-methylpiperazinyl)phenyl)urea (4I): 4-(4- Methylpiperazinyl)phenyl isocyanate reacted with amine 8 to yield compound 4I as a solid; TLC (10% MeOH/DCM) R = 0.31; H-NMR (500MHz, DMSO): δ 11.28 (s, 1H, NH), 8.27 (s, 1H, NH), 7.79 (d, J= 1.10 Hz, 1H, H6), 7.20-7.31 (m, 2H, H-Ph), 6.82- 6.91 (m, 2H, H-Ph), 6.17 (qt, J= 3.75 Hz, 1H, H7), 6.12 (t, J= 5.87 Hz, 1H, NH), 5.46 (d, J= 3.34 Hz, 1H, OH), 4.17-4.22 (m, 2H, H3' and H4), 3.20-3.27 (m, 1H, H5), 3.07- 3.14 (m, 1H, H5), 2.99 (m, 4H, CH₂), 2.54-2.59 (m, 1H, H2), 2.42-2.51 (m, 4H, CH₂), 2.17-2.23 (s, 3H, CH₃), 1.91-1.97 (m, 1H, H2), 1.78 (s, 3H, CH3); ³C-NMR (125MHz, DMSO): δ 163.8 (C4), 155.4 (CO), 150.5 (C2), 136.9 (C6), 146.0, 132.5, 132.0, 119.4, 119.0, 116.2, 116.1 (C-Ph), 108.8 (C5), 87.0 (C7), 84.6 (C4), 79.2 (CH₂), 70.8 (C3), 54.7 (CH₂), 48.9, 48.9 (CH₂), 45.8 (C5), 41.0 (C2), 12.3 (CH₃); LCMS (ES+): m/z (%) 459 (100) [M+H]+; HRMS (ES+): calcd for C₂₂H₃₁N₆0₅ [M+H]+ 459.2350 m/z, found 459.2361 m/z (-2.31 ppm). A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(4-tetrahydropyran-4-oxyphenyl)urea (4m): 4- tetrahydropyran-4-oxyphenyl isocyanate reacted with amine 8 to yield compound 4m as a solid; TLC (10% MeOH/DCM) R = 0.21; H-NMR (500MHz, DMSO): δ 11.27 (s, 1H, NH), 8.35 (s, 1H, NH), 7.76 (d, J = 1.15 Hz, 1H, H6), 7.24-7.27 (m, 2H, H-Ph), 6.83-6.86 (m, 2H, H-Ph), 6.14-6.17 (m, 2H, NHand H7), 5.43 (d, J=3.25 Hz, 1H, OH), 4.39-4.44 (m, 1H, CH), 4.13-4.18 (m, 2H, H3' and H4'J, 3.80-3.84 (m, 2H, CH₂), 3.41-

3.46 (m, 2H, CH₂), 3.19-3.24 (m, 1H, H5), 3.06-3.11 (m, 1H, H5), 2.53-2.58 (m, 1H, H2), 1.89-1.94 (m, 3H, H2'and CH₂), 1.76 (s, 3H, CH₃), 1.49-1.56 (m, 2H, CH₂); ³C- NMR (125MHz, DMSO): δ 163.8 (C4), 155.3 (CO), 151.3 (C2), 136.9 {C6), 155.3, 133.8, 119.3, 116.4 (C-Ph), 108.8 (C5), 87.0 (C7), 84.6 (C4), 71.7 (C3), 70.8 (CH), 64.5 (CH₂), 41.0 (C5), 39.0 (C2), 31.8 (CH₂), 12.3 (CH₃); LCMS (ES+): m/z (%) 461 (100) [M+H]+; HRMS (ES+): calcd for C₂₂H₂₉N₄0₇ [M+H]+ 461.2031 m/z, found 461.2024 m/z (1.46 ppm).

A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(4-benzyloxyphenyl)urea (4n): 4-Benzyloxyphenyl isocyanate reacted with amine 8 to yield compound 4n as a solid; TLC (10% MeOH/DCM) R = 0.36; H-NMR (500MHz, DMSO): δ 11.29 (s, 1H, NH), 8.37 (s, 1H, NH), 7.78 (s, 1H, H6), 7.28-7.44 (m, 7H, H-Ph), 6.90 (d, J= 9.01 Hz, 2H, H-Ph), 6.18 (m, 2H, Wand NH), 5.45 (d, J= 3.16 Hz, 1H, OH), 5.03 (s, 2H, CH₂-Ph), 4.19 (m, 2H, H3' and H4), 3.24 (m, 1H, H5), 3.11 (m, 1H, H5'), 2.57 (m, 1H, H2), 1.93 (m, 1H, H2), 1.78 (s, 3H, CH₃); ³C-NMR (125MHz, DMSO): δ 163.9 (C4), 155.4 (CO), 150.5 (C2), 137.3 (C6), 153.0, 133.7, 128.4, 127.7, 119.3, 114.9 (C-Ph), 108.8 (C5), 87.0 (C7), 84.7 (C4), 79.1 (C3), 70.8 (CH₂-Ph), 69.3 (C5), 41.04 (C2), 12.3 (CH₃); LCMS (ES+): m/z (%) 467 (100) [M+H]+; HRMS (ES+): calcd for C₂₄H₂₇N₄0₆ [M+H]+ 467.1925 m/z, found 467.1937 m/z (-2.53 ppm).

A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(4-benzyloxyphenyl)thiourea (4o) 4-

Benzyloxyphenyl isothiocyanate reacted with amine 8 to yield compound 4o as a solid; TLC (10% MeOH/DCM) R = 0.27; H-NMR (500MHz, DMSO): δ 11.28 (s, 1H, NH),

9.47 (s, 1H, NH), 7.79 (d, J= 1.15 Hz, 1H, H6), 7.59 (s, 1H, NH), 7.25-7.46 (m, 7H, H- Ph), 6.97-6.99 (m, 2H, H-Ph), 6.19 (qt, J = 5.46 Hz, 1H, H7), 5.48 (d, J=3.15 Hz, 1H, OH), 4.35 (t, J= 5.35 Hz, 1H, H3), 4.24 (t, J= 2.67 Hz, 1H, H4), 3.58-3.62 (m, 1H, H5), 3.48-3.50 (m, 1H, H5), 2.56-2.61 (m, 1H, H2), 1.92 (d, J= 14.40 Hz, 1H, H2), 1.78 (s, 3H, CH₃); ³C-NMR (125MHz, DMSO): δ 163.8 (C4), 155.6 (CO), 150.5 (C2), 137.0 (C6), 137.1, 128.4, 127.8, 127.7, 125.7, 114.8 (C-Ph), 108.7 (C5), 86.0 (C7), 84.7 (C4), 70.8 (C3), 69.3 (CH₂), 46.5 (C5), 39.0 (C2), 12.36 (CH₃); LCMS (ES+): m/z (%) 483 (100) [M+H]+; HRMS (ES+): calcd for

[M+H]+ 483.1697 m/z, found 483.1688 m/z (1.71 ppm).

A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(2-(phenoxylmethyl)phenyl) urea (4p): 2- (Phenoxylmethyl)phenyl isocyanate reacted with amine 8 to yield compound 4p as a solid; TLC (10% MeOH/DCM) R = 0.16; HNMR (500MHz, DMSO): δ 11.28 (s, 1H, NH), 7.94 (s, 1H, NH), 7.85 (d, J= 7.60 Hz, 1H, NH), 7.79 (d, J = 1.15 Hz, 1H, H6), 7.39 (qt, J = 3.00 Hz, 1H, H-Ph), 7.25-7.32 (m, 3H, H-Ph), 6.88-7.03 (m, 5H, HPh), 6.19 (qt, J = 3.75 Hz, 1H, H7), 5.47 (d, J = 3.20 Hz, 1H, OH), 5.04 (s, 2H, CH₂), 4.17- 4.22 (m, 2H, H3' and H4), 3.26-3.31 (m, 1H, H5), 3.09-3.18 (m, 1H, H5), 2.54-2.60 (m, 1H, H2), 1.92-1.96 (m, 1H, H2), 1.78 (s, 3H, CH₃); ³C-NMR (125MHz, DMSO): δ 163.8 (C4), 155.4 (CO), 150.5 (C2), 158.3, 141.1, 138.0, 129.4, 129.3, 128.4, 126.3, 122.2, 121.6, 120.7 (C-Ph), 136.9 (C6), 108.8 (C5), 87.0 (C7), 84.6 (C4), 70.9 (C3), 66.3 (CH₂), 41.2 (C5), 39.0 (C2), 12.3 (CH₃); LCMS (ES+): m/z (%) 467 (100) [M+H]+; HRMS (ES+): calcd for C24H27N4O6 [M+H]+ 467.1925 m/z, found 467.1921 m/z (0.93 ppm).

