Title of Invention	"A PHOSPHONATE COMPOUND OF FORMULA 2"
Abstract	A phosphonate compound represented by the following formula (2) Wherein, R1, R2, R3, R7 and R8 independently of one another represent hydrogen, halogen, hydroxy, amino, C1-C7-alkyl, C2-C6-alkenyl, C1-C5-alkylamino, C1-C5-aminoalkyl, or Cr C5-alkoxy, R4 and R5 independently of one another represent hydrogen, or represent C1-C4-alkyl optionally substituted by one or more substituents selected from the group consisting of halogen (particularly, fluorine), C1-C4-alkoxy, phenoxy, C7-C10-phenylalkoxy and C2-C5-acyloxy, or represent C1-C7-acyl, C6-C12-aryl or optionally substituted carbamoyl, or represent -(CH2)m-OC(=0)-R6 wherein m denotes an integer of 1 to 12 and R6 represents C1-C12-alkyl, C2-C7-alkenyl, C1-C5-alkoxy, C1-C7-alkylamino, di(C1-C7-alkyl) amino, C3-C6-cycloalkyl, or 3 to 6-membered heterocycle having 1 or 2 hetero atoms selected from a group consisting of nitrogen and oxygen, Y represents -0-, -S-, -CH(Z)-, =C(Z)-, -N(Z)-, =N-,-SiH(Z)-, or =Si(Z)-, wherein Z represents hydrogen, hydroxy or halogen, or represents C1-C7alkyl, C1-C5-alkoxy, allyl, hydroxy-C1-C7-alkyl, C1-C7aminoalkyl or phenyl, and L represents a leaving group.

Title of Invention

"A PHOSPHONATE COMPOUND OF FORMULA 2"

Abstract

A phosphonate compound represented by the following formula (2) Wherein, R1, R2, R3, R7 and R8 independently of one another represent hydrogen, halogen, hydroxy, amino, C1-C7-alkyl, C2-C6-alkenyl, C1-C5-alkylamino, C1-C5-aminoalkyl, or Cr C5-alkoxy, R4 and R5 independently of one another represent hydrogen, or represent C1-C4-alkyl optionally substituted by one or more substituents selected from the group consisting of halogen (particularly, fluorine), C1-C4-alkoxy, phenoxy, C7-C10-phenylalkoxy and C2-C5-acyloxy, or represent C1-C7-acyl, C6-C12-aryl or optionally substituted carbamoyl, or represent -(CH2)m-OC(=0)-R6 wherein m denotes an integer of 1 to 12 and R6 represents C1-C12-alkyl, C2-C7-alkenyl, C1-C5-alkoxy, C1-C7-alkylamino, di(C1-C7-alkyl) amino, C3-C6-cycloalkyl, or 3 to 6-membered heterocycle having 1 or 2 hetero atoms selected from a group consisting of nitrogen and oxygen, Y represents -0-, -S-, -CH(Z)-, =C(Z)-, -N(Z)-, =N-,-SiH(Z)-, or =Si(Z)-, wherein Z represents hydrogen, hydroxy or halogen, or represents C1-C7alkyl, C1-C5-alkoxy, allyl, hydroxy-C1-C7-alkyl, C1-C7aminoalkyl or phenyl, and L represents a leaving group.

Full Text	1 NOVEL ACYCLIC NUCLEOSIDE PHOSPHONATE DERIVATIVES, SALTS THEREOF AND PROCESS FOR THE PREPARATION OF THE SAME TECHNICAL FIELD The present invention relates to an acyclic nucleoside phosphonate derivative represented by the following formula (1): (Formula Removed) in which lii:: represents single bond or double bond, R1. R2, R3, R7 and R8 independently of one another represent hydrogen, halogen, hydroxy, amino, C1-C7-alkyl, C2-C6-aIkenyl, C1-C5-alkylamino, C1-C5-aminoalkyl, or C1-C5-alkoxy. R4 and R3 independently of one another represent hydrogen, or represent C1-G4-alkyl optionally substituted by one or more substituents selected from the group consisting of halogen (particularly, fluorine), CrGralkoxy, phenoxy, C7-C10-phenylalkoxy and C2-C5-acyloxy, or represent C1-C7-acyl, C6-C12-aryl or optionally substituted carbamoyl, or represent -(CH2)m-OC(=O)-R6 wherein m denotes an integer of 1 to 12 and R6 represents C1-C12-alkyl, C2-C7-alkenyl. C1-C5-aIkoxy, C1-C7-alkylamino, di(C1-C7-alkyl)amino, C3-C6-cycloalkyl, or 3 to 6-membered heterocycle having 1 or 2 hetero atoms selected from a group consisting of nitrogen and oxygen, Y represents -0-, -S-, -CH(Z)-, =C(Z)-. -N(Z)-, =N-, -SiH(Z)-. or =Si(Z)-, wherein Z represents hydrogen, hydroxy or halogen, or represents C1-C-alkyl, C1-C5-alkoxy. allyl, hydroxy-C1-C7-alkyI, C1-C7-aminoalkyl or phenyl, Q represents a group having the following formula: (Formula Removed) wherein X1, X2, X3 and X4 independently of one another represent hydrogen, amino, hydroxy or halogen, or represent C1-C7-alkyl, C1-C5-alkoxy, allyl, hydroxy-C1-C7-alkyl, phenyl or phenoxy each of which is'optionally substituted by nitro or C1-C5-alkoxy, or represent C6-C10-arylthio which is optionally substituted by nitro, amino, C1-C6-alkyl or C1-C4-alkoxy, or represent C6-C12-arylamino, C1-C7-alkylamino, di(C1-C7-alkyl)amino. o+ C3-C6-cycloalkylamino or a structure of ™ wherein n denotes an integer of 1 or 2 and Y1 represents O, CH2 or N-R (R represents C1-C7-alkyl or C6-C12-aryl), which is useful as an antiviral agent (particularly, against hepatitis B virus). pharmaceutically acceptable salts, stereoisomers, and a process for the preparation thereof. BACKGROUND ART Purine or pyrimidine derivatives have anti-cancer and antiviral activities, and more than 10 kinds of the compounds including AZT, 3TC and ACV have already been commercialized. Particularly, since acyclic nucleoside phosphonate derivatives show a potent antiviral effect, cidopovir has been commercialized as an antiviral agent and many compounds including PMEA and PMPA now entered into the step of clinical trials. However, the earlier developed compounds were not perfect in the aspects of toxicity or pharmaceutical activity, and thus, it is still desired to develop a compound having no toxicity as well as a superior activity. The prior researches for purine or pyrimidine derivatives or acyclic nucleoside phosphonate derivatives as reported heretofore are as follows. Patents: US 5817647; US 5977061; US5886179; US 5837871; US 6069249; WO 99/09031; WO96/09307; WO95/22330; US 5935946; US 5877166; US 5792756; Journals: International Journal of Antimicrobial Agents 12 (1999), 81-95; Nature 323 (1986), 464: Heterocycles 31(1990), 1571; J. Med. Chem. 42 (1999), 2064; Pharmacology & Therapeutics 85 (2000), 251; Antiviral Chemistry & Chemotherapy 5 (1994), 57-63.: Bioorganic & Medicinal Chemistry Letters 10 (2000) 2687-2690; Biochemical Pharmacology 60 (2000), 1907-1913; Antiviral Chemistry & Chemotherapy 8 (1997) 557-564; Antimicrobial Agent and Chemotherapy 42 (1999) 2885-2892. DISCLOSURE OF INVENTION Thus, the present inventors extensively studied to develop a compound having a superior biological activity (pharmaceutical effect) to as well as a lower toxicity than the existing acyclic nucleoside phosphonates commercialized or entered into the step of clinical trials. As a result, we found that the above compound of formula (1) characterized by its unique chemical structure exhibits a potent pharmaceutical activity, and then completed the present invention. Therefore, one object of the present invention is to provide the compound of formula (I) having a good use of antiviral agent, pharmaceutically acceptable salts or isomers thereof. It is another object of the present invention to provide a process for the preparation of the compound of formula (1). It is still another object of the present invention to provide intermediates which are advantageously used for the preparation of the compound of formula (I). BEST MODE FOR CARRYING OUT THE INVENTION The compound of formula (1) according to the present invention, as represented below, is a type of acyclic nucleoside phosphonate derivative having a natural base, such as for example, adenine, guanine, uracil, cytosine, thymine or derivatives thereof: (Formula Removed) in which —represents single bond or double bond. R1, R2, R3, R7 and R8 independently of one another represent hydrogens halogen, hydroxy. amino, C1-Cralkyl, C2-C6-alkenyl, C1-C5-alkylamino, C1-C5-aminoalkyl, or C1-C5-alkoxy, R4and R5 independently of one another represent hydrogen, or represent C1-C4-alkyl optionally substituted by one or more substituents selected from the group consisting of halogen (particularly, fluorine), CrC4-alkoxy, phenoxy, C7-C10-phenylalkoxy and C2-C5-acyIoxy, or represent C1-C7-acyl, C6-C12-aryl or optionally substituted carbamoyl, or represent -(CH2)m-OC(=O)-R6 wherein m denotes an integer of 1 to 12 and R6 represents C1-C12-alkyl, C2-C7-alkenyl, C1-C5-alkoxy, C1-C7-alkylamino. di(C1-C7-alkyl)amino, C3-C6-cycloalkyl, or 3 to 6-membered heterocycle having 1 or 2 hetero atoms selected from a group consisting of nitrogen and oxygen, Y represents -0-, -S-, -CH(Z)-, =C(Z)-, -N(Z)-, =N-, -SiH(Z)-, or =Si(Z)-, wherein Z represents hydrogen, hydroxy or halogen, or represents C1-C7-alkyl, C1-C5-alkoxy. allyl, hydroxy-C1-C7-alkyl, C1-C7-aminoaIkyI or phenyl, Q represents a group having the following formula: (Formula Removed) wherein X1, X2, X3 and X4 independently of one another represent hydrogen, amino, hydroxy or halogen, or represent C1-C7-alkyI, C1-C5-alkoxy, allyl, hydroxy-C1-C7-alkyl. phenyl or phenoxy each of which is optionally substituted by nitro or C1-C5-alkoxy, or represent C6-C10-arylthio which is optionally substituted by nitro, amino, C1-C6-alkyl or C1-C4-alkoxy, or represent C6-C12-arylamino. C1-C7-alkylamino. di(C1-C7-alkyl)amino. C3-C6-cycloalkylamino or a structure of (Formula Removed) wherein n denotes an integer of 1 or 2 and Y1 represents O, CH2 or N-R (R represents C1-C7-alkyl or C6-C12-aryl). Since the compound of formula (1) according to the present invention may have one or more asymmetric carbon atoms in the structure depending on the kind of substituents, it can be present in the form of the individual enantiomers, diastereomers, or mixtures thereof including racemate. Further, when a double bond is included in the structure, it can be present in the form of E or Z isomer. Thus, the present invention also includes all, of these isomers and their mixtures. Also, the compound of formula (1) according to the present invention can form a pharmaceutically acceptable salt Such salt includes non-toxic acid addition salt containing pharmaceutically acceptable anion, for example a salt with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydriodic acid, etc., a salt with organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, etc., or a salt with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc., particularly preferably with sulfuric acid, methanesulfonic acid or hydrohalic acid, etc. Among the compound of formula (1) showing a potent pharmaceutical activity, the preferred compounds are those wherein — represents single bond, R1, R2, R3, R7 and R8 independently of one another represent hydrogen, fluorine, hydroxy, C1-C7-alkyl, C2-C6-alkenyl, C1-C5-alkylamino, C1-C5-aminoalkyl. or C1-C5-alkoxy, R4 and R5 independently of one another represent hydrogen, or represent d-d-alky! optionally substituted by one or more substituenis selected from the group consisting of fluorine, C1-C4ralkoxy and phenoxy, or represent carbamoyl substituted by C1-C5-alkyl, or represent -(CH2)m-OC(=O)-R° wherein m denotes an integer of 1 to 12 and R6 represents C1-C12-alkyl, C2-C7-alkenyl, C1-C5-alkoxy, C1-C7-alkylamino, di(C1-C7-alkyl)amino, C1-C6-cycloalkyl, or 3 to 6-membered heterocycle having 1 or 2 hetero atoms selected from a group consisting of nitrogen and oxygen, Y represents -0-, -S-, or -N(Z)-, wherein Z represents hydrogen, hydroxy, C1-C7-alkyl. or hydroxy-C1-C7-alkyl, Q represents a group having the following formula: (Formula Removed) wherein X1 represents hydrogen, amino, hydroxy or halogen, or represents C1-C7-alkyl, C1-C5-alkoxy, hydroxy-C1-C7-alkyl or phenoxy each of which is optionally substituted by nitro or C1-C5-alkoxy, or represents C6-C10-arylthio which is optionally substituted by nitro, amino, C1-C6flkyl or C1-C4-alkoxy, or represents C6-C12-arylamino. C1-C7-alkylamino, di(C1-C7-alkyl)amino, C3-C6cycloalkylamino or a structure of an integer of 1 or 2 and Y1 represents O, CH2or N-R (R represents C1-C7-alkyl), and X2, X3 and X4 independently of one another represent hydrogen, amino, hydroxy, halogen, C1-Cr-alkyl, C1-C5-alkoxy, or C1-C7-alkylamino. Most preferred compounds are those wherein — represents single bond, R1, R3, R7 and R8 independently of one another represent hydrogen, R2 represents hydrogen or methyl, R4 and R5 independently of one another represent t-butylcarbonyloxymethyl, isopropoxycarbonyloxymethyl or 2,2,2-trifluoroethyl, Y represents -0-, Q represents -(Formula Removed) wherein X1 represents hydrogen, hydroxy, ethoxy, 4-methoxyphenylthio or 4-nitrophenylthio, and X2 represents amino. Typical examples of the compound of formula (1) according to the present invention are described in the following Tables 1 and 7. (Table Removed) 1to23 Table (Formula Removed) More particularly preferable compounds among the compounds described in the above Tables 1 and 7 are as follows: ."> ([ 1 -[(6-amino-9H-purin-9-yl)methyl]cyclopropylloxy)methylphosphonie acid (Compound I); 3-[( 1 -[(6-amino-9H-purin-9-yl)methyl]cyclppropyl }oxy)methyl]-8,8-dimethyl-3.7-dioxo-2,4,6-rrioxa-3 5-phosphanon-1-yl pivalate(Compound 2); ([1 -[(2-amino-6-chloro-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid(Compound 3); 3-[( {1 -[(2-amino-6-cbloro-9H-purin-9-yl)methyl]cyclopropyl} oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3 5-phosphanonrl-yl pivalate(Compound 4); ({1 -[(2-amino-6-hydroxy-9H-purin-9-yl)methylJcyclopropyl }oxy)methyl phosphonic acid(Compound S): 3-[({1-[(2-amino-6-hydroxy-9H-purin-9-yl)methyI]cyclopropyl!oxy)methyl]-8.v dimethyl-3.7-dioxo-2,4,6-trioxa-3 5-phosphanon-1-yl pivaJate(Compound 6): ([ 1 -[(2-amino-6-fluoro-9H-purin-9-yl)methyl]cyclopropyl ; oxy)methylphosphonie acid(Compcund 7); 3-[( {1 -[(2-amirio-6-fluoro-9H-purin-9-yl)methyl]cyclopropyl J oxy )methyl]-X.S-dimethyl-3.7-dioxo-2.4,6-trioxa-3 -phosphanon-l-yl pivalate(Compound 8): ([1 -[(2-amino-9H-purin-9-yi imethyl]cyclopropyl! oxyjmethylphosphonic acid (Compound 9): 3-[( J l-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl]oxy(methyl]-.S.s-dimethyl- • 3.7-dioxo-2.4.6-trioxa-3 '5-phosphanon-l-yl pivalatc(Compound 10): (! 1 -[(2-amino-6-cydopropyiamino-9H-purin-9-yl)meihyl]cyclopropyl: oxy) meth-ylphosphonio acid(Compound 11): 3-[(1-[(2-amino-6-cyclopropylamino-9H-purin-9-yl )methyl ]cyclopropyl i oxy) methyl]-8.8-dimethyl-3.7-dioxo-2.4..0-trioxa-3 5-phosphanon-1 -yl pi valate( Compound 12) [(1 - {[2-amino-6-(dimethylamino)-9H-purin-9-yl]methyl; cyclopropyl loxy]methy. phosphonic acid(Compound 15): 3-![(1 - {[2-amino-6-ldimethylamino)-9H-purin-9-y\|]methyl! cyclopropyl )oxy\| methyl \| -8.8-dimethyl-3,7-dioxo-2.4.o-trioxa-3 5-phosphanon-1 -yl pivalate(Compound 16); [(1 [2-amino-6-(isopropylamino)-9H-purin-9-yl]methyI \ cyclopropyl )oxy]methy: phosphonic acid(Compound 17): 3-![(l-{[2-amino-6-(isopropyiamino)-9H-purin-9-y\|]methyi;cyclopropyl)oxy] methyl }-8.8-dimethyl-3,7-dioxo-2.4.0-rrioxa-3 5-phosphanon-l-yl pivalate(Compound 18); (! l-[(2,6-diamino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid(Compound 19); 3-[(1 1 -[(2.6-diamino-9H-punn-9-yl)methyl]cyclopropyl \| oxy)methyl]-8.8-dimethyl-3.7-dioxo-2,4.6-trioxa-3 5-phosphanon-l-yl pivalate(Compound 20): (; l-[(2-amino-6-methoxy-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl phosphonic acid (Compound 21): 3-[( {I-[(2-amino-6-methoxy-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8.8- dimethyl-3,7-dioxo-2,4,6-trioxa-3 5-phosphanon-l-yI pivalate(Compound 22); ({1 -[(2-amino-6-ethoxy-9H-purin-9-yl)methyl]cycIopropyl} oxy)methyl phosphonic acid (Compound 23); 3-[( {l-[(2-amino-6-ethoxy-9H-purin-9-yl)methyl]cyclopropyl }oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3 5-phosphanon-l-yl pivalate(Compound 24); ({l-[(2-amino-6-methyl-9H-purin-9-yl)methyl]cycIopropyl; oxy)methyl phosphonic acid(Compound 25); 3-[(1 1 -[(2-amino-6-methyl-9H-purin-9-yl)methyl]cyclopropl] oxy)methyl]-8.8-dimethyl-3,7-dioxo-2,4,6-trioxa-3 3-phosphanon-l-yI pivalate(Compound 26): [(1-{[5-methyl-2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]methyl J cyclopropyl )oxy ]methylphosphonic acid(Compound 31): 8,8-dimethyI-3- {[(1 -! [5-methyl-2.4-dioxo-3.4-dihydro-1 (2H )-pyrimidinyl ]methyl J cyclopropyl)oxy]methyl}-3.7-dioxo-2.4.6-trioxa-3 5-phosphanon-1 -yl pivalate (Compound 32): [(1- [2-amino-6-(4-morpholinyl )-9H-purin-9-yl]methyl] cyclopropyl )oxy\|merhyi phosphonic acid(Comp'ound 37); 3-![(l-{[2-amino-6-(4-morpholinyl)-9H-purin-9-yI]methyl \| cyclopropyl )oxy] met-hyl} -8,8-dimethyl-3,7-dioxo-2.4,6-trioxa-3 5-phosphanon-1 -yl pivalate( Compound 38); bis(2.2.2-trifluoroethyl) (! l-[(2amino-6-hydroxy-9H-purin-9-yl)methyl] cyclopropyl}oxy)methylphosphonate (Compound 45): bis(2.2.2-trifluoroethyl) (! l-[(2-amino-6-chloro-9H-purin-9-yl)methyl] cyclopropyl \| oxy)methylphosphonate(Compound 46): bis(2.2.2-trifluoroediyl) ({1-[(2.6-diamino-9H-purin-9-yl)merhyl]cyclopropyl] oxy)methylphosphonate(Compound 47): bis(2.2,2-trifluoroethyl) (\| l-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl] oxy)methylphosphonate(Compound 48): bis(2.2,2-trifluoroethyl) ([ l-[(2-amino-9H-purin-9-yl)methyljcyclopropyl] oxy)methylphosphonate(Compound 49); bis(2.2,2-trifluoroethyl) ({l-[(2-amino-6-dimethylamino-9H-purin-9-yl)meth\ I] cyclopropyl }oxy)methylphosphonate( Compound 52); bis(2.2,2-trifluoroethyl) ({1 -[(2-amino-6-isopropyIamino-9H-purin-9-yl) methyl)cycIopropyl}oxy)methylphosphonate(Compound 53); bis(2,2,2-trifluoroethyl) ({t-[(2-amino-6-methoxy-9H-purin-9-yl)methyl] cyclopropyl }oxy)methylphosphonate(Compound 54): bis(2.2.2-trifluoroethyl) [(l-{[2-amino-6-(4-morpholinyl)-9H-purin-9-yl]methyl; cyclopropyl)oxy]methylphosphonatc(Compound 58): bis(2,2,2-trifluoroethyl) [(1 - {[2-amino-6-(phenylsuIfanyl)-9H-purin-9-yl] methyl} cyclopropyl)oxy]methylphosphonate(Compound 61); bis(2,2,2-trifluoroethyl) {[1-({2-amino-6-[(4-methylphenyl)sulfanyl]-9H-purin-9-yl} methyl )cyclopropyl]oxy} methyIphosphonatc(Compound 62); bis(2,2,2-trifluoroethyl) {[1-({2-amino-6-[(4-methoxyphenyl)sulfanyl]-9H-purin-9-yl} methyl)cyclopropyl]oxy} methylphosphonate(Compound 63): bis(2.2.2-trifluoroethyl) {[I-({2-amino-6-[(4-nitrophenyl)sulfanyl]-9H-purin-9-yl} methyl)cyclopropyl]oxy}methylphosphonate(Compound 64): [(1 - {[2-amino-6-(phenylsulfanyl )-9H-purin-9-yl]methyl \| cyclopropyl )oxy]methyl phosphonic acid(Compound 65); {[ 1 -(12-amino-6-[(4-methylphenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl] oxyjmethylphosphonic acid(Compound 66); 3-( \|[l-( 12-amino-6-[(4-methylphenyl)sultanyl]-9H-purin-9-yl]methyl)cyclo propyljoxyl methyl)-8.8-dimethyl-3.7-dioxo-2.4.6-trioxa-3 5-phosphanon-1-yl pivalate (Compound 68): bis {[(t-butoxycarbonyl)oxy]methyl}(\| l-[(2-amino-9H-purin-9-yl)methyl]cyclo propyl }oxy)methylphosphonate(Compound 69): bis{[(isopropoxycarbonyl)oxy]methyl[(11-[(2-amino-9H-purin-9-yl)methyl]cyclo propyl! oxy)methylphosphonate (Compound 70): bis J [(ethoxycarbonyl)oxy]methyl}({1 -[(2-amino-9H-purin-9-yl )methy 1 ]cyclo propyl ]oxy)methylphosphonate (Compound 71): bis J[(isobutoxycarbonyl)oxy]methyl}(; l-[(2-amino-9H-purin-9-yl)mothyl]eyclo propyl foxy )methylphosphonate (Compound 72): 3-[( {1 -[(2-amino-9H-purin-9-yl)methyl]cyclopropyl }oxy)methyi]-9-methyl-3.7-dioxo-2.4,6-trioxa-3 5-phosphadec-I-yI 3-methylbutanoate(Compound 74); 3-[( {1 -[(2-amino-9H-purin-9-yl)methyl]cyclopropyl }oxy)methyl]-8-methyl-3.7-dioxo-2.4.6-trioxa-3 5-phosphanon-1-yl 2-methylpropanoate(Compound 78); 3-( [[ I-(12-amino-6-[(4-methoxyphenyl)sulfanyl]-9H-purin-9-yl i methyl)cyclo propyl]oxy\| methyJ)-8.8-dimethyI-3.7-dioxo-2.4.6-trioxa-3 5-phosphanon-1-yl pivalate (Compound 79): 3-[(1 l-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-3.7-dioxo-7-( I-pyrrolidinyl)-2.4.6-trioxa-3 5-phosphahept-l-yl l-pyrrolidinecarboxylate(Compound SO): 3-[(1 l-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-3,7-dioxo-7-( I-piperidinyl)-2,4.6-rrioxa-3 5-phosphahept-l-yl 1-piperidinecarboxylate(Compound 81): 3-[(1 -[(2-amino-9H-purin-9-yl)methyl]cyclopropyl }oxy)methyl]-7-(4-morpholi-nyl)-3.7-dioxo-2,4,6-trioxa-3 5-phosphahept- 1-yl 4-morpholinecarboxylate(Compound 82): is{[(t-butoxycarbonyl)oxy]methyl}[(l-{[2-amino-6-hydroxy-9H-purin-9-yl] methyl}cyclopropyl)oxy]methylphosphonate(Compound 83); bis {[(isopropoxycarbonyl)oxy]methyl} [(1 - {[2-amino-6-hydroxy-9H-purin-9-yl] methyl} cyclopropyl)oxy]methylphosphonate(Compound 84); bis {[(isopropoxycarbonyl)oxy]methyl} {[ 1 -({2-amino-[6-(4-methoxyphenyl) sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl]oxy}methylphosphonate(Compound 85); 3-[( {l-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-7-cyclopentyl-3,7-dioxo-2.4,6-trioxa-3 5-phosphahept-1-yl cyclopentanecarboxviate (Compound 86); 3-( {[ 1 -({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purin-9-yl} methyl )cyclopropyl] oxy] methyl)-8,8-dimethyl-3.7-dioxo-2,4,6-trioxa-3 5-phosphanon-1 -yl pivalate (Compound 87); bis{[(isopropoxycarbonyl)oxy]methyl] [l-(12-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl]oxy}methylphosphonate(Compound 88): bis {[(isopropoxycarbonyl)oxy]methyl} ({1 -[(6-amino-9H-purin-9-yl )methyl]cyclo-propyl }oxy)methylphosphonate(Compound 89); 3-[( {1 -[(6-amino-9H-purin-9-yl)methyl]cyclopropyl }oxy)methyl]-9-methyl-3.7-dioxo-2,4,6-trioxa-3 5-phosphadec-1-yl 3-methylbutanoate(Compound 90); 3-[( {1 -[(6-amino-9H-purin-9-yl)methyl]cyclopropyl }oxy)methyI]-7-cyclopentyl-3.7-dioxo-2,4.6-trioxa-3 5-phosphahept-l-yl cyclopentanecarboxylate(Compound 91): bis {[(t-butoxycarbonyl )oxy]methyl}{[ 1-({2-amino-[6-(4-methoxyphenyl )sul fiinyl ] -9H-purin-9-yl} methyl)cyclopropyl]oxy,lmethylphosphonate(Compound 92): bis{[(t-butoxycarbonyl)oxy]methyl} {[l-(;2-amino-[6-(4-hitrophenyl)sultanyl]-9H -purin-9-yl} methyl)cyclopropyl]oxy} methylphosphonate(Compound 93); {[ 1 -({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purin-9-yl} methyl)cyclopropyl]oxy i methylphosphonic acid(Compound 95); {[l-({2-amino-[6-(4-methoxyphenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl] oxyj methylphosphonic acid(Compound 96); ({1 -[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]-2-methylcyclopropyl J oxy) methylphosphonic acidi(Compound 97); ({1 -[(2-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl }oxy)methylphosphonic acid( Compound 98); J [ 1 -({2-amino-[6-(4-methoxyphenyl)sulfanyl]-9H-purin-9-yl }methyl)-2-methyl oyclopropyl]oxy} methylphosphonic acid(Compound 99): \| [ 1 -({2-amino-[6-(4-nitrophenyl)su;lfanyI]-9H-purin-9-yl \ methyl)-2-methylcyclo-propyl]oxy} methylphosphonic acid(Compound 100); {[ 1-({2-amino-[6-(4-methylphenyl)sulfanyl]-9H-purin-9-yl} methyl )-2-methyl cyclopropyl]oxy}methylphosphonic acid(Compound 101); ({1 -[(2,6-diamino-9H-purin-9-yl)methyI]-2-methylcyclopropyl} oxy)methyl phosphonic acid(Compound 102); ({1 -[(6-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl} oxy)methylphosphonic acid(Compound 103); 3-[( {1 -[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]-2-methylcyclopropyl J oxy) methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3 5-phosphanon-1-yl pivalate(Compound 105); 3-[({ 1 -[(2-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl}oxy)methyl]-8.8-dimethyl-3,7-dioxo-2.4.6-trioxa-3 5-phosphanon-1-yl pivalate(Compound 106): 3-[({1-[(6-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl!oxy)methyl]-8.8-dimethyl-3.7-dioxo-2.4.6-trioxa-3 5-phosphanon-1-yl pivalate(Compound 107): 3-({[l-( !2-amino-6-[(4-methoxyphenyl)sulfanyl;-9H-purin-9-yl } methyl )-2-methyl cyclopropyljoxy! methyl)-8.8-dimethyl-3.7-dioxo-2,4.6-irioxa-3 5-phosphanon-1 -yl pivalate (Compound 108): bis{[(isopropoxycarbonyl)oxy]methyi; [(1- i[2-arnino-6-hydroxy-9H-purin-9-yl] methyl ]-2-methylcyclopropyl)oxy]methylphosphonate( Compound 109): bis{[(isopropoxycarbonyl)oxy]methyl}({l-[(2-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl}oxy)rnethylphosphonate(Compound 110); bis {[(isopropoxycarbonyl)oxy]methyl} {[ 1 -({2-amino-[6-(4-methoxypheny I) sulfanylj-9H-purin-9-yl} methyl)-2-methylcyclopropyl]oxy; methylphosphonate (Compound 112); bis{[(t-butoxycarbonyl)oxy]methyl},'[1-(12-amino-[6-(4-methoxyphenyl)sulf'anyl] -9H-purin-9-yl }methyl)-2-methylcyclopropyl]oxy} methylphosphonate( Compound 113); bis(2,2,2-trifluoroethyl){ [ l-( {2-amino-6-[(4-methoxyphenyl)sulfanylj-9H-purin-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate(Compound 114); bis(2,2,2-trifluoroethyl) {[I-({2-amino-6-[(4-nitrophenyl)sulfanyl]-9H-purin-9-yl} methyl)-2-methylcyclopropyl] oxy}methylphosphonate( Compound 115): bis{[(t-butoxycarbonyl)oxy]methyl] [1-(12-amino-[6-(4-nitrophenyl)sult'anyl]-9H -purin-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate(Compound 116): bis{[(isopropoxycarbonyl)oxy]methyl] [ 1 -({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purin-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate( Compound 117); 3-( {[ 1 -({2-amino-6-[(4-nitrophenyl)suli'anyl]-9H-purin-9-yl} methyl)-2-methyl cyclopropyljoxy} methyl)-8.8-dimethyl-3.7-dioxo-2,4,6-trioxa-3 5-phosphanon-1-yl pivalate (Compound 118); ({1 -[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl} amino)methyl phosphonic acid( Compound 119); {1 -[(2-amino-9H-purin-9-yl)methyl]cyclopropyl} amino)methylphosphonic acid(Compound 120); ({1 -[(6-amino-9H-purin-9-yl)methyI]cyclopropyl} amino)methylphosphonic acid(Compound 121); [ {1 -[(2-amino-6-hydroxy-9H-purin-9-yl jmethyl]cyclopropyl (methyl)amino] methylphosphonic acid(Compound 122): [ {1 -[(6-amino-9H-purin-9-yl)methyl]cyclopropyl {(ethyl)amino]methylphosphonic acid(Compound 125); 3-{[{(l-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl)( methyl )amino)methyl)-8.8-dimethyl-3.7-dioxo-2,4,6-trioxa-3 5-phosphanon-l-yl pivalate(Compound 126): bis{[(isopropoxycarbonyl)oxy]methyl } [{1-[(6-amino-9H-purin-9-yl)methyl]cyclo propyl}( methyl )amino]methylphosphonate( Compound 127): 3-1[{ l-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl!(ethyl)amino]methyl} -.8.8-dimethyl-3,7-dioxo-2,4,6-trioxa-3 5-phosphanon-l-yl pivalate(Compound 129): (E)-2-{I-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl}ethenyl phosphonic acid(Compound 130): (E)-2-{l-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}ethenylphosphonic acid (Compound 131); (E)-2-{I-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl]ethenylphosphonic acid (Compound 132); 3-((E)-2-{ l-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl]ethenyl)-.8.8-dimethyl-3,7-dioxo-2,4,6-trioxa-3 5-phosphanon-l-yl pivalate(Compound 133): 3-((E)-2-{l-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl]ethenyl)-8.8-dimethyl-3.7-dioxo-2,4,6-trioxa-3 5-phosphanon-1-yl pivalate(Compound 134): (E)-2- {1 -[(6-amino-9H-purin-9-yl)methyl]cyclopropyl} -1 -propenylphosphonic acid(Compound 137): 2-{ l-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl \| ethylphosphonic acid(Compound 138); 2- {1 -[(2-amino-9H-purin-9-yl)methyl]cyclopropyl} ethylphosphonic acid (Compound 139); 2- {1-[(6-amino-9H-purin-9-yl)methyl]eycIopropyl}ethylphosphonic acid (Compound 140); 2-[ 1 -({2-amino-6-[(4-methylphenyl)sulfanyl]-9H-purin-9-yl} methyl )cyclopropyl ] ethylphosphonic acid(Compound 141): 2-{ l-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl \| propylphosphonic acid( Compound 142): 2- {1 -[(6-amino-9H-purin-9-yl)methyl]cyclopropyl j propylphosphonic acid (Compound 143); 2-{1 -[(2-amino-9H-purin-9-yl)methyl]cyclopropyl }propylphosphonic acid (Compound 144); 3-(2-{l-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}propyl)-8,8-dimethyl-3,7-dioxo-2,4.6-trioxa-3 5-phosphanon-I-yl pivalate(Compound 145): ({l-[(2-amino-6-hydroxy-9H-purin-9-yl)methyI]-2,2-dimethylcyclopropyl j oxy) methylphosphonic acid(Compound 146); ({ l-[(2-amino-9H-purin-9-yl)methyl]-2,2-dimethylcyclopropyl }oxy)methyl phosphonic acid(Compound 147); ({1 -[(6-amino-9H-purin-9-yl)methyl]-2,2-dimethylcyclopropyl} oxy)methy] . phosphonic acid(Compound 148): 3-[(,' I-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]-2,2-dimethylcyclopropyl]oxy methyl]-8.8-dimethyl-3.7-dioxo-2.4.6-trioxa-3 5-phosphanon-1 -yl pivalate(Compound 149): 3-[({ l-[(2-amino-9H-purin-9-yl)methyl]-2.2-dimethyIcyclopropyl!oxy)methyl]-8.8 -dimethyl-3.7-dioxo-2.4,6-trioxa-3 .5-phosphanon-l-yl pivalate(Compound 150): 3-[(1 l-[(6-amino-9H-purin-9-yl)methyl]-2.2-dimethylcyclopropyl}oxy)methyl]-8.8 -dimethyl-3.7-dioxo-2,4,6-trioxa-3 5-phosphanon-1-yl pivalate(Compound 151); bis {[(isopropoxycarbonyl)oxy]methyl} ({1 -[(6-amino-9H-purin-9-yl)methyl]-2.2-dimethylcyclopropyl}6xy)methylphosphonate(Cornpound 152); and bis J [(isopropoxycarbonyl)oxy]methyl}[(1-{[2-amino-6-hydroxy-9H-purin-9-yl] methyl} -2.2-dimeth.ylcyclopropyl)oxy]methylphosphonate(Compound 153). The compound of formula (l) according to the present invention can be prepared by a process as explained below, and thus, it is another object of the present invention to provide such a preparation process. However, conditions of the process, such as for example, reactants, solvents, bases, amounts of the reactants used. etc. are not restricted to those explained below. The compound of the present invention may also be conveniently prepared by optionally combining the various synthetic ways described in the present specification or known in the arts, and such a combination can be easily performed by one of ordinary skill in the art to which the present invention pertains. The compound of formula (1) of the present invention can be prepared characterized in that (a) a compound represented by the following formula (2): (Formula Removed) in which R1, R2. R3, R4, R5, R7, R8 and Y are defined as previously described, and L represents a leaving group, preferably methanesulfonyloxy. p-toluenesulfonyloxy or halogen, is reacted with a compound represented by the following formula (3): QH (3) in which Q is defined as previously described, to produce rhe compound of formula (1). (b) a compound represented by the following formula (9): (Formula Removed) in which Rl, R2 R3 R7, R8 Y and L are defined as previously described, and R9 and R10 independently of one another represent optionally substituted alkyl. is reacted with the compound of formula (3) to produce a compound represented by the following formula (10): (Formula Removed) in which R1, R2. R3 R4 R5, Y, Q, R9 and R10are defined as previously described, and the resulting compound of formula (10) is hydrolyzed in the presence of a Lewis acid to produce a compound represented by the following formula (la): (Formula Removed) in which R1, R2, R3. R7. R8. Y and Q are defined as previously described, or (c) groups R4 and R5 are introduced into the compound of formula (la) to produce a compound represented by the following formula (lb): (Formula Removed) in which R1, R2, R3, R7, R8, Y and Q are derlned as previously described, and R4 and R5 represent R4 and R3 with the exception of hydrogen, respectively, or further the compounds thus obtained are subjected to conventional conversions (see: USP 6.1)37.335. 5.935.946. and 5.792,756). In the above process variants (a) to (c) for preparing the compound of formula (1). the reactions may be carried out in a solvent and in the presence of a base. As the solvent, one or more selected from a group consisting of dimethylformamide. dichloromethane. tetrahydrofuran. chloroform, l-methyl-2-pyrrolidinone and dimethylacetamide can be mentioned, and as the base one or more selected from a group consisting of sodium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium t-butoxide, hydrogen bis(trimethylsilyl)amide. sodium amide, cesium carbonate and potassium bis(trimethylsilyl)amide can be mentioned. The Lewis acid which can be used in the process variant (b) includes trimethylsilylhalide. Further, in the process variant (c) for introducing the groups R4 and R5 into the compound of formula (la), this compound is subjected to an ether-forming reaction with an alkylhalide in the, presence of a base, or is treated with thionyl chloride, oxalyl chloride or phosphorus pentachloride to produce a dichlorophosphonate derivative which is then reacted with a '33 suitable alcohol or amine to give the desired compound. The phosphonate compound of formula (2) used as a starting material in the above process is itself a novel compound. Therefore, it is another object of the present invention to provide the compound of formula (2). The compound of formula (2) wherein Y is 0, R1 is hydrogen, and each of R2, R3. R7 and R8 is hydrogen or alkyl, that is, a compound of the following formula (8), can be prepared characterized in that ( i ) an ethylgiycolate. the alcohol group of which is protected, represented by the following formula (Formula Removed) in which P1 represents an alcohol-protecting group, preferably benzyl(Bn). tetrahydropyranyl(THP), t-butyldiphenylsilyl(TBDPS), or t-butyldimethylsilyl(TBDMS), is reacted with ethyl magnesium bromide[C2H5MgBr] or the corresponding alkyl magnesium bromide or alkyl magnesium chloride in the presence of titanium tetraisopropoxide[Ti(OiPr)4], (ii) the resulting cyclopropanol represented by the following formula (5): (Formula Removed) in which P1 is defined as previously described and each of R2, R3, R4 and R'8 represents hydrogen or alkyl, is subjected to an ether-forming reaction in the presence of a base with a compound represented by the following formula {by. (Formula Removed) in which L, R4 and R5 are defined as previously described, to produce a phosphonate compound represented by the following formula (7): (Formula Removed) m which P1, R1:, R3, R7, R8', R4and R5are defined as previously described, and (in) the alcohol-protecting group of the resulting compound of formula (7) is removed and a leaving group(L) is introduced to produce a compound represented by the following formula (8): (Formula Removed) in which L. R2. R3. R7. R8. R4 and R5 are defined as previously described. The process for preparing the simplest compound of formula (8) (that is. all of R2. R6. R7 and R8 are hydrogen) is briefly depicted in the following Reaction Scheme I. Reaction Scheme 1 (Formula Removed) The specific reaction conditions of the above process can be referred to the following Preparations and Examples. Further, die compound of formula (2) wherein Y is -CH2-, and each of R1. R2. R3. R7 and R8 is hydrogen, that is a compound of the following formula (II): (Formula Removed) in which L. R4and R3are defined as previously described, can be prepared by a process as depicrd in the following Reaction Scheme 2: Reaction Scheme 2 (Scheme Removed) . Reaction Scheme 2 is briefly explained below. ( i ) According to a known method isee: JOC. 1975, Vol.40, 2969-2970), dialkylmalonate is reacted with dihaloethane to give malonic acid wherein cyclopropyl group is introduced into its 2-position. (ii) The malonic acid is reduced to give diol compound, one hydroxy group of which is then protected with a suitable protecting group (P1 is defined as previously described). Then, the other hydroxy group is oxidized to an aldehyde group, (iii) The resulting aldehyde compound is reacted with tetraalkylmethylenediphosphonate to give the desired phosphonate compound, (iv) The phosphonate compound thus obtained is reduced to give a compound having no unsaturated bond, alcohol-protecting group (P1) is removed, and a leaving group (L) is introduced to give the compound of formula (11). Further, the compound of formula (2) wherein Y is -N(CH3)- and each of R1. R". R3. R7 and R8 is hydrogen, that is a compound of the following formula (12): (Formula Removed) in which L. R4 and R5 are defined as previously described, can be prepared by a process as depictd in the following Reaction Scheme 3: Reaction Scheme 30 (Scheme Removed) Reaction Scheme 3 is briefly explained below. ( i) Diethyl 1.1cylopropyl dicarboxylate is selectively hydrolyzed to give a monocarboxylic acid, (ii) An amine group is introduced into the monocarboxylic acid according to the known Curtious Reaction (see: S. Linke, G. T. Tisue and W. Lowowski, J. Am. Chem. Soc. 1967, 89, 6308). (iii) The amine group is protected with a suitable protecting group [P2 may be carbamate or various benzyl protecting groups, or alkyl group (methyl, ethyl, etc.)]