A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(3-(phenoxylmethyl)phenyl) urea (4q): 3-

(Phenoxylmethyl)phenyl isocyanate reacted with amine 8 to yield compound 4q as a solid; TLC (10% MeOH/DCM) R = 0.24; HNMR (500MHz, DMSO): δ 11.29 (s, 1H, NH), 8.63 (s, 1H, NH), 7.78 (d, J= 1.15 Hz, 1H, H6), 7.49 (s, 1H, H-Ph), 7.22-7.35 (m, 4H, H-Ph), 6.92-7.00 (m, 4H, H-Ph), 6.27 (t, J = 5.87 Hz, 1H, NH), 6.18 (qt, J= 3.73 Hz, 1H, H1), 5.45 (d, J= 3.30 Hz, 1H, OH), 5.04 (s, 2H, CH₂), 4.16-4.21 (m, 2H, H3' and H4), 3.23-3.28 (m, 1H, H5), 3.09-3.15 (m, 1H, H5), 2.55-2.60 (m, 1H, H2), 1.92- 1.96 (m, 1H, H2), 1.78 (s, 3H, CH₃); ³C-NMR (125MHz, DMSO): δ 163.8 (C4), 155.1 (CO), 150.5 (C2), 158.3, 140.5, 137.7, 129.5, 128.8, 120.6, 120.27, 117.0, 116.5, 114.7 (C-Ph), 136.9 (C6), 108.8 (C5), 86.9 (C7), 84.6 (C4), 70.8 (C3), 69.1 (CH₂), 41.0 (C5), 39.0 (C2), 12.3 (CH₃); LCMS (ES+): m/z (%) 467 (100) [M+H]+; HRMS (ES+): calcd for C₂4H₂₇N₄0₆[M+H]+ 467.1925 m/z, found 467.1929 m/z (-0.76 ppm). A/-(5'-deoxy-a-thymidin-5'-yl)-A 4-(6-methyl-2-benzothiazolyl)phenyl) urea (4r): 4-

(6-Methyl-2-benzothiazolyl)phenyl isocyanate reacted with amine 8 to yield compound 4r as a solid; TLC (10% MeOH/DCM) R = 0.26; H-NMR (500MHz, DMSO): δ 11.17 (s, 1H, NH), 8.86 (s, 1H, NH), 7.81-7.83, 7.74-7.77 (m, 4H, H-Ph), 7.67 (d, J= 1.15 Hz, 1H, H6), 7.46 (qt, J = 2.93 Hz, 2H, H-Ph), 7.21 (qt, J = 3.16 Hz, 2H, H-Ph), 6.32 (t, J = 5.34 Hz, 1H, NH), 6.08 (qt, J = 3.75 Hz, 1H, H7), 5.36 (d, J = 3.30 Hz, 1H, OH), 4.07- 4.10 (m, 2H, H3' and H4), 3.15-3.20 (m, 1H, H5), 3.00-3.05 (m, 1H, H3), 2.44-2.51 (m, 1H, H2), 2.33 (s, 3H, CH₃), 1.81-1.86 (m, 1H, H2), 1.66 (s, 3H, CH₃); ³C-NMR (125MHz, DMSO): δ 163.8 (C4), 150.5 (C2), 154.8, 151.8, 143.3, 134.7, 134.2, 127.9, 125.7, 121.9, 117.6 (C-Ph), 136.9 {C6), 108.9 (C5), 86.7 (C7), 84.6 (C4), 70.8 (C3), 41.0 (C5), 39.0 (C2), 21.0 (CH₃), 12.3 (CH₃); LCMS (ES+): m/z (%) 508 (100) [M+H]+; HRMS (ES+): calcd for C^H^NsOsS! [M+H]+ 508.1649 m/z, found 508.1658 m/z (- 1.82 ppm). A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(4-morpholinophenyl) thiourea (4s): 4-

Morpholinophenyl isothiocyanate reacted with amine 8 to yield compound 4s as a solid; TLC (10% MeOH/DCM) R = 0.31; H-NMR (500MHz, DMSO): δ 11.25 (s, 1H, NH), 9.40 (s, 1H, NH), 7.78 (d, J=1.15 Hz, 1H, H6), 7.50 (s, 1H, HH), 7.20 (d, J = 8.90 Hz, 2H, H-Ph), 6.91 (d, J= 9.05 Hz, 2H, H-Ph), 6.18 (qt, J= 3.61 Hz, 1H, H1), 5.45 (d, J = 3.30 Hz, 1 H, OH), 4.34-4.37 (m, 1 H, H3), 4.23-4.26 (m, 1 H, H4), 3.73 (t, J = 4.80 Hz, 4H, CH₂), 3.60-3.63, 3.47-3.52 (m, 2H, H5), 3.08 (t, J = 4.82 Hz, 4H, CH₂), 2.56-2.61, 1.90-1.94 (m, 2H, H2), 1.78 (s, 3H, CH₃); ³C-NMR (125MHz, DMSO): δ 180.8 (CS), 163.8 (C4), 150.5 (C2), 137.0 {C6), 148.4, 125.2, 115.2 (C-Ph), 108.7 (C5), 86.0 (C7), 84.7 (C4), 70.8 (C3), 66.1 (CH₂), 48.6 (CH₂), 45.5 (C5), 39.0 (C2), 12.3 (CH₃); LCMS (ES+): m/z (%) 462 (100) [M+H]+; HRMS (ES+): calcd for C₂₁H₂₈N₅0₅S₁ [M+H]+ 462.1806 m/z, found 462.1794 m/z (2.48 ppm).

A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(4-phenlyoxyphenyl) urea (4t): 4-Phenlyoxyphenyl isocyanate reacted with amine 8 to yield compound 4t as a solid; TLC (10% MeOH/DCM) R = 0.26; H-NMR (500MHz, DMSO): δ 11.25 (s, 1H, NH), 8.56 (s, 1H, NH), 7.78 (d, J= 1.15 Hz, 1H, H6), 7.39-7.42, 7.33-7.37 (m, 4H, H-Ph), 7.05-7.09 (m, 1H, H-Ph), 6.92-6.95 (m, 4H, H-Ph), 6.24 (t, J = 5.85 Hz, 1H, NH), 6.19 (qt, J= 3.73 Hz, 1H, H7), 5.43 (d, J = 3.25 Hz, 1H, OH), 4.17-4.22 (m, 2H, H3' and H4), 3.24-3.29, 3.10-3.18 (m, 2H, H5), 2.57-2.61 (m, 1H, H2), 1.92-1.97 (m, 1H, H2), 1.79 (s, 3H, CH₃); ³C-NMR (125MHz, DMSO): δ 163.8 (C4), 155.2 (CO), 150.5 (C2), 136.5 {C6), 157.8, 150.0, 136.9, 129.8, 122.6, 119.8, 119.2, 117.4 (C-Ph), 108.8 (C5), 86.9 (C7), 84.7 (C4), 70.9 (C3), 41.1 (C5), 39.0 (C2), 12.3 (CH₃); LCMS (ES+): m/z (%) 453 (100) [M+H]+; HRMS (ES+): calcd for C23H25N4O6 [M+H]+ 453.1769 m/z, found 453.1756 m/z (2.76 ppm).

A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(4-benzylphenyl) urea (4u) : 4-Phenlyoxyphenyl isocyanate reacted with amine 8 to yield compound 4t as a solid; TLC (10% MeOH/DCM) R = 0.26; H-NMR (500MHz, DMSO): δ 11.28 (s, 1H, NH), 8.48 (s, 1H, NH), 7.07-7.30 (m, 9H, H-Ph), 6.22 (t, J= 5.82 Hz, 1H, NH), 6.18 (qt, J= 3.71 Hz, 1H, H7), 5.45 (d, J= 3.25 Hz, 1H, OH), 4.15-4.20 (m, 2H, H3' and H4), 3.84 (s, 2H, CH₂), 3.21-3.26, 3.08-3.13 (m, 2H, H5), 2.54-2.59, 1.91-1.95 (m, 2H, H2), 1.78 (s, 3H, CH₃); 3CNMR (125MHz, DMSO): δ 163.8 (C4), 155.2 (CO), 150.5 (C2), 136.9 {C6), 141.7, 138.3, 133.9, 128.9, 128.5, 128.3, 125.8, 117.8 (C-Ph), 108.8 (C5), 86.9 (C7), 84.6 (C4), 70.8 (C3), 41.0 (CH₂), 40.4 (C5), 39.0 (C2), 12.3 (CH₃); LCMS (ES+): m/z (%) 451 (100) [M+H]+; HRMS (ES+): calcd for C24H27N4O5 [M+H]+ 451.1976 m/z, found 451.1965 m/z (2.35 ppm).

A/-(5'-deoxy-a-thymidin-5'-yl)-A 4-(6-(trifluoromethyl)pyridin-3-yl)phenyl) urea (4v) : 4-(6-(Trifluoromethyl)pyridin-3-yl)phenyl isocyanate reacted with amine 8 to yield compound 4v as a solid; TLC (10% MeOH/DCM) R = 0.27; H-NMR (500MHz, DMSO): 511.28 (s, 1H, NH), 8.97 (t, J= 1.12 Hz, 1H, H-Ph), 8.88 (s, 1H, NH), 8.21 (qt, J= 3.51 Hz, 1H, H-Ph), 8.08-8.12 (m, 3H, H-Ph), 7.79 (t, J= 1.12 Hz, 1H, H6), 7.56 (d, J= 8.85 Hz, 2H, H-Ph), 6.40 (t, J = 5.70 Hz, 1H, NH), 6.20 (qt, J = 3.75 Hz, 1H, H1), 5.48 (d, J =3.30 Hz, 1H, OH), 4.18-4.23 (m, 2H, H3' and H4), 3.26-3.31, 3.12-3.17 (m, 2H, H5), 2.56-2.62, 1.93-1.97(m, 2H, H2), 1.78 (s, 3H, CH₃); ³C-NMR (125MHz, DMSO): δ 163.8 (C4), 155.9 (CO), 150.5 (C2), 136.9 (C6), 159.5, 129.7, 127.8, 119.2, 117.5 (C-Ph), 108.9 (C5), 86.7 (C7), 84.6 (C4), 70.8 (C3), 41.0 (C5), 39.0 (C2), 12.3 (CH₃); LCMS (ES+): m/z (%) 506 (100) [M+H]+; HRMS (ES+): calcd for C23H23F3N5O5 [M+H]+ 506.1646 m/z, found 506.1636 m/z (1.91 ppm).