. (iv) The opposite ester group is reduced into a hydroxy group, which is then protected (P1 is defined as previously described), (v) The compound protected with protecting groups is reacted with methyl iodide in the presence of sodium hydride to introduce methyl group into the amine group. (vi) The amine-protecting group is removed and the resulting compound is reacted with dialkylbromomethylphosphonate to give the desired phosphonate compound, (vii) The alcohol-protecting group (P1) is removed from the phosphonate compound thus obtained and then a leaving group (L) is introduced to give the compound of formula (12). The specific reaction conditions of the above processes can be referred to the following Preparations and Examples. After the reaction is completed, the resulting product may be further separated and purified by usual work-up processes, such as for exampie. chromatography, recrystallization. etc. The compound of formula (1) of the present invention can be effectively used as an antiviral agent. Therefore, it is another object of the present invention to provide a composition for the treatment of viral diseases, which comprises as an active ingredient the compound of formula (1), pharmaceutically acceptable salt, hydrate, solvate or isomer thereof together with the pharmaceutically acceptable carrier. When the active compound according to the present invention is used for clinical purpose, it is preferably administered in an amount ranging generally from 0.1 to 10000mg. preferably from 0.5 to 100mg per kg of body weight a day. The total daily dosage may be administered in once or over several times. However, the specific administration dosage for the patient can be varied with the specific compound used, body weight, sex or hygienic condition of the subject patient, diet, time or method of administration, excretion rate, mixing ratio of the agent, severity of the disease to be treated, etc. The compound of the present invention may be administered in the form of injections or oral preparations. Injections, for example, sterilized aqueous or oily suspension for injection, can be prepared according to the known procedure using suitable dispersing agent, wetting agent, or suspending agent. Solvents which can be used for preparing injections include water, Ringer's fluid and isotonic NaCl solution, and also sterilized fixing oil may be conveniently used as the solvent or suspending media. Any non-stimulative fixing oil including mono-, di-glyceride may be used for this purpose. Fatty acid such as oleic acid may also be used for injections. As the solid preparation for oral administration, capsules, tablets, pills, powders and granules, etc., preferably capsules and tablets can be mentioned. It is also desirable for tablets and pills to be formulated into enteric-coated preparation. The solid preparations may be prepared by mixing the active compound of formula (1) according to the present invention with at least one carrier selected from a group consisting of inactive diluents such as sucrose, lactose, starch, etc., lubricants such as magnesium stearate. disintegrating agent and binding agent. When the compound according to the present invention is clinically applied for obtaining the desired antiviral effect, the active compound of formula (I) can be administered in combination with one or more substances selected from the known anti-cancer or antiviral agents. As the anti-cancer or antiviral agents which can be administered together with the compound of the present invention in such a manner. 5-Fluorouracil, Cisplatin, Doxorubicin, Taxol. Gemcitabine, Lamivudine. etc. can be mentioned. However, preparations comprising the compound of the present invention are not restricted to those explained above, but may contain any substances useful for the treatment or prevention of cancers or viral diseases. The present invention will be more specifically explained in the following Examples and Experiments. However, it should be understood that these Examples and Experiments are intended to illustrate the present invention but not in any manner to limit the scope of the present invention. Preparation 1 Synthesis of l-({\|t-butyl(diphenyl)silyl]oxy}methyl)cvciopropanol According to the description in a reference (see: Syn. Lett. 07, 1053-1054, 1999), the title compound was prepared as follows. 12g(35 mmole) of ethyl 2-{[t-butyl(diphenyl)silyl]oxy} acetate was dissolved in 200ml of tetrahydrofuran(THF) and 2.2ml of titaniumtetraisopropoxide was added thereto. To the mixture was slowly added 29.2mlof ethylmagnesiumbromide(3.0M in THF), and the reaction solution was stirred for 12 hours at room temperature. 20ml of saturated ammonium chloride was added to stop the reaction. About 150ml of tetrahydrofuran (THF) used as a solvent was removed by distillation under reduced pressure, and the reaction mixture was extracted twice with 200ml of ethyl acetate. The ethyl acetate extract was distilled under reduced pressure to give 11.4g( Yield 100%) of the title compound as a white solid. 1H NMR(CDCl3) 5 0.44 (q. 2H), 0.7S (q, 2H). 1.09 Is. 9H). 3.6 is. 2H). 7.41 (m.6H),7.70(m.4H) ESI: 344 (M+NH4)+, C20H26O2Si Preparation 2 Synthesis of diisopropyl {[l-({\|t-buryl(diphenyl)silyl]oxy}metliyl)cydopropyl] oxy} methylphosphonate The compound prepared in Preparation 1 (6.5g) was dissolved in lOml' of dimethylformamide(DMF), 32ml of lithium t-butoxide( 1.0M in THF) was added thereto, and the resulting mixture was stirred for 10 minutes. To the mixture was added 7.0g of diisopropyl bromomethylphosphonate, and then the temperature was raised to 40 C and the mixture was stirred for 4 hours. Dimethylformamide(DMF) was removed by distillation under reduced pressure, 40ml of saturated ammonium chloride was added to the residue, which was then extracted with ethyl acetate. The ethyl acetate extract was distilled under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane= 1 /1. v/v) to give G.8g( Yield 70%) of the title compound. 1H NMR(CDCl3) 6 0.53 (m, 2H), 0.88 (m. 2H). 1.07 (s. 9H), 1.29 (t. 12H), 3.78 (s, 2H). 3.98 (d, 6H), 475 (m, 2H), 7.40(m. 611). 7.67(m. 4H) Preparation 3 Synthesis of diisopropyI{l-f(hydroxymethyl)cyclopropyl]oxy}methyl phosphonate The compound prepared in Preparation 2 (8.3g) was dissolved in l00ml. of methanol, 3.1g of ammonium fluoride was added thereto, and the resulting mixture was heated under reflux for 2 hours. After the reaction was completed, methanol was removed by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichloromethane/'methanol=20/I, v\v) to give 3.6g(Yield 82%) of the title compound. 1H NMR(CDC13) 5 0.60 (t, 2H), 0.87 (t, 2H), 1.28 (d, 12H), 2.5 (br s. 1H). 3.65 (s. 2H).3.83(d,2H),4.82(m.2H) ESI:267(M-rl)".CllH2304P Preparation 4 Synthesis of )l-[(diisopropoxyphosplioryl)methoxy\|cyclopropyl[methyl methane- sulfonate The compound prepared in Preparation 3 (1.5g) was dissolved in 50ml' of dichloromethane, 0.85ml! of triethylamine and 0.84g of methanesulfonylchioride were added thereto, and the resulting mixture was stirred for 30 minutes at room temperature. Saturated ammonium chloride was added to stop the reaction. The product was extracted with dichloromethane. and the dichloromethane extract was concentrated by distillation under reduced pressure. The residue was purified by silica ge! column chromatography(eluent: ethyl acetate/n-hexane=l/l, v/v) to give 1.63g( Yield 81%) of the title compound. 1H NMR(CDCl3) 5 0.77 (m, 2H), 1.09 (m. 2H). 1.32 (m. 12H). 3.10 (s. 3H). 3.82 (m. 2H), 4.33 (s, 2H). 4.71 (m, 2H) Preparation 5 Synthesis of diisopropyl({l-[(6-amino-9H-purin-9-yl)methyl]cyclopropy!