A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(4-(2-chlorobenzyloxy)phenyl)urea (11a): 4-(2- Chlorobenzyloxy)phenyl isocyanate reacted with amine 8 to yield compound 11a as a solid; TLC (10% MeOH/DCM) R = 0.19; 1H-NMR (500MHz, DMSO): δ 11.28 (s, 1H, NH), 8.40 (s, 1H, NH), 7.78 (d, J = 1.20 Hz, 1H, H6), 7.57-7.60, 7.50-7.53, 7.37-7.40, 7.29-7.31, 6.90-6.94 (m, 8H, H-Ph), 6.16-6.19 (m, 2H, H7'and NH), 5.45 (d, J = 3.20 Hz, 1H, OH), 5.09 (s, 2H, H2), 4.18-4.21 (m, 2H, H3' and H4), 3.21-3.28, 3.09-3.13 (m, 2H, H5), 2.53-2.60, 1.91-1.97 (m, 2H, H2), 1.78 (s, 3H, CH3); 13C-NMR (125MHz, DMSO): δ 163.8 (C4), 155.4 (CO), 150.5 (C2), 136.9 (C6), 152.8, 134.6, 132.5, 130.0, 129.7, 129.3, 127.3, 119.3, 114.9 (C-Ph), 108.8 (C5), 86.9 (C7), 84.7 (C4), 70.8 (C3), 67.0 (CH2), 55.0 (C5), 41.0 (C5), 39.0 (C2), 12.3 (CH3); LCMS (ES+): m/z (%) 501 (100) [M+H]+; HRMS (ES+): calcd for C24H26CI1 N406 [M+H]+ 501.1535 m/z, found 501.1533 m/z (0.54 ppm).

A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(4-(3-chlorobenzyloxy)phenyl)urea (11b): 4-(3- Chlorobenzyloxy)phenyl isocyanate reacted with amine 8 to yield compound 11b as a solid; TLC (10% MeOH/DCM) R = 0.25; 1H-NMR (500MHz, DMSO): δ 11.28 (s, 1H, HH), 8.38 (s, 1H, HH), 7.78 (d, J = 1.20 Hz, 1H, H6), 7.37-7.42, 7.28-7.30, 6.89-6.91 (m, 8H, H-Ph), 6.16-6.19 (m, 2H, H7'and NH), 5.45 (d, J= 3.25 Hz, 1H, OH), 5.06 (s, 2H, CH2), 4.16-4.20 (m, 2H, H3' and H4), 3.12-3.22 (m, 1H, H5), 2.57 (m, 1H, H2), 1.92-1.95 (m, 1H, H2), 1.78 (s, 3H, CHS); 13C-NMR (125MHz, DMSO): δ 163.8 (C4), 155.3 (CO), 150.5 (C2), 136.9 (C6), 152.7, 136.9, 133.9, 133.0, 130.0, 127.6, 127.2, 126.1, 119.3, 115.0 (C-Ph), 108.8 (C5), 86.9 (C7), 84.7 (C4), 70.8 (C3), 68.4 (CH2), 41.0 (C5), 39.0 (C2), 12.3 (CH3); LCMS (ES+): m/z (%) 501 (100) [M+H]+; HRMS (ES+): calcd for C24H26CI1 N406 [M+H]+ 501.1535 m/z, found 501.1533 m/z (0.54 ppm).

A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(4-(4-chlorobenzyloxy)phenyl)urea (11c): 4-(4- Chlorobenzyloxy)phenyl isocyanate reacted with amine 8 to yield compound 11c as a solid; TLC (10% MeOH/DCM) R = 0.23; 1H-NMR (500MHz, DMSO): δ 11.28 (s, 1H, NH), 8.37 (s, 1H, NH), 7.77 (d, J = 1.20 Hz, 1H, H6), 7.44-7.45, 7.27-7.29, 6.88-6.90 (m, 8H, H-Ph), 6.16-6.19 (m, 2H, H7'and HH), 5.45 (d, J= 3.30 Hz, 1H, OH), 5.03 (s, 2H, CH2), 4.16-4.18 (m, 2H, H3' and H4), 3.75 (s, 3H, CHS), 3.22-3.32 (m, 1H, H5), 3.15-3.27 (m, 1H, H5'), 2.57 (m, 1H, H2), 1.92-1.94 (m, 1H, H2), 1.78 (s, 3H, CHS); 13C-NMR (125MHz, DMSO): δ 163.8 (C4), 155.3 (CO), 150.5 (C2), 136.9 (C6), 152.7, 136.4, 133.8, 132.2, 129.4, 128.4, 119.2, 115.0 (C-Ph), 108.8 (C5), 86.9 (C7), 84.6 (C4), 70.8 (C3), 68.9 (CH2), 41.0 (C5), 39.0 (C2), 12.3 (CH3); LCMS (ES+): m/z (%) 501 (100) [M+H]+; HRMS (ES+): calcd for C24H26CI1 N406 [M+H]+ 501.1535 m/z, found 501.1519 m/z (3.33 ppm). A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(4-(4-methyoxybenzyloxy)phenyl)urea (11 d): 4-(4- Methyoxybenzyloxy)phenyl isocyanate reacted with amine 8 to yield compound 11 d as a solid; TLC (10% MeOH/DCM) flf = 0.15; 1 H-NMR (500MHz, DMSO): δ 11.28 (s, 1 H, HH), 8.37 (s, 1H, HH), 7.78 (d, J = 1.20 Hz, 1H, H6), 7.27-7.31, 6.99-7.00, 6.87-6.90 (m, 8H, H-Ph), 6.16-6.19 (m, 2H, H7'and NH), 5.45 (d, J= 3.25 Hz, 1H, OH), 5.01 (s, 2H, CH2), 4.16-4.18 (m, 2H, HS' and H4), 3.75 (s, 3H, CHS), 3.22-3.32 (m, 1H, H5), 3.15-3.27 (m, 1H, H5'), 2.57 (m, 1H, H2), 1.94 (m, 1H, H2), 1.78 (s, 3H, CHS); 13C- NMR (125MHz, DMSO): δ 163.8 (C4), 155.4 (CO), 150.5 (C2), 136.9 {C6), 159.3, 152.9, 138.9, 129.5, 119.2, 114.9, 113.1, 113.0 (C-Ph), 108.8 (C5), 87.0 (C7), 84.6 (C4), 70.8 (C3), 69.2 (CH2), 55.0 (CH3), 41.0 (C5), 39.0 (C2), 12.3 (CH3); LCMS (ES+): m/z (%) 497 (100) [M+H]+; HRMS (ES+): calcd for C25H29N407 [M+H]+ 497.2031 m/z, found 497.2031 m/z (-0.12 ppm).

A/-(5'-deoxy-a-thymidin-5'-yl)-A'-(4-(4-ieributylbenzyloxy)phenyl)urea (11e): 4-(4- te/1butylbenzyloxy)phenyl isocyanate reacted with amine 8 to yield compound 11e as a solid; TLC (10% MeOH/DCM) R = 0.21; 1 H-NMR (500MHz, DMSO): δ 11.23 (s, 1H, NH), 8.37 (s, 1H, NH), 7.77 (d, J = 1.20 Hz, 1H, H6), 7.67-7.76, 7.26-7.41, 6.77-6.89 (m, 8H, H-Ph), 6.16-6.19 (m, 2H, H7'and NH), 5.45 (d, J= 3.20 Hz, 1H, OH), 4.99 (s, 2H, CH2), 4.18-4.21 (m, 2H, H3'and H4), 3.21-3.28, 3.09-3.13 (m, 2H, H5), 2.52-2.59, 1.91-1.98 (m, 2H, H2), 1.78 (s, 3H, CHS), 1.28 (s, 9H, CHS); LCMS (ES+): m/z (%) 523 (100) [M+H]+; HRMS (ES+): calcd for C28H35N406 [M+H]+ 523.2551 m/z, found 523.2554 m/z (-0.57 ppm).

General Coupling Procedure for amine 31 and (thio)isocyanate derivatives to give compounds according to formula (III)

Amine 31 (1 eq.) was dissolved in DMF at 0 °C. The coupling reagents (1.1 eq.) were added and the reaction mixture was allowed to stir at room temperature for 3 h. After the completion of the reaction, the reaction mixture was evaporated to dry (ethanol and toluene were used to co-evaporate) and the residue was purified by column chromatography to yield the compounds according to formula (III).

A/-(5'-deoxy-thymidin-5'-yl)-A'-(2-methoxyl-phenyl)urea (38): 2-Methoxyphenyl isocyanate reacted with amine 31 to yield compound 38 as a solid; TLC (10%MeOH/DCM) R = 0.33; H-NMR (500MHz, DMSO): 511.33 (s, 1H, NH), 8.09 (qt, J = 3.16 Hz, 1H, HH), 8.03 (s, 1H, HH), 7.51 (d, J = 0.8 Hz, 1H, H6), 7.07 (t, J = 5.80 Hz, 1H, H-Ph), 6.89-6.96 (m, 1H, H-Ph), 6.81-6.89 (m, 2H, H-Ph), 6.19 (qt, J= 4.66 Hz, 1H, H1), 5.35 (d, J=4.30 Hz, 1H, OH), 4.14-4.17 (m, 1H, H3), 2.1A-2.11 (m, 1H, H4), 3.45-3.50 (m, 1H, H5), 3.36 (s, 3H, CH₃), 3.20-3.25 (m, 1H, H5), 2.14-2.19 (m, 1H, H2), 2.05-2.09 (m, 1H, H2), 1.77 (s, 3H, CH₃); ³C-NMR (125MHz, DMSO): δ 163.7 (C4), 155.2 (CO), 150.5 (C2), 147.3 (CPh), 136.0 (C6), 129.3, 121.0, 120.4, 117.9, 110.5 (C-Ph), 109.8 (C6), 85.4 (C7), 83.6 (C4), 71.1 (C3), 55.6 (CH₃), 41.3 (C5), 38.4 (C2), 12.0 (CH₃); LCMS (ES+): m/z (%) 391 (100) [M+H]+; HRMS (ES+): calcd for C₁₈H₂₃N₄0₆ [M+H]+ 391.1612 m/z, found 391.1614 m/z (-0.57 ppm). A/-(5'-deoxy-thymidin-5'-yl)-A/'-(3-methoxyl-phenyl)urea (39): 3-Methoxyphenyl isocyanate reacted with amine 31 to yield compound 38 as a solid; TLC (10%MeOH/DCM) R = 0.14; H-NMR (500MHz, DMSO): δ 11.33 (s, 1H, NH), 8.55 (s, 1H, NH), 7.52 (s, 1H, H6), 7.09-7.15 (m, 2H, H-Ph), 6.84 (t, J= 4.52 Hz, 1H, H-Ph), 6.47 (qt, J = 3.40 Hz, 1H, H-Ph), 6.29 (t, J = 5.82 Hz, 1H, NH), 6.18 (t, J= 7.0 Hz, 1H, H1), 5.35 (d, J = 4.20 Hz, 1H, OH), 4.16-4.17 (m, 1H, H3), 3.75-3.78 (m, 1H, H4), 3.70 (s, 3H, CH₃), 3.43-3.48 (m, 1H, H5), 3.20-3.25 (m, 1H, H5'), 2.13-2.19 (m, 1H, H2), 2.04-2.09 (m, 1H, H2), 1.78 (s, 3H, CH₃); ³C-NMR (125MHz, DMSO): δ 163.7 (C4), 159.6 (CO), 155.1 (C2), 150.5, 141.6 (CPh), 136.1 (C6), 129.4, 109.9, 109.8, 106.5 (C-Ph), 103.3 (C5), 85.3 (C7), 83.7 (C4), 71.1 (C3), 54.8 (CH₃), 41.4 (C5), 38.4 (C2), 12.0 (CH₃); LCMS (ES+): m/z (%) 391 (100) [M+H]+; HRMS (ES+): calcd for C₁₈H₂₃N₄0₆ [M+H]+ 391.1612 m/z, found 391.1615 m/z (-0.78 ppm).