}oxy) methylphosphonate (Formula Removed) The compound prepared in Preparation 4 (430mg) was dissolved in 18ml of dimethylformamide, 57.6mg (60% purity) of sodium hydride and 162mg of adenine were added thereto, and the resulting mixture was heated under reflux over 4 hours. Saturated ammonium chloride was added to stop the reaction. The product was extracted with ethyl acetate, and the ethyl acetate extract was distilled under reduced pressure. The residue was purified by silica gel column chromatography!eluent: dichloromethane/methanol=20 I. v, v) to give 20 lmg( Yield 44%) of the title compound. H NMR(CDC13) 6' 0.86 (t, 2H), 1.01 (t. 2H), 1.24 (d. 6H), 1.34 (d. 6H). 3.NA .d. 2H). 4.34 (s,2H), 4.71 (m, 2H). 5.97 (br s, 2H). 8.32 (s. lH).8.58(s. 1H) ESI: 384 (M+l)+, C16H25N504P Preparation 6 Synthesis of diisopropyI({l-{(2-amino-6-chloro-9H-purin-9-vl)mcfliy\|\| cyclopropyl} oxy)methyIphosphonate (Formula Removed) The compound prepared in Preparation 4 (l.64g) was dissolved in "Onn of dimethylformamide. 219mg(60% purity) of sodium hydride and 7~3mg of 2-amino-C1-Chloro-9H-purine were added thereto, and the resulting mixture was stirred for 4 hours while heating at a temperature of up to 80 °C. Saturated ammonium chloride was added to stop the reaction. The product was extracted with ethyl acetate, and the ethyl acetate extract was distilled under reduced pressure. The residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol-20/I, v/v) to give 765mg(Yield 40%) of the title compound. 1H NMR(CDCl3) ' 0.80 (t, 2H), 1.02 (t. 2H), 1.27 id. 6H), 1.28 (d, 6H). 3.82 id. 2H).4.21 (s.2H).4.68(m,2H),5.13(brs,2H).8.15(s. 1H) ' 42 ESI: 418 (M+l)+, C16H25CIN504P Preparation 7 Synthesis of diisopropyl[(l {[5-methyI-2,4-dioxo-3,4-dihydro-l(2H)- pyrimidinyl]methyl} cyclopropyl)oxy\|methylphosphonate (Formula Removed) The compound prepared in Preparation 4 (118mg) and thymine were reacted according to the same procedure as Preparation 6 to give 26mgi Yield 2l%)of the title compound. 1H NMR(CDCl3)  0.82 (t, 2H). 0.95 (t, 2H). 1.31 (m 12H), 1.92(s. 311). 3.74 (d. 2H), 3.89 (s. 2H), 4.71 (m. 2H), 7.62 (s. 1H), 9.15 (s, 1H) ESI:375(M+I) C16H27N206P Preparation 8 Synthesis of l-({[t-butyl(diphenyl)silyl]oxy}methyl)-2-methylcyclopropanol (Formula Removed) According to the description in a reference (see: Syn. Let:. 07. 1053-1054, 1999). the title compound was prepared as follows. 50g(146 mmole) of ethyl 2- i[t-butyl(diphenyl)silyl]oxy}acetate was dissolved in 700mC of tetrahydrofuran(THF) and 30.0ml of titaniumtetraisopropoxide was added thereto. To the mixture was slowly added 290ml of propylmagnesiumchloride(2.0M in THF) at -10ºC. and the reaction solution was stirred for. 12 hours at room temperature. 200ml of saturated ammonium chloride was added to stop the reaction. The tctiahydrofuran (THF) used as a solvent was removed by distillation under reduced pressure, and the reaction mixture was extracted twice with 2000ml of n-hexane. The n-hexane extract was distilled under reduced pressure and purified by silica gel column to give 42g of the title compound. 1H NMR(CDC13)  0.06 (t, 1H), 0.88 (dd, 2H), 0.97 (d, 3H). 1.09 (s, 9H) 1.1 (mr 1H), 2.78 (s, 1H), 3.70 (d, 1H), 3.86 (d, 1H), 7.41 (m. 6H), 7.70 (m. 4H) ESI: 363 (M+Na)+, C21H2802Si Preparation 9 Synthesis of diisopropyl {[l-({[t-butyl(diphenyl)silyl]oxy}methyl)-2-methyl cyclopropyl]oxy}methylphosphonate (Formula Removed) The compound prepared in Preparation 8 (4.2g) was reacted according to the same procedure as Preparation 2 to give 3.3g of the title compound. 1H NMR(CDC13) ' 0.04 (t, 1H). 0.96 (dd. 1H), 0.97 (d. 3H. 1.05 (m. 1H). 1.06 (s, 9H), 1.23 (t. I2H). 3.72 (d. 1H), 3.95 (d. 2H). 3.98 (d. 1H). 4.75 (m. 211). ".40 (m. 611), 7.68 (m, 4H) Preparation 10 Synthesis of diisopropyl{ l-[(hydroxymethyl)-2-methylcyclopropyl]oxy} methylphosphonate (Formula Removed) The compound prepared in Preparation 9 (3.3g) was reacted according to the same procedure as Preparation 3 to give l.7g of the title compound. 1H NMR(CDCL3) ' 0.03 (t. 1H). 0.95 (dd. 1H), 0.96 (m. 1 H). I.N (d.. 3H), 1.35 (d, 12H),2.l7(brs. 1H). 3.80 (d, 2H). 3.96 (d. 1H). 4.80 (m. 211) ESI: 303 (M+Na)+, C12H22504 Preparation 11 Synthesis of diisopropyl({l-f(6-amino-9H-purin-9-yl)methyl]-2-methyl cycIopropyl}oxy)methylphosphonate (Formula Removed) The compound prepared in Preparation 10 (I.5g) was dissolved in 50ML of dichloromethane. O.85ml of triethylamine and 0.84g of methanesulfonylehloride were added thereto, and the resulting mixture was stirred for 30 minutes at room temperature. Saturated ammonium chloride was added to stop the reaction. The product was extracted with dichloromethane and the dichloromethane extract was concentrated by distillation under reduced pressure. The residue was used in the next reaction without any purification. 1H NMR(CDCl3)  0.42 (m, 1H). 1.12 (d. 3H). 1.25 (m. 1H). 1.32 (m. 12H). 1.33 (m. 1H). 3.10 (S.3H), 3.76 (m,2H). 4.31 (d. 1H). 4.71 (d. 1H). 4.76 (m. 2H) The methanesulfonate thus obtained (430mg) was dissolved in 18ml' of dimethylformamide, and 57.6mg (60% purity) of sodium hydride and 162mg of adenine were added thereto. The reaction mixture was refluxed under heating over 4 hours. Saturated ammonium chloride was added to stop the reaction. The product was extracted with ethyl acetate and the ethyl acetate extract was concentrated by distillation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/l, v/v) to give 201mg(Yield 44%) of the title compound. lHNMR(CDCl3)  0.53 (t/lH), 1.13 (d,3H), 1.15 (m. 1H). 1.30 (m. 12H). 1.41 (m, 1H), 1.85 (brs, 2H). 3.81 (m, 2H), 4.43 (m. 2H). 4.70 (m, 2H). 5.65 (br s. 2H), 8.26 (s. 1H).8.34(s.1H) ESI: 398 (M1). C17H28N504P Preparation 12 Synthesis of diisopropyl({l-[(2-amino-6-chloro-9H-purin-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonate (Formula Removed) The compound prepared in Preparation 10 was reacted according to the same procedure as Preparation 11 except that 6-chloroguanine (2-amino-6-chloro-9H-purine) was used instead of adenine to give the title compound. 1H NMR(CDCl3)_  0.47 (t, J=6.4Hz, 1H), 1.12 (m, 4H), 1.24 (dd. J= 2.8Hz. .4Hz.oH). 1.28 (t. J=6.0Hz. 6H). 1.38 (m, 1H), 3.80 (m. 2H),.4.28 (m. 2H). 4.68 (m. 2H). 5.13 (brs. 2H), 8.15 (s, 1H) ESI: 432 (M+l)+. C17H27C1N504P Preparation 13 Synthesis of diisopropyl[(l{\|5-methyl-2,4-dioxo-3,4-dihydro-l(2H)- pyrimidinyl]methyl}-2-methylcyclopropyl)oxy\|methylphosphonate (Formula Removed) The compound prepared in Preparation 10 was reacted according to the same procedure as Preparation 11 except that thymine was used instead of adenine to give the title compound. 1H NMR(CDCL3) 0.48 (t, 1H), 1.10 (m, 4H), 1.24 (dd, 6H), 1.28 (t. J= 6H). 1.38 (m, 1H), 1.92 (s, 3H). 3.80 (m, 2H), 4.28 (m, 2H), 4.68 (m, 2H), 7.62 (s. 1H). 9.15 (s. 1H) ESI: 389 (M1)+ C17H29N206P Preparation 14 Synthesis of (-(ethoxycaibonyl)cyclopropanecarboxylie acid (Formula Removed) Diethyl 1,1-cyclopropane dicarboxylate (20g) was hydrolyzed in IN NaOH (107 ml.) and ethanol (220ml) for 16 hours, and the ethanol was removed by distillation under reduced pressure. The remaining starting material was removed by using ethyl acetate and the aqueous layer was acidified by IN HC1. The reaction mixture was extracted with ethyl acetate and distilled under reduced pressure. The residue was purified by silica gel column to give the title compound in a yield of 94%. 1HNMR(CDCI3)  1.06 (t.3H), 1.53 (m.2H). 1.62 (m. 2H). 4.21 (q. 2H ESI: 159(M-I)~C7HI0O4 Preparation 15 Synthesis of ethyl l-{((benzyIoxy)carbonyl]amino}cyclopropanecarboxylate (Formula Removed) The carboxylic acid prepared in Preparation 14 (16g) was dissolved ;n dichloromethane, l0.8ml of oxalyl chloride was added dropwise, and 2 drops of dimethylformamide was added. The reaction mixture was stirred at room temperature for 3 hours and distilled under reduced pressure to give ethoxycarbonyl 1,1 -cyclopropane carbonylchloride. This compound, not purified, was dissolved in 30im' of dimethylformamide and the resulting solution was cooled with water-ice. 36g of NaV. was added and the reaction was carried out at room temperature for 3 hours. The reaction solution was extracted with 100ml of water and 200ml' of diethylether, and the diethylether extract was concentrated to give crude compound which was purified by silica gel column to give an azide compound. 1H NMR(CDC13)  1.28 (t, 3H), 1.54 (m, 4H), 4.19 (q, 2H) To the azide compound thus obtained (13g) was added dropwise 11ml of benzyl alcohol and the reaction mixture was heated to 100ºC. by which the reactants were vigorously reacted with each other with the generation of gas. The-reaction mixture was heated at lOOºC for further 1 hour, cooled to room temperature, and distilled under reduced pressure to remove benzyl alcohol. The residue was purified by silica gel column to give the title compound. 