A/-(5'-deoxy-thymidin-5'-yl)-A'-(4-methoxyl-phenyl)urea (40): 4-Methoxyphenyl isocyanate reacted with amine 31 to yield compound 40 as a solid; TLC (10%MeOH/DCM) R = 0.26; H-NMR (500MHz, DMSO): δ 11.33 (s, 1H, NH), 8.32 (s, 1H, NH), 7.52 (d, J = 1.00 Hz, 1H, H6), 7.28 (qt, J= 3.0 Hz, 2H, H-Ph), 6.81 (qt, J = 3.00 Hz, 2H, H-Ph), 6.17-6.20 (m, 2H, NH and H1), 5.34 (d, J = 4.25 Hz, 1H, OH), 4.14-4.18 (m, 1H, H3), 3.75-3.78 (m, 1H, H4), 3.43-3.48 (m, 1H, H5), 3.36 (s, 3H, CH₃), 3.19-3.24 (m, 1H, H5), 2.13-2.18 (m, 1H, H2), 2.05-2.09 (m, 1H, H2), 1.78 (s, 3H, CH₃); ³C-NMR (125MHz, DMSO): δ 163.7 (C4), 155.4 (CO), 153.9 (C-Ph), 150.5 (C2), 136.0 (C6), 133.5 (C-Ph), 119.3, 113.8 (CPh), 109.8 (C5), 85.4 (C7), 83.7 (C4), 71.1 (C3), 55.4 (CH₃), 41.4 (C5), 38.4 (C2), 12.0 (CH₃); LCMS (ES+): m/z (%) 391 (100) [M+H]+; HRMS (ES+): calcd for C₁₈H₂₃N₄0₆ [M+H]+ 391.1612 m/z, found 391.1599 m/z (3.43 ppm). A/-(5'-deoxy-thymidin-5'-yl)-A'-(2-chloro-phenyl)urea (41): 2-Chlorophenyl isocyanate reacted with amine 31 to yield compound 41 as a solid; TLC (10%MeOH/DCM) R = 0.12; H-NMR (500MHz, DMSO): δ 11.34 (s, 1H, NH), 8.16 (d, J= 8.10 Hz, 2H, NH), 8.12 (s, 1H, NH), 7.51 (s, 1H, H6), 7.39 (d, J= 7.40 Hz, 1H, H- Ph), 7.23 (t, J = 7.32 Hz, 2H, H-Ph), 6.95 (t, J = 7.17 Hz, 1H, H-Ph), 6.20 (t, J = 6.95 Hz, 1H, H1), 5.38 (d, J= 4.15 Hz, 1 H, OH), 4.17 (d, J= 2.35 Hz, 1H, H3), 3.77 (t, J = 3.47 Hz, 1H, H4), 3.50-3.55 (m, 1H, H5), 3.22-3.27 (m, 1H, H5), 2.16-2.22 (m, 1H, H2), 2.06-2.11 (m, 1H, H2), 1.77 (s, 3H, CH₃); ³C-NMR (125MHz, DMSO): δ 163.7 (C4), 154.8 (CO), 150.5 (C2), 136.6 (C6), 136.0, 129.0, 127.4, 122.5, 121.1, 120.7 (C- Ph), 109.8 (C5), 85.2 (C7), 83.6 (C4), 71.1 (C3), 41.4 (C5), 38.4 (C2), 12.0 (CH₃); LCMS (ES+): m/z (%) 395 (100) [M+H]+; HRMS (ES+): calcd for C₁₇H₂oCI₁N₄0₅ [M+H]+ 395.1117 m/z, found 395.1103 m/z (3.45 ppm).

A/-(5'-deoxy-thymidin-5'-yl)-A'-(3-trifluoromethyl-4-chlorophenyl)urea (45): 3- Trifluoromethyl-4-chlorophenyl isocyanate reacted with amine 31 to yield compound 45 as a solid; TLC (10%MeOH/DCM) R = 0.14; H-NMR (500MHz, DMSO): δ 11.35 (s, 1H, NH), 9.05 (s, 1H, NH), 8.10 (d, J= 2.20 Hz, 1H, H6), 7.52-7.56 (m, 3H, H-Ph), 6.50 (t, J= 5.90 Hz, 1H, HH), 6.18 (qt, J=4.70 Hz, 1H, H1), 5.35 (d, J=4.25 Hz, 1H, OH), 4.15-4.18 (m, 1H, H3), 3.78-3.81 (m, 1H, H4), 3.43-3.48 (m, 1H, H5), 3.23-3.28 (m, 1H, H5), 2.13-2.18, 2.04-2.09 (m, 2H, H2), 1.76 (s, 3H, CH₃); ³C-NMR (125MHz, DMSO): δ 163.7 (C4), 154.9 (CO), 150.5 (C2), 136.1 (C6), 140.0, 131.9, 126.7, 122.3, 121.4, 116.0 (C-Ph), 109.7 (C5), 85.1 (C7), 83.8 (C4), 71.1 (C3), 41.5 (C5), 38.3 (C2), 12.3 (CH₃); LCMS (ES+): m/z (%) 463 (100) [M+H]+; HRMS (ES+): calcd for

[M+H]+ 463.0991 m/z, found 463.0977 m/z (2.85 ppm).

A/-(5'-deoxy-thymidin-5'-yl)-A'-(3-trifluoromethyl-4-chloro-phenyl)thiourea (46): 3-

Trifluoromethyl-4-chlorophenyl isothiocyanate reacted with amine 31 to yield compound 46 as a solid; TLC (10%MeOH/DCM) R = 0.21; H-NMR (500MHz, DMSO): δ 11.35 (s, 1H, H), 9.99 (s, 1H, NH), 8.19 (m, 2H, NHand H-Ph), 7.72 (d, J= 10.80 Hz, 1H, H- Ph), 7.52 (s, 1 H, H6), 6.20 (t, J = 6.35 Hz, 1 H, H1), 5.40 (d, J = 4.36 Hz, 1 H, OH), 4.23 (m, 1 H, H4), 3.94 (m, 2H, H5), 3.62 (m, 1 H, H3), 2.21 (m, 1 H, H2), 2.08 (m, 1 H, H2), 1.78 (s, 3H, CH₃); ⁹F-NMR (470MHz, DMSO): δ 61.47; LCMS (ES+): m/z (%) 479 (100) [M+H]+; HRMS (ES+): calcd for C^H^ChFaN^S_! [M+H]+ 479.0762 m/z, found 479.0775 m/z (-2.68 ppm). A/-(5'-deoxy-thymidin-5'-yl)-A'-(4-nitro-phenyl)urea (47): 4-Nitrophenyl isocyanate reacted with amine 31 to yield compound 47 as a solid; TLC (10%MeOH/DCM) R = 0.33; H-NMR (500MHz, DMSO): δ 11.34 (s, 1H, NH), 9.34 (s, 1H, NH), 8.15 (d, J = 12.14 Hz, 2H, H-Ph), 7.62 (d, J = 11.97 Hz, 2H, H-Ph), 7.51 (s, 1H, H6), 6.61 (t, J = 6.00 Hz, NH), 6.19 (t, J= 7.53 Hz, H1), 5.37 (d, J= 17.05 Hz, OH), 4.17 (m, 1H, H3), 3.79 (m, 1H, H4), 3.50 (m, 1H, H5), 3.26 (m, 1H, H5), 2.19 (m, 1H, H2), 2.08 (m, 1H, H2'), 1.78 (s, 3H, CH₃); ³C-NMR (125MHz, DMSO): δ 163.7 (C4), 154.5 (CO), 150.5 (C2), 147.0 (C-Ph), 140.4 (C-Ph), 136.1 {C6), 125.2 (C-Ph), 116.8 (C-Ph), 109.8 (C5), 85.0 (C7), 83.7 (C4), 71.1 (C3), 41.5 (C5), 38.3 (C2), 12.1 (CH₃); LCMS (ES+): m/z (%) 406 (100) [M+H]+; HRMS (ES+): calcd for C₁₇H₂oN₅0₇ [M+H]+ 406.1357 m/z, found 406.1374 m/z (-4.17 ppm).

A/-(5'-deoxy-thymidin-5'-yl)-A'-phenylurea (6a): Phenyl isocyanate reacted with amine 31 to yield compound 6a as a solid; TLC (10% MeOH/DCM) Rf = 0.21; H-NMR (500MHz, DMSO): 511.33 (s, 1H, NH), 8.54 (s, 1H, NH), 7.53 (d, J= 0.75 Hz, 1H, H6), 7.38 (d, J = 7.65 Hz, 2H, H-Ph), 7.22 (t, J = 7.90 Hz, 2H, H-Ph), 6.89 (t, J = 7.32 Hz, 1H, H-Ph), 6.31 (t, J = 5.65 Hz, 1H, NH), 6.18 (qt, J = 4.68 Hz, 1H, H1), 5.35 (d, J = 4.20, 1H, OH), 4.17 (d, J= 2.6 Hz, 1H, H3), 3.76-3.79 (m, 1H, H4), 3.44-3.49 (m, 1H, H5), 3.20-3.26 (m, 1H, H5 2.14-2.19 (m, 1H, H2), 2.05-2.09 (m, 1H, H2), 1.78 (s, 3H, CH₃); ³C-NMR (125MHz, DMSO): δ 163.7 (C4), 155.2 (CO), 150.5 (C2), 136.1 (C5), 140.4, 128.6, 121.1, 117.5 (C-Ph), 109.8 (C6), 85.3 (C7), 83.7 (C4), 71.1 (C3), 41.4 (C5), 38.4 (C2), 12.0 (CH₃); LCMS (ES+): m/z (%) 361 (100) [M+H]+; HRMS (ES+): calcd for C₁₇H₂₁N₄0₅ [M+H]+ 361.1506 m/z, found 361.1513 m/z (-1.80 ppm). A/-(5'-deoxy-thymidin-5'-yl)-A'-(4-chloro-phenyl)thiourea (6b): 4-Chlorophenyl isocyanate reacted with amine 31 to yield compound 6b as a solid; TLC (10% MeOH/DCM) Hf = 0.29; H-NMR (500MHz, DMSO): δ 11.30 (s, 1H, NH), 8.72 (s, 1H, NH), 7.51 (d, J = 1.05 Hz, 1H, H6), 7.40-7.43 (m, 2H, H-Ph), 7.25-7.28 (m, 2H, H-Ph), 6.36 (t, J = 5.82 Hz, 1H, NH), 6.18 (qt, J = 4.70 Hz, 1H, H1), 5.33 (d, J = 4.25 Hz, 1H, OH), 4.15-4.18 (m, 1H, H3), 3.76-3.78 (m, 1H, H4), 3.44-3.49 (m, 1H, H5), 3.21-3.26 (m, 1H, H5), 2.14-2.19 (m, 1H, H2), 2.05-2.09 (m, 1H, H2), 1.77 (s, 3H. CH₃); ³C- NMR (125MHz, DMSO): δ 163.68 (C4), 155.06 (CO), 150.45 (C2), 139.38 (C-Ph), 136.05 (C6), 128.46, 124.49, 119.01 (C-Ph), 109.77 (C5), 85.21 (C7), 83.67 (C4), 71.08 (C3), 41.39 (C5), 38.35 (C2), 12.02 (CH₃); LCMS (ES+): m/z (%) 395 (100) [M+H]+; HRMS (ES+): calcd for C17H20CI1N4O5 [M+H]+ 395.1117 mlz, found 395.1123 m/z (-1.69 ppm).

A/-(5'-deoxy-thymidin-5'-yl)-A'-(4-chloro-phenyl)thiourea (6c): 4-Chlorophenyl isothiocyanate reacted with amine 31 to yield compound 6c as a solid; TLC (10% MeOH/DCM) R = 0.29; H-NMR (500MHz, DMSO): δ 11.35 (s, 1H, NH), 9.70 (s, 1H, NH), 7.92 (s, 1H, NH), 7.48-7.51, 7.34-7.37 (m, 5H, H6 and H-Ph), 6.19 (qt, J = 4.70 Hz, 1H, H1), 5.39 (d, J = 4.40 Hz, 1H, OH), 4.23 (d, J= 2.55 Hz, 1H, H3), 3.92-3.94 (m, 2H, H4' and H5 3.61-3.63 (m, 1H, H5), 2.17-2.22, 2.06-2.10 (m, 2H, H2), 1.79 (s, 3H, CH₃); ³C-NMR (125MHz, DMSO): δ 180.7 (CS), 163.7 (C4), 150.5 (C2), 136.1 (C6), 138.3, 128.3, 127.8, 124.4 (C-Ph), 109.8 (C5), 84.1 (C7), 83.9 (C4), 71.2 (C3), 46.3 (C5), 38.2 (C2), 12.2 (CH₃); LCMS (ES+): m/z (%) 411 (100) [M+H]+; HRMS (ES+): calcd for C₁₇H₂oCI₁N₄0₄S₁ [M+H]+ 411.0888 m/z, found 411.0885 m/z (0.74 ppm).

A/-(5'-deoxy-thymidin-5'-yl)-A'-(4-bromo-phenyl)urea (6d): 4-Bromophenyl isocyanate reacted with amine 31 to yield compound 6d as a solid; TLC (10% MeOH/DCM) R = 0.29; H-NMR (500MHz, DMSO): δ 11.34 (s, 1H, NH), 8.70 (s, 1H, NH), 7.51 (s, 1H, H6), 7.35-7.41 (m, 4H, H-Ph), 6.37 (t, J=5.03 Hz, 1H, NH), 6.18 (t, J=7.35 Hz, 1H, H7), 5.35 (d, J=4.20 Hz, 1H, OH), 4.16 (m, 1H, H3), 3.77 (m, 1H, H4), 3.46 (m, 1H, H5), 3.22 (m, 1H, H5), 2.16 (m, 1H, H2), 2.06 (m, 1H, H2'), 1.77 (s, 3H, CH₃); ³C-NMR (125MHz, DMSO): δ 163.7 (C4), 155.0 (CO), 150.5 (C2), 136.1 (C6), 139.8, 131.6, 119.5, 112.3 (C-Ph), 109.8 (C5), 85.2 (C7), 83.7 (C4), 71.1 (C3), 41.4 (C5), 38.3 (C2), 12.0 (CH₃); LCMS (ES+): m/z (%) 439 and 441 (100) [M+H]+; HRMS (ES+): calcd for C₁₇H₂oBr₁N₄0₅ [M+H]+ 439.0612ml z, found 436.0615 mlz (-0.72 ppm).

A/-(5'-deoxy-thymidin-5'-yl)-A'-(4-bromo-phenyl)thiourea (6e): 4-Bromophenyl isothiocyanate reacted with amine 31 to yield compound 6e as a solid; TLC (10% MeOH/DCM) R = 0.32; H-NMR (500MHz, DMSO): δ 11.32 (s, 1H, H), 9.68 (s, 1H, HH), 7.93 (s, 1H, HH), 7.44-7.51 (m, 5H, H-Ph), 6.19 (qt, J=4.70 Hz, 1H, H1), 5.36 (d, J= 4.35 Hz, 1H, OH), 4.22-4.23 (m, 1H, H3), 3.92-3.94 (m, 2H, H4' and H5), 3.61- 3.64 (m, 1H, H5), 2.17-2.22, 2.06-2.11 (m, 2H, H2), 1.79 (s, 3H. CH₃); ³CNMR (125MHz, DMSO): δ 180.7 (CS), 163.7 (C4), 150.5 (C2), 136.1 (C6), 138.8, 131.2, 124.7 (C-Ph), 109.8 (C5), 84.1 (C7), 83.9 (C4), 71.3 (C3), 40.0 (C5), 38.2 (C2), 12.3 (CH₃); LCMS (ES+): m/z (%) 455 (100) [M+H]+; HRMS (ES+): calcd for C₁₇H₂oBr₁N₄0₄S₁ [M+H]+ 455.0383 m/z, found 455.0393 m/z (-2.12 ppm).

A/-(5'-deoxy-thymidin-5'-yl)-A'-(4-iert-butyl-phenyl)urea (6f): 4-te/t-Butylphenyl isocyanate reacted with amine 31 to yield compound 6f as a solid; TLC (10% MeOH/DCM) R = 0.2; H-NMR (500MHz, DMSO): δ 11.33 (s, 1H, NH), 8.43 (s, 1H, NH), 7.52 (d, J= 1.1 Hz, 1H, H6), 7.28-7.30 (m, 2H, H-Ph), 7.22-7.24 (m, 2H, H-Ph), 6.24 (t, J = 5.90 Hz, 1H, NH), 6.18 (qt, J =4.70 Hz, 1H, H1), 5.34 (d, J =4.25 Hz, 1H, OH), 4.16 (qt, J = 3.18 Hz, 1H, H3), 3.75-3.78 (m, 1H, H4), 3.43-3.49 (m, 1H, H5), 3.19-3.24 (m, 1H, H5), 2.13-2.19 (m, 1H, H2), 2.04-2.09 (m, 1H, H2), 1.78 (s, 3H, CH₃); ³C-NMR (125MHz, DMSO): δ 163.7 (C4), 155.3 (CO), 150.5 (C2), 143.3, 173.7 (C-Ph), 136.1 {C6), 125.2, 117.4 (C-Ph), 109.8 (C5), 85.4 (C7), 83.7 (C4), 71.1 (C3), 41.4 (C5), 38.4 (C2), 33.8 (C(CH₃)₃), 31.2 (CH3), 12.0 (CH₃); LCMS (ES+): m/z (%) 417 (100) [M+H]+; HRMS (ES+): calcd for C21H29N4O5 [M+H]+ 417.2132 m/z, found 417.2131 m/z (0.39 ppm).

A/-(5'-deoxy-thymidin-5'-yl)-A'-(2-phenylphenyl)urea (6g): 2-Phenylphenyl isocyanate reacted with amine 31 to yield compound 6g as a solid; TLC (10% MeOH/DCM) R = 0.33; H-NMR (500MHz, DMSO): δ 11.32 (s, 1H, NH), 7.90 (d, J = 7.90 Hz, 1H, NH), 7.04-7.48 (m, 10H, H6 and H-Ph), 6.79 (t, J=5.77 Hz, 1H, NH), 6.16 (t, J = 7.00 Hz, 1H, H1), 5.33 (d, J = 4.25 Hz, 1H, OH), 4.11-4.14 (m, 1H, H3), 3.70- 3.73 (m, 1H, H4), 3.43-3.48 (m, 1H, H5), 3.15-3.20 (m, 1H, H5), 2.04-2.14 (m, 2H, H2), 1.73 (s, 3H, CH₃); ³C-NMR (125MHz, DMSO): δ 163.7 (C4), 155.6 (CO), 150.4 (C2), 138.6, 136.4 (CPh), 136.0 (C6), 136.0, 132.0, 130.2, 129.1, 128.7, 127.6, 127.3, 122.5, 122.2 (C-Ph), 109.8 (C5), 85.4 (C7), 83.6 (C4), 71.1 (C3), 41.5 (C5), 38.5 (C2), 12.0 (CH₃); LCMS (ES+): m/z (%) 437 (100) [M+H]+; HRMS (ES+): calcd for C₂₃H₂₅N₄0₅ [M+H]+ 437.1819 m/z, found 437.1829 m/z (-2.16 ppm).

A/-(5'-deoxy-thymidin-5'-yl)-A'-(4-phenylphenyl)urea (6h): 4-Phenylphenyl isocyanate reacted with amine 31 to yield compound 6h as a solid; TLC (10% MeOH/DCM) Hf = 0.57; H-NMR (500MHz, DMSO): δ 11.34 (s, 1H, NH), 8.66 (s, 1H, HH), 7.28-7.62 (m, 10H, H6 and H-Ph), 6.36 (t, J = 5.72 Hz, 1H, NH), 6.20 (t, J = 7.00 Hz, 1H, H1), 5.37 (d, J= 4.15 Hz, 1H, OH), 4.18 (d, J= 2.50 Hz, 1H, H3), 3.79-3.81 (m, 1H, H4), 3.47-3.52 (m, 1H, H5), 3.22-3.28 (m, 1H, H5), 2.15-2.21 (m, 1H, H2), 2.06-2.10 (m, 1H, H2), 1.79 (s, 3H, CH₃); ³C-NMR (125MHz, DMSO): δ 163.7 (C4), 155.1 (CO), 150.5 (C2), 139.9, 139.9 (C-Ph), 136.1 (C6), 132.8, 128.8, 126.9, 126.6, 126.0, 117.9 (C-Ph), 109.8 (C5), 85.3, 83.7 (C4), 71.1 (C3), 41.5 (C5), 38.4 (C2), 12.1 (CH₃); LCMS (ES+): m/z (%) 437 (100) [M+H]+; HRMS (ES+): calcd for C23H25N4O5 [M+H]+ 437.1819 m/z, found 437.1823 m/z (-0.79 ppm).

A/-(5'-deoxy-thymidin-5'-yl)-A'-(4-piperdin-1-ylphenyl)urea (6i): 4-Piperdin-1 - ylphenyl isocyanate reacted with amine 31 to yield compound 6i as a solid; TLC (10% MeOH/DCM) R = 0.15; H-NMR (500MHz, DMSO): δ 11.30 (s, 1H, NH), 8.21 (s, 1H, NH), 7.52 (d, J= 0.8 Hz, 1H, H6), 7.21 (d, J= 8.95 Hz, 2H, H-Ph), 6.82 (d, J= 8.95 Hz, 2H, H-Ph), 6.14-6.19 (m, 2H, NHand H1), 5.32 (d, J=4.25 Hz, 1H, OH), 4.14-4.18 (m, 1H, H3), 3.75-3.78 (m, 1H, H4), 3.42-3.47 (m, 1H, H5), 3.19-3.24 (m, 1H, H5), 2.99 (t, J= 5.35 Hz, 4H, CH₂), 2.09-2.18, 2.05-2.09 (m, 2H, H2), 1.78 (s, 3H, CH₃), 1.59- 1.63 (m, 4H, CH₂), 1.47-1.52 (m, 2H, CH₂); ³C-NMR (125MHz, DMSO): δ 163.7 (C4), 155.5 (CO), 150.5 (C2), 136.0 (C6), 146.9, 132.4, 119.0, 116.8 (C-Ph), 109.8 (C5), 85.4 (C7), 83.7 (C4), 71.1 (C3), 50.6 (CH₂), 41.0 (C5), 38.4 (C2), 25.4 (CH₂), 23.8 (CH₂), 12.3 (CH₃); LCMS (ES+): m/z (%) 444 (100) [M+H]+; HRMS (ES+): calcd for C22H30N5O5 [M+H]+ 444.2241 m/z, found 444.2232 m/z (2.11 ppm).

A/-(5'-deoxy-thymidin-5'-yl)-A'-(4-(4-methylpiperazinyl)phenyl)urea (6j): 4-(4- Methylpiperazinyl)phenyl isocyanate reacted with amine 31 to yield compound 6j as a solid; TLC (10% MeOH/DCM) R = 0.17; 1H-NMR (500MHz, DMSO): δ 11.33 (s, 1H, NH), 8.27, 8.24 (s, 2H, NH), 7.52(d, J= 1.10 Hz, 1H, H6), 7.21-7.28 (m, 2H, H-Ph), 6.81-6.87 (m, 2H, H-Ph), 6.15-6.19 (m, 1H, H1), 5.33 (d, J= 4.25 Hz, 1H, OH), 4.14- 4.16 (m, 1H, H3), 2.1A-2.11 (m, 1H, H4), 3.42-3.47 (m, 1H, H5), 3.18-3.23 (m, 1H, H5), 3.00-3.04 (m, 4H, CH2), 2.42-2.45 (m, 4H, CH2), 2.21 (s, 3H, CH3), 2.12-2.18 (m, 1H, H2), 2.04-2.08 (m, 1H, H2), 1.78 (s, 3H, CH3); 13C-NMR (125MHz, DMSO): δ 163.7 (C4), 155.4 (CO), 150.5 (C2), 136.0 (C6), 146.3, 146.0, 132.0, 119.4, 118.9, 116.1 (C-Ph), 109.8 (C5), 85.4 (C7), 83.7 (C4), 71.1 (C3), 54.7 (CH2), 48.93, 48.87 (CH2), 45.8 (C5), 38.4 (C2), 12.2 (CH3); LCMS (ES+): m/z (%) 459 (100) [M+H]+; HRMS (ES+): calcd for C22H31 N605 [M+H]+ 459.2350 m/z, found 459.2340 m/z (2.20 ppm).

A/-(5'-deoxy-thymidin-5'-yl)-A'-(4-tetrahydropyran-4-oxyphenyl)urea (6k): 4- tetrahydropyran-4-oxyphenyl isocyanate reacted with amine 31 to yield compound 6k as a solid; TLC (10% MeOH/DCM) R = 0.23; 1H-NMR (500MHz, DMSO): δ 11.33 (s, 1H, NH), 8.33 (s, 1H, NH), 7.52 (d, J = 1.15 Hz, 1H, H6), 7.25-7.28 (m, 2H, H-Ph), 6.84-6.87 (m, 2H, H-Ph), 6.16-6.21 (m, 2H, NHand H7), 5.34 (d, J =4.25 Hz, 1H, OH), 4.40-4.45 (m, 1H, CH), 4.14-4.17 (m, 1H, H3), 3.81-3.85 (m, 2H, CH2), 3.74-3.78 (m, 1H, H4), 3.42-3.47 (m, 2H, CH2), 3.16-3.24 (m, 1H, H5), 2.12-2.18, 2.04-2.08 (m, 2H, H2), 1.90-1.94 (m, 2H, CH2), 1.77 (s, 3H, CH3), 1.50-1.57 (m, 3H, CH3); 13C-NMR (125MHz, DMSO): δ 163.7 (C4), 155.4 (CO), 150.5 (C2), 136.0 (C6), 151.3, 133.8, 119.3, 116.4 (C-Ph), 109.8 (C5), 85.4 (C7), 83.7 (C4), 71.7 (C3), 71.1 (CH), 64.5 (CH2), 41.4 (C5), 39.0 (C2), 31.8 (CH2), 12.3 (CH3); LCMS (ES+): m/z (%) 461 (100) [M+H]+; HRMS (ES+): calcd for C22H29N407 [M+H]+ 461.2031 m/z, found 461.2029 m/z (0.44 ppm).

A/-(5'-deoxy-thymidin-5'-yl)-A'-(4-benzyloxyphenyl)urea (6I): 4-Benzyloxyphenyl isocyanate reacted with amine 31 to yield compound 6I as a solid; TLC (10% MeOH/DCM) R = 0.24; 1H-NMR (500MHz, DMSO): δ 11.34 (s, 1H, NH), 8.34 (s, 1H, NH), 7.52 (s, 1H, H6), 7.28-7.44 (m, 7H, H-Ph), 6.89 (d, J=7.05 Hz, 2H, H-Ph), 6.20 (m, 2H, H7'and NH), 5.03 (s, 2H, CH2-Ph), 4.17 (s, 1H, H3), 3.77 (m, 1H, H4), 3.44 (m, 1H, H5), 3.22 (m, 1H, H5), 2.16 (m, 1H, H2), 2.07 (m, 1H, H2), 1.78 (s, 3H, CH3); 13C-NMR (125MHz, DMSO): δ 163.7 (C4), 155.4 (CO), 150.5 (C2), 152.9, 137.3, 133.7, 128.4, 127.7, 127.6, 119.2, 114.9 (C-Ph), 136.1 (C6), 109.8 (C5), 85.4 (C7), 83.7 (C4), 71.1 (C3), 69.3 (CH2-Ph), 41.4 (C5), 38.4 (C2), 12.1 (CH3); LCMS (ES+): m/z (%) 467 (100) [M+H]+; HRMS (ES+): calcd for C24H27N406 [M+H]+ 467.1925 m/z, found 467.1941 m/z(-3.51 ppm).

A/-(5'-deoxy-thymidin-5'-yl)-A'-(2-(phenoxymethyl)phenyl)urea (6m): 2- (Phenoxymethyl)phenyl isocyanate reacted with amine 31 to yield compound 6m as a solid; TLC (10% MeOH/DCM) R = 0.31; 1H-NMR (500MHz, DMSO): δ 11.29 (s, 1H, NH), 7.91 (s, 1H, NH), 7.85 (qt, J = 2.98 Hz, 1H, NH), 7.52 (d, J = 1.20 Hz, 1H, H6), 7.39 (qt, J= 3.01 Hz, 1H, H-Ph), 7.24-7.31 (m, 3H, H-Ph), 6.89-7.03 (m, 5H, H-Ph), 6.18 (qt, J = 4.66 Hz, 1H, H7), 5.33 (d, J = 4.35 Hz, 1H, OH), 5.03 (s, 2H, CH2), 4.16- 4.18 (m, 1H, H3), 3.75-3.78 (m, 1H, H4), 3.47-3.51 (m, 1H, H5), 3.22-3.27 (m, 1H, H5), 2.13-2.17 (m, 1H, H2), 2.06-2.09 (m, 1H, H2), 1.75 (s, 3H, CH3); 13C-NMR (125MHz, DMSO): δ 163.7 (C4), 154.5 (CO), 150.5 (C2), 158.3, 138.0, 129.4, 129.3, 128.3, 126.4, 122.3, 121.6, 120.7, 114.8 (C-Ph), 136.1 (C6), 109.8 (C5), 85.4 (C7), 83.6 (C4), 71.1 (C3), 66.3 (CH2), 41.6 (C5), 38.4 (C2), 12.3 (CH3); LCMS (ES+): m/z (%) 467 (100) [M+H]+; HRMS (ES+): calcd for C24H27N406 [M+H]+ 467.1925 mlz, found 467.1919 mlz (1.28 ppm).

A/-(5'-deoxy-thymidin-5'-yl)-A'-(3-(phenoxylmethyl)phenyl)urea (6n): 3- (Phenoxylmethyl)phenyl isocyanate reacted with amine 31 to yield compound 6n as a solid; TLC (10% MeOH/DCM) R = 0.44; 1HNMR (500MHz, DMSO): δ 11.33 (s, 1H, NH), 8.60 (s, 1H, NH), 7.52 (d, J= 1.15 Hz, 1H, H6), 7.49, 7.21-7.34, 6.92-7.00 (m, 9H, H-Ph), 6.31 (t, J = 5.35 Hz, 1H, NH), 6.18 (qt, J = 4.68 Hz, 1H, H7), 5.35 (d, J = 4.25 Hz, 1H, OH), 5.03 (s, 2H, CH2), 4.15-4.17 (m, 1H, H3), 3.76-3.79 (m, 1H, H4), 3.45- 3.47 (m, 1H, H5), 3.23-3.25 (m, 1H, H5), 2.13-2.16, 2.06-2.09 (m, 2H, H2), 1.77 (s, 3H, CH3); 13C-NMR (125MHz, DMSO): δ 163.69 (C4), 155.15 (CO), 150.46 (C2), 158.29, 140.53, 137.65, 129.46, 128.73, 120.26, 116.94, 116.49, 114.70 (C-Ph), 136.04 (C6), 85.29 (C7), 83.68 (C4), 71.09 (C3), 69.11 (CH2), 41.38 (C5), 39.36 (C2), 12.32 (CH3); LCMS (ES+): m/z (%) 467 (100) [M+H]+; HRMS (ES+): calcd for C24H27N406 [M+H]+ 467.1925 mlz, found 467.1910 m/z (3.18 ppm).

A/-(5'-deoxy-thymidin-5'-yl)-A'-(4-(6-methyl-2-benzothiazolyl)phenyl)urea (6o): 4-

(6-Methyl-2-benzothiazolyl)phenyl isocyanate reacted with amine 31 to yield compound 6o as a solid; TLC (10% MeOH/DCM) R = 0.21; 1H-NMR (500MHz, DMSO): δ 11.34 (s, 1H, NH), 8.95 (s, 1H, NH), 7.53 (d, J= 1.15 Hz, 1H, H6), 7.86-7.95, 7.57-7.59, 7.32- 7.34 (m, 7H, H-Ph), 6.47 (t, J = 5.34 Hz, 1H, NH), 6.19 (qt, J = 4.70 Hz, 1H, H7), 5.37 (d, J = 4.25 Hz, 1H, OH), 4.18-4.20 (m, 1H, H3), 3.79-3.80 (m, 1H, H4), 3.47-3.53 (m, 1H, H5), 3.23-3.28 (m, 1H, H5), 2.45 (s, 3H, CH3), 2.16-2.23 (m, 1H, H2), 2.06-2.10 (m, 1H, H2), 1.79 (s, 3H, CH3); 13C-NMR (125MHz, DMSO): δ 163.7 (C4), 151.8 (CO), 150.5 (C2), 136.1 (C6), 145.9, 143.3, 134.2, 127.9, 125.7, 121.9, 117.6 (C-Ph), 109.8 (C5), 85.2 (C7), 83.7 (C4), 71.1 (C3), 41.5 (C5), 38.3 (C2), 21.0 (CH3), 12.2 (CH3); LCMS (ES+): m/z (%) 508 (100) [M+H]+; HRMS (ES+): calcd for C25H26N505S1 [M+H]+ 508.1649 mlz, found 508.1634 mlz (3.05 ppm). A/-(5'-deoxy-thymidin-5'-yl)-A'-(4-(2-chlorobenzyloxy)phenyl)urea (12a): 4-(2-

Chlorobenzyloxy)phenyl isocyanate reacted with amine 31 to yield compound 12a as a solid; TLC (10% MeOH/DCM) R = 0.14; 1H-NMR (500MHz, DMSO): δ 11.33 (s, 1H, NH), 8.37 (s, 1H, NH), 7.57-7.59, 7.50-7.52, 7.37-7.39, 7.29-7.31 , 6.90-6.92 (m, 9H, H6 and H-Ph), 6.17-6.23 (m, 1H, H7'and NH), 5.35 (d, J=4.30 Hz, 1H, OH), 5.09 (s, 2H, CH2), 4.15-4.17 (m, 1H, H3), 3.75-3.77 (m, 4H, H4), 3.44-3.45, 3.22-3.24 (m, 2H, H5), 2.14-2.16, 2.07-2.09 (m, 2H, H2), 1 .78 (s, 3H, OH 3); 13C-NMR (125MHz, DMSO): δ 163.7 (C4), 155.4 (CO), 150.5 (C2), 152.8, 134.6, 134.0, 132.5, 130.00, 129.7, 129.3, 127.3, 1 19.2, 1 14.9 (C-Ph), 136.1 (C6), 109.8 (C5), 85.4 (C7 ), 83.7 (C4), 71 .1 (C3), 67.0 (CH2), 41 .4 (C5), 38.4 (C2), 12.0 (CH3); LCMS (ES+): m/z (%) 501 (100) [M+H]+; HRMS (ES+): calcd for C24H26CI1 N406 [M+H]+ 501 .1535 m/z, found 501 .1516 m/z (3.91 ppm).

A/-(5'-deoxy-thymidin-5'-yl)-A '-(4-(4-methoxybenzyloxy)phenyl)urea (12b): 4-(4- Methoxybenzyloxy)phenyl isocyanate reacted with amine 31 to yield compound 12b as a solid; TLC (10% MeOH/DCM) FA = 0.15; 1 H-NMR (500MHz, DMSO): δ 1 1 .32 (s, 1 H, HH), 8.33 (s, 1 H, HH), 7.52 (d, J = 1.15 Hz, 1 H, H6), 7.72-7.79, 6.98-7.00, 6.88-6.89 (m, 8H, H-Ph), 6.18-6.22 (qt, J = 3.48 Hz, 1 H, H7 ), 5.35 (d, J = 3.10 Hz, 1 H, OH), 5.01 (s, 2H, CH2), 4.15-4.19 (m, 1 H, H3), 3.75-3.78 (m, 4H, H4' and CH3), 3.42-3.46,3.18- 3.24 (m, 2H, H5), 2.13-2.17, 2.05-2.08 (m, 2H, H2), 1 .77 (s, 3H, OH 3); 13C-NMR (125MHz, DMSO): δ 163.7 (C4), 150.5 (C2), 155.4 (CO), 152.9, 137.3, 133.7, 128.4, 127.7, 127.6, 1 19.2, 1 14.9 (C-Ph), 136.1 (C6), 109.8 (C5), 85.37 (C7 ), 83.7 (C4), 71 .1 (C3), 69.3 (CH2-Ph), 41 .4 (C5), 38.4 (C2), 12.1 (CH3); LCMS (ES+): m/z (%) 497 (100) [M+H]+; HRMS (ES+): calcd for C25H29N407 [M+H]+ 497.2031 m/z, found 497.2017 m/z (2.74 ppm).

Biology

Antiplasmodial assay

In vitro activity against the erythrocytic stages of P. falciparum was determined by using a SYBR-green assay [Smilkstein et al. Antimicrob. Agents Chemother. 2004, 48, 1803].