1H NMR(CDC13)  1.19 (m, 5H), 1.54 (m, 2H), 4.11 (m, 2H), 5.15 (br.s, 2H), 7.32 (m. 5H) Preparation 16 Synthesis of benzyl l-{[t-butyl(diphenylsilyl)oxy\|methylcyclopropylJ (methyl)carbamate (Formula Removed) The carboxylate prepared in Preparation 15.(13.2g) was dissolved in diethylether. to which 1.3g of LiBH4 dissolved in diethylether was slowly added dropwise. The reaction misture was stirred at room temperature for 16 hours, and 50mC of methanol and 5 ml, of IN HC1 were added dropwise thereto. The reaction mixture was stirred for 2 hours, the precipitate was removed by suction filtration, and the solvent in the filtrate was removed by distillation under reduced pressure. The residue was purified by silica gel column to give benzyl l-(hydroxymethyl)cyclopropylcarbamate. This compound (9.3g) was dissolved in dichloromethane. and 4.2g of imidazole and 13.5ml(' of t-butyldiphenylsilylchloride were added in order. The reaction mixture was stirred at room temperature for 4 hours and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column to give benzyl l-({[t-butyl(diphenyl)silyl]oxy}methyl)cyclopropylcarbamate. 1H NMR(CDCL3)S 0.71-1.19 (m. 4H). 1.04 (s, 9H). 3.68 (br.s. 2H), 5.04 (s. 211). 7.25-7.45 (m. 11H), 7.62 (d,4H) The carbamate thus obtained (5.5g) was dissolved in THF. 3.5ml of methane iodide (Mel) was added dropwise and then 1g of NaH was added. The reaction mixture was stirred at room temperature for 4 hours and then extracted with 100ml of diethylether and lOOml of water. The diethylether extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column to give the title compound. 1H NMR(CDC13)  0.78-0.84 (m, 4H), 1.03 (s, 9H), 3.03 (s, 3H). 3.55- 3.80 (m, 2H), 5.10 (s, 2H), 7.24-7.45 (m, 11H), 7.61 (m, 4H) Preparation 17 Synthesis of diisopropyl[l-({\|t-butyl(diphenyl)silyl]oxy}methyl)cyclopropyl) (methyl)amino\|methylphosphonate (Formula Removed) The carbamate prepared in Preparation 16 (1.0g) was dissolved in erhanol. lOOmg of 10% Pd/C was added, and the reaction mixture was subjected to a hydrogenation under hydrogen atmosphere. After the reaction was completed, the solvent was removed by-distillation under reduced pressure. The residue was purified by silica gel column to give I -({[t-butyl(diphenyl)silyl]oxy} methyl )-N-methylcyclopropancamine. 1H NMR(CDC13)  0.36 (m. 2H). 0.65 (m, 2H), 1.05 (s. 9H). 2.36 (s. 3H). 3.57 (s, 2H), 7.37-7.45 (m, 11H), 7.66 (d. 4H) The methylcyclopropaneamine thus obtained (l.Og) was dissolved in dichloromethane, to which l.03mC of diisopropylethylamine and 1.3ml' of (diisopropyl phosphoryl)methyl trifluoromethansulfonate were added dropwise. The reaction mixture was reacted under stirring at room temperature for 4 hours, and then extracted with l00ml' of diethylether and l00ml. of water. The solvent in the diethylether extract was removed by distillation under reduced pressure and the residue was purified by silica gel column to give the title compound. 1H NMR(CDCL3)  0.42 (m. 2H). 0.69 (m, 2H), 1.04 (s. 9H). 1.25 (d, 6H), 1.30, (d, 6H), 2.62 (s, 3H), 3.25 (d, 2H), 3.64 (s. 2H), 4.68 (m, 2H), 7.39 (m. 611), 7.65 (d. 4H) Preparation 18 Synthesis of diisopropyl(l-{((6-amino-9i/-purin-9-yl)methyl)cyclopropyl} (methyl)amino)methylphosphonate The compound prepared in Preparation 17 (0.32g; was dissolved in methanol and 1.5g of ammonium fluoride was added dropwise. The reaction mixture was reacted under stirring at 60ºC) for 24 hours and then the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column to give methylaminediisopropylmethylphosphone 1.1-cyclopropane ethyl alcohol. 1H NMR(CDC13)  0.56 (m. 2H). 0.73 (m, 2H). 1.31 (m. 1211). 2.56 (s. 311). 3.11 (d, 2H), 3.55 (s, 2H), 4.70 (m. 2H) The compound thus obtained was consecutively reacted according to the same procedure as Preparations 4 and 5 to give the title compound. 1H NMR(CDCL3)  0.78 (m, 2H). 0.S6 (m, 2H). 1.25 (m. I2H). 2.35 (s. 311). 4.10 (s. 2H), 4.68 (m 2H), 5.13 (m. 2H), 8.32 (s. 1H). 8.58 (s. 1H) ESI:397(M1)+.C17H29N603P Preparation 19 Synthesis of diisopropyl(l-{[(2-amino-6-chloro-9H-:puriii-9-yl)methyl] cyclopropyl}(methyl)amino)methylphosphonate (Formula Removed) The compound prepared in Preparation 17 (0.32g) was dissolved in methanol and 1.5g of ammonium fluoride was added dropwise. The reaction mixture was reacted under stirring at 60ºC for 24 hours and then the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column to give methylaminediisopropylmethylphosphone 1,1-cyclopropane ethyl alcohol. 1H NMR(CDCl3)  0.56 (m, 2H), 0.73 (m, 2H), 1.31 (m, 12H), 2.56 (s. 3H), 3.11 (d, 2H), 3.55 (s, 2H), 4.70 (m, 2H) The compound thus obtained was consecutively reacted according to the same procedure as Preparations 4 and 6 to give the title compound. 1H NMR(400MHz. CD3OD):  0.79 (m. 2H). 0.89 (m. 2H), 1.26 (m. 12H). 2.38 (s. 3H), 2.76 (d. 2H, 7=7Hz), 4.11 (s, 2H), 4.65 (m. 2H), 5.13 (m, 2H), 8.02 (s. 1H ) ESI: 431(M1)+C17H28C1N603P Preparation 20 Synthesis of diisopropyl((l-{[5-methyl-2,4-dioxo-3,4-dihydro-l(2H)- pyrimidinyl]methyl}cyclopropyl)(metliyl)amino\|methylphosphonate (Formula Removed) The compound prepared in Preparation 17 (0.32g) was dissolved in methanol and 1.5g of ammonium fluoride was added dropwise. The reaction mixture was reacted under stirring at 60 T? for 24 hours and then the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column to give methylaminediisopropylmethylphosphone 1.1-cyclopropane ethyl alcohol. 1H NMR(CDCl3) " 0.56 (m, 2H). 0.73 (m. 2H), 1.31 (m, 12H), 2.5o (s. 3H), 3.11 (d, 2H), 3.55 (s, 2H), 4.70 (m, 2H) The compound thus obtained was consecutively reacted according to the same procedure as Preparations 4 and 7 to give the title compound. 1H NMR(CDC13) 79 (m, 2H), 0.90 (m. 2H), 1.31 (m, 12H), 1.92 (s. 3H). 2.38 (s, 3H), 3.75 (d, 2H). 4.10 (s, 2H), 4.65 (m, 2H). 7.62 (s, 1H), 9.1,5 (s. 1 H) Preparation 21 Synthesis of 1,1-cyclopropanedicarboxylic acid (Formula Removed) In 50% NaOH 187ml was dissolved 15g of diethylmalonate at room temperature. Benzyltriethylammoniumchloride (21.3g) was added and the resulting mixture was stirred for 10 minutes. 1,2-Dibromoethane (12.3g) was added to the reaction solution and the resulting mixture was stirred for more than 18 hours at room temperature. The reaction mixture was neutralized by adding dropwise cone, sulfuric acid and then extracted with ethyl acetate. The extract was distilled under reduced pressure to give j.2g of the title compound as a white solid. 1H NMR(CDCl3)  1.88 (s, 4H) Preparation 22 Synthesis of [l-({[t-butyl(diphenyl)silyl]oxy}methyl)cyclopropyljmethanol (Formula Removed) Lithium aluminum hydride (LAH) 15.3g was dissolved in 39g of tetrahydrofuran, and 11.7g of the carboxylic acid prepared in Preparation 21 was slowly added dropwise at 0T. The reaction solution was refluxed for 17 hours. The reaction was stopped by adding 10% HC1 at room temperature and the mixture was extracted with ethyl acetate. The extract was distilled under reduced pressure and the residue was purified by silica gel column to give 8.2g of diol compound. 1H NMR(CDC13)  0.56 (s, 4H), 2.22 (s, 2H), 3.63 (s, 4H) • The compound thus obtained (400mg) was dissolved in 12ml. of THF, 184mg of NaH and 1.16g of t-butyldiphenylsilylchloride (TBDPSC1) were added, and the resulting mixture was refluxed for 6 hours. The reaction was stopped by adding 10ml of water and the mixture was extracted with ethyl acetate. The extract was distilled under reduced pressure and the residue was purified by silica gel column to give l.lg of the title compound. 1H NMR(CDC13)  0.33 (t, 2H), 0.48 (t, 2H), 1.23 (s, 9H), 3.59 (d, 4H), 7.42 (m, 6H), 7.68 (m, 4H) Preparation 23 Synthesis of diethyI(E)-2-[l-({[t-butyl(diphenyl)silyl]oxy}methyl)cyclopropyl] ethenylphosphonate (Formula Removed) ; 53 by silica gel column to give 2.32g of the title compound. 1H NMR(CDC13)  0.76 (t, 2H), 0.81 (t, 2H), 1.04 (s, 9H), 1.31 (t, 6H), 3.71 (s, 2H), 4.05 (m, 4H), 5.70 (m, 1H), 6.42 (m, 1H), 7.43 (m, 6H), 7.64 (d, 4H) ESI: 501 (M+l)+C28H4104PSi Preparation 24 Synthesis of diethyl 2-[l-(hydroxymethyl)cyclopropyl]ethenylphosphonate (Formula Removed) The compound prepared in Preparation 23 was reacted according to the same procedure as Preparation 3 to give the title compound. 1H NMR(CDC13)  0.76 (t, 2H), 0.81 (t, 2H), 1.04 (s, 9H), 1.31 (t, 6H), 3.71 (s. 2H), 4.05 (m, 4H), 5.70 (m, 1H), 6.42 (m, 1H), 7.43 (m, 6H), 7.64 (d, 4H) ESI: 501 (M+l)+C28H4104PSi Preparation 25 Synthesis of diethyl 2-{l-[(6-amino-9H-purin-9-yl)methyi\|cyclopropyl} ethenylphosphonate (Formula Removed) The compound prepared in Preparation 24 was reacted according to the same procedure as Preparations 4 and 5 to gi\ e the title compound. 