The parasite Plasmodium falciparum 3D7 was cultured using standard methods, and synchronized using 5% sorbitol. Compounds were dissolved in DMSO at 100 mM and added to 48 hr postsynchronization parasite cultures incubated in RPMI 1640 medium with hypoxanthine (150 μΜ), NaHC03 (0.2 %), gentamycin (12.5 g/mL), Albumax (0.5 %), human serum (2 %) and washed human red cells 0+ at 5 % haematocrit (0.3 % parasitaemia).

Experiments were carried out at least twice independently and the different concentrations were tested in duplicate. After 48 h of growth, 100μΙ of SYBR green I (Molecular Probes) in lysis buffer (Tris 20 mM, pH.7.5, EDTA 5 mM, saponin 0.008 %, tritonX-100 0.08 %, 0.2 μΙ of SYBR-green/ml of lysis buffer) was added to each well, and mixed and after 1 h of incubation in the dark at RT, fluorescence was measured with excitation and emission wavelength bands centred at 485 and 530 nm. The percent inhibition of each compound at each concentration was determined. Chloroquine was used as standard drug. EC₅₀ values were calculated from hyperbolic or sigmoidal dose-response curves using Sigmaplot 10.0. EC₅₀ values represent the concentration of compounds reducing Plasmodium falciparum growth by 50%.

Human MRC-5 cell based assay

Certain derivatives were also screened for growth inhibition for human MRC-5 cells. MRC-5 cells were seeded at 2000 cells per well in a volume of 200 μΙ of DMEM containing 10% FCS and allowed to adhere for 24 h prior to use. The MRC-5 cells assay was performed as described previously [Patterson et al. Chemmedchem 2009, 4(8), 1341 -1353]. CC₅₀ values stand for the concentration of compounds reducing MRC-5 cells growth by 50%.

Results are shown for selected compounds in Tables 1 , 2 and 3.

4a-4v

R Yield (%) X ECgg

s Ml

4a - 46 0 24

4b^c 4-chloro 67 0 2.6 >50

4c^c 4-cl loro 54 s 13 >50

4d 4~bromo 59 0 1.4 >50

4e^e 4- romo 54 s 20

4f 3 -trifluoromeiiiyl -4-chloro 70 0 9.0 >50

4g^c 3 ~ riiluoromethyl-4-cMoro 75 s ?.3 >50

4h 4-ieri-butyl 82 0 2.9 >50

4i 2-phenyl 91 0 96

4j 4-phenyl 85 0 0.29 >50

4k 4-piperidine~ 1 -yl 55 0 0.34 >50

41 4-(4-inct.b>i-pipera2inyl) 75 0 2.9

4ffl 4-fefm^'hydropyraB-4-oxy 70 0 13 >50

4n 4-benzvloxy 80 0 0.24 >50

4o 4- benzyl oxy 86 s 9,5 >50

4p 2~(phenoxyf-methyl) 77 0 7.2 >50

4q 3 -(p.herj.oxyl-meibyl) 80 0 1.8 >50

4r 4-{6-iTseihyl-2-berszothIazolyl) 67 0 4.6 >50

4B 4-morpholino 41 s 35

4t 4~phenyioxy 78 0 0,24 44

4u 4-benzyl 49 o 1.5 >50

4v 4-{5-(2~trifmorometliyl) pyridine) 50 0 1.4 >50 ufee 0.02

a: ECs values represented the concentration of compounds reducing P. falciparum growth by 50%;

: CC50 values represented the concentration of compounds reducing human M C-5 cells growth by 50%;

CC59

(%) (μΜ)'

6a - 70 0 >100

6b^c 4-chloro 67 0 >100

6c^c 4-chloro 59 s >200

6d 4-bromo 48 0 >200

6e^c 4-bromo 59 s 172

6f 4~fer/-butyl 87 0 64

6g 2-phenyl 64 0 253

61i 4~phenyl 78 0 3.3

61 4-pipendine-l-yi 43 0 4.8 -50

6j 4-(4-methyI-piperazi nyl) 45 0 25

6k 4-fe/rahydropyran~4-oxy 57 0 33

61 4-benzySoxy 60 0 4.0

6m 2-phenoxyl~meihyl 60 0 48

6n 3-phenox.yl~Kiethyl 75 0 148

6o 4-(6-methyi=2- 58 0 >200

!orocptae 0,02 ^a: EC-₃₀ values represented the concentration of compounds reducing P. falciparum growth by 50%;

b; CCso values represented the concentration of compounds reducing human MRC-5 cells growth by 50%; ^c: Compounds reported previously (Chapter 3).

Tatste 3; Biologies! ev lu tive of 4~h& yl®$.y~ph yl urea «~2^?~deoxytfeyMMMe derivatives

Compd M Yield X €€«_5δ<μ

(%)

11 a 4-{2-chlofO"benzylox y) 67 0 0.028 29 l ib 4-(3-c oro-benzyloxy) 83 0 0.24 >50

11c 4"(4-cblorO"ben yloxy) 75 0 0.88 >50 i id 4-(4-methyoxy~benzy]ox.y) 81 0 0.21 >50 l ie 4"(4-/eri- ut. 1 -benzyloxy) 78 0 1.8 >50

12a 4-{2-c !orc-benzyi oxy) 69 0 0.41 >50

12b 4-(4-methyoxy~benzyloxY) 83 0 3.8 >50

0.02

In vitro DM K

In vitro DMPK studies were carried out on some derivatives. Studies investigated solubility, bepatic microsomal stability and plasma protein binding and were carried out as described previously [Ruda et. al. J. Med, Chem. 2010, 53, 6071-6078]. Results shown for selected compounds in Table 4.

Table 4i Stability aad plasma protein femd data

Compd Microsomal stability Plasms ro ein M dtag EC» C€<_¾

(ml/i n/g) (% Bound) (μΜ) (μΜ)

11a 6 94.1 0.028 29

4j 1.9 92.0 0.29 >50

4n 3 81.2 0.24 >50

4k 0.5 523 0.34 >50

4t 1.8 90,5 0,24 43.6

CMoroqtikie 0.02

Claims

CLAIMS:

1 ) A compound of formula (I) for use as an anti-malarial agent:

(I)

wherein:

X may be O or S; and

R , R², R³, R⁴ and R⁵ may each be independently selected from H, halo, C C₆ alkyl, C C₆ haloalkyl, nitro, phenyl, heteroaryl, substituted heteroaryl wherein the substituents may be C C₆ alkyl or C C₆ haloalkyl, benzyl, -CH₂OAr, -OR⁶ and six-membered ring heterocyclic groups containing 1 or more O and/or N heteroatoms wherein any N heteroatom may be C C₆ alkyl-substituted; and R⁶ may be selected from CrC₆ alkyl, phenyl, six-membered ring heterocyclic groups containing at least one O heteroatom, benzyl and substituted benzyl wherein the substituents may be halo, C C₆ alkyl or C C₆ alkoxy; and wherein R⁷ may be H or C C₆ alkyl; and

the stereochemistry of the bond depicted as ^ is either a or β.

2) A compound according to any preceding claim, wherein R⁷ is C C₆ alkyl. 3) A compound according to any preceding claim, wherein X is O.

4) A compound according to any preceding claim, wherein halo is selected from fluoro, chloro and bromo. 5) A compound according to any preceding claim, wherein C C₆ alkyl is C C₄ alkyl.

6) A compound according to any preceding claim, wherein C C₆ alkyl is tert- butyl. 7) A compound according to any preceding claim, wherein d-C₆ haloalkyl is fluoroalkyl.

8) A compound according to any preceding claim, wherein C C₆ haloalkyl is trifluoromethyl.

9) A compound according to any preceding claim, wherein the substituted heteroaryl is selected from 6-methyl benzothiazole and 2- trifluoromethylpyridine.

10) A compound according to any preceding claim, wherein the six-membered ring heterocyclic group is selected from piperidine, 4-methylpiperazine, tetrahydropyran and morpholine.

1 1 ) A compound according to any preceding claim, wherein the stereochemistry of the bond depicted as is a.

12) A compound of formula (I):

wherein:

X may be O or S; and

R , R², R³, R⁴ and R⁵ may each be independently selected from H, halo, C C₆ alkyl, C C₆ haloalkyl, nitro, phenyl, heteroaryl, substituted heteroaryl wherein the substituents may be C C₆ alkyl or C C₆ haloalkyl, benzyl, -CH₂OAr -OR⁶ and six-membered ring heterocyclic groups containing 1 or more O and/or N heteroatoms wherein any N heteroatom may be C C₆ alkyl-substituted; and R⁶ may be selected from C C₆ alkyl, phenyl, six membered ring heterocyclic groups containing at least one O heteroatom, benzyl and substituted benzyl groups wherein the substituents may be halo, C C₆ alkyl or C C₆ alkoxy; and wherein R⁷ may be H or C C₆ alkyl; and

subject to the proviso that when R and R⁵ are each H and either R² or R⁴ is halo or C

C₆ haloalkyl, R³ may not be halo; or subject to the proviso that when X is S, then R , R², R³, R⁴ and R⁵ may not each be H; or when X is S and R\ R², R⁴ and R⁵ are each H, then R³ may not be C C₆ alkoxy, C C₆ alkyl, halo or morpholino. 13) A compound according to any preceding claim which is A/-(5'-deoxy-a- thymidin-5'-yl)-/V'-(4-(2-chlorobenzyloxy)phenyl)urea.

14) An anti-malarial composition, which comprises a compound according to any preceding claim together with a pharmaceutically acceptable carrier.

15) A method of preparation of a compound according to any preceding claim, as defined herein in schemes 1 to 5.

16) A method of inhibiting a malaria-causing parasite comprising administering a composition which comprises a compound according to claims 1 to 13.

17) A method according to claim 16, which comprises administering the composition to an individual.

18) A method according to claim 16, which comprises applying the composition to an environment or to a mosquito.