1H NMR(CDC13)  1.07 (t, 2H), 1.19 (t, 2H), 1.22 (t, 6H), 3.93 (s, 4H), 4.33 (s. 2H). 5.55 (s, 2H), 5.63 (m, 1H), 6.49 (m, 1H), 7.88 (s, 1H), 8.37 (s, 1H) ESI:352 (M1)+C15H22N503P Preparation 26 Synthesis of diethyl 2-{l-[(2-amino-6-chloro-9^-purin-9-yl)methyl] cyc!opropyI}ethenylphosphonate (Formula Removed) The compound prepared in Preparation 24 was reacted according to the same procedure as Preparations 4 and 6 to give the title compound. 1H NMR(CDC13)  1.06 (t, 2H). 1.15 (t, 2H), 1.23 (t, 6H). 3.93 (s, 4H), 4.18 (s, 2H), 5.12 (s, 2H), 5.59 (m, 1H), 6.58 (m, 1H), 7.81 (s, 1H) ESI:386(M1)+'C15H21CIN503P Preparation 27 Synthesis of diethyl 2-(l-{(5-methyl-2,4-dioxo-3,4-dihydro-l(2H)-pyrimidinyl] methyl}cyclopropyl)ethenylphosphonate (Formula Removed) The compound prepared in Preparation 24 was reacted according to the same procedure as Preparations 4 and 7 to give the title compound. 1H NMR(CDC13)  0.93 (t, 2H). 1.01 (t, 2H), 1.24 (t, 6H), 1.92 (s, 3H), 3.91 (s, 2H). 3.96 (m, 4H). 5.49 (m, lH),5.87(m. 1H). 7.62 (s, 1H). 9.15 (s. 1H) ESI:343 (M1)+,C15H23N205P Preparation 28 Synthesis of l-({[t-butyl(diphenyl)silyl]oxy}methyl)-2,2-dimethylcyclo- (Formula Removed) According to the description in a reference (see: Syn. Lett. 07, 1053-1054, 1999), the title compound was prepared as follows. 10g(29 mmole) of ethyl 2- {[t-butyl(diphenyl)silyl]oxy}acetate was dissolved in 100ml of tetrahydroftiran (THF) and 6.0ml of titaniumtetraisopropoxide was added thereto. To the mixture was slowly added 37ml of isobutylmagnesiumbromide(2.0M in THF) at -10 ºC, and the reaction solution was stirred for 12 hours at room temperature.50ml of saturated ammonium chloride was added to stop the reaction. The tetrahydroftiran (THF) used as a solvent was removed by distillation under reduced pressure, and the reaction mixture was extracted twice with 500mlof n-hexane. The n-hexane extract was distilled under reduced pressure-and purified by silica gel column to give 5.0g of the title compound. 1H NMR(CDC13) 0.25 (d, 1H), 0.51 (d. 2H), 0.99 (s. 3H), 1.07 (s. 9H), 1.22 (s, 3H), 3.71 (d, 1H), 3.91 (d. 1H), 7.41 (m, 6H), 7.70 (m. 4H) ESI: 355 (M+l)+ C22H30O2Si Preparation 29 Synthesis of diisopropyl {{l-({[t-buryl(diphenyl)silyl]oxy}methyl)-2.2-dimethyl cyclopropyl]oxy}methylphosphonate (Formula Removed) The compound prepared in Preparation 2S was reacted according to the same procedure as Preparation 2 to give the title compound.. 1H NMR(CDCl3)  0.29 (d, 1H), 0.60 (d. 1H), 1.06 (s, 3H), 1.09 (s. 9H), 1.27 (s, 3H), 1.30 (m, 12H), 3.75 (m. 2H), 3.92 (m, 2H). 4.72 (m, 2H), 7.41 (m,-6H), 7.67 (m, 4H) ESI: 519 (M1)+, C28H4305PSi Preparation 30 Synthesis of diisopropyl{l-l(hydroxymethyl)-2,2-dimethylcyclopropyl]oxy} methylphosphonate (Formula Removed) The compound prepared in Preparation 29 was reacted according to the same procedure as Preparation 3 to give the title compound. 1H NMR(CDC13)  0.39 (d. 1H), 0.59 (d, 1H). 1.13 (s. 3H), 1.21 (s, 3H), 1.33 (d, 12H), 3.76 (m, 2H), 3.86 (m, 2H), 4.76 (m, 2H) ESI: 295 (M+l)+ C13H2704P Preparation 31 Synthesis of diisopropyl({l-[(6-amino-9H-purin-9-yl)methyIl-2,2-dimcthyI cyclopropyl}oxy)methylphosphonate (Formula Removed) The compound prepared in Preparation 30 was reacted according to the same procedure as Preparation 11 to give the title compound. 1H NMR(500MHZ, CDC13):  0.62 (d, J=5.9Hz, 1H), 0.81 (d, J=5.9Hz. 1H), 1.10 (s,3H), 1.23 (m, 15H), 3.72 (dd, J= 15.1, 11.0Hz. 1H), 3.85 (dd, J=l5.1, 5.5Hz, 1H), 4.28 (d, J=15.1Hz, 1H), 4.58 (d, J=15.1Hz, 1H), 4.68 (m. 2H), 5.79 (bs, 2H), 8.19 (s, 1H), 8.32 (s,lH) ESI: 412 (M+l)+, C18H30N5O4P Preparation 32 Synthesis of diisopropyl({l-{(2-amino-6>iodo-9H-purin-9-yl)inethyl]-2,2-dimethylcyclopropyl}oxy)methylphosphonate (Formula Removed) The compound prepared in Preparation 30 was reacted according to the same procedure as Preparation 12 except mat 6-iodoguanine was used instead of 6-chloroguanine to give the title compound. 1H NMR(500MHZ, CDCl3): 0.58 (d, J=6.4Hz, 1H), 0.80 (d, J=6.4Hz, 1H), 1.10 (s, 3H), 1.24 (m, 8H), 3.72 (dd, J=13.0, 11.0Hz. 1H), 3.88 (dd, J=13.0, 9.3Hz, 1H) 4.08 (d,J=l5.1Hz, lH),4.47(d,J=15.1Hz, 1H), 4.67 (m, 2H), 5.05 (bs, 1H), 8.10 (s. 1H) ESI: 538 (M+l)+, C18H29IN504P Preparation 33 Synthesis of diisopropyl[(l {(5-methyl-2,4-dioxo-3,4-dihydro-l(2H)- pyrimidinyl]methyI}-2,2-dimethylcyclopropy!)oxy\|methylphosphonate (Formula Removed) The compound prepared in Preparation 30 was reacted according to the same procedure as Preparation 13 to give the title compound. 1H NMR(CDC13)  0.58 (d, 1H), 0.80 (d, 1H), 1.10 (s, 3H), 1.24 (dd. 6H), 1.28 (t. 6H), 1.58 (s, 3H), 1.92 (s, 3H), 3.72 (dd. 1H), 3.88 (dd, 1H), 4.08 (d, 1H), 4.47 (d, 1H), 4.67 (m, 2H), 7.62 (s, 1H), 9.15 (s, 1H) ESI: 403 (M1)+- C18H31N206P Preparation 34 Synthesis of l-[l-({\|t-butyl(diphcnyl)silyl]oxy}methyl)cyclopropyl]-l-methyl alcohol (Formula Removed) 6g of the compound prepared in Preparation 22 was dissolved in 150ml of dichloromethane. 3.0g of N-oxide and 103mg of tetrapropylammoniumperruthenate (TPAP) were added thereto at room temperature. The reaction mixture was stirred for about 1 hour at room temperature and quenched by adding 20ml of water. The reaction mixture was extracted with dichloromethane and the extract was concentrated under reduced pressure to give 6.0g of aldehyde compound which went to next reaction without further purification. 5.23g of the aldehyde was dissolved in 350ml of THF. The solution was cooled to -78 ºC and 10.3ml of methylmagnesiumbromide (3.0M solution) was slowly added to the solution and then, stirred for 1 hour at room temperature. The reaction mixture was quenched by 0.5ml of water and O.5ml of methanol and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=l/8, v/v) to 3.57g of title compound. ■H NMR(CDC13)  0.22 (m, 1H), 0.39 (m, 2H), 0.61 (m, 1H), 1.06 (s, 9H), 1.24 (d, 3H), 3.3 (d, 1H), 3.47 (s, 2H), 3.9 (d, 1H), 7.43 (m, 6H), 7.64 (m, 6H) Preparation 35 Synthesis of diethyl (E)-2-l-(l-({(t-buryl(diphenyl)siIyl]oxy}methyl)cyclopropyl]-1-propenylphosphonate (Formula Removed) 4g of the compound prepared in preparation 34 was dissolved in 10ml of dichloromethane. 2.1g of n-morpholine N-oxide and 209mg of tetrapropylammoniumperruthenate (TPAP) were added thereto at room temperature. The reaction mixture was stirred for about 1 hour at room temperature and quenched by adding 20ml. of water. The reaction mixture was extracted with dichloromethane and the extract was concentrated under reduced pressure to give 4.0g of compound which went to next reaction without further purification. Tetraethylmethylene diphosphonate (2.7g) was dissolved in 30ml of tetrahydrofuran (THF) at -78 and 4ml of n-butyllithium was added. The resulting mixture was stirred for 20 minutes, and then 1.0 g of the ketone compound as obtained above was added. The reaction mixture was stirred at room temperature for 1 hour and was stopped by adding 20ml of water. The reaction mixture was extracted with ethyl acetate and concentrated under reduced pressure. The residue was purified by silica gel column to give 654mg of the title compound. 1H NMR(CDCl3)  0.58 (m, 1H), 0.69 (m, 2H), 1.02 (s, 9H), 1.20 (t, 6H), 2.09 (d, 3H), 3.59 (s, 2H), 4.05 (m, 4H), 5.61 (d, 1H), 7.38 (m, 6H), 7.63 id, 4H) Example 1 Synthesis of ({l-[(6-amino-9H-purin-9-yl)methyljcyclopropyl}oxy)methyl phosphonic acid (Compound 1) The compound prepared in Preparation 5 (159mg) was dissolved in 15ML. of dichloromethane, 1.27g of trimethylsilylbromide was added thereto, and the resulting mixture was heated under reflux for 18 hours. After the completion of reaction, the reaction mixture was extracted with water, and the water extract was distilled under reduced pressure. The residue was purified by high performance liquid chromatography (HPLC) to give 0.89g(Yield 90%) of the title compound as a white powder. lH NMR(MeOH-d4)  1.02 (d, 4H), 3.95 (d. 2H), 4.55 (s, 2H), 8.40 (s, 1H). 8.55 (s, 1H) ESI: 300 (M+l)+, C10H14N5O4P Example 2 Synthesis of 3-l({l-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-385-phosphanon-l-yl pivalate (Compound 2) The title compound was prepared according to the method known in a reference(see: J. Med. Chem., 37(12), 1857 (1994)) and USP 5,663,159 (1998). The compound prepared in Example 1 (1.00g) was dissolved in 150ml of dry dimethylformamide, and 2.08g(7.32 mmol) of N,N'-dicyclohexyl-4-morpholine- carboxamidine and 2.75g(18.3 mmol) of chloromethyl pivalate were added thereto. When the reaction mixture became homogeneous after about 1 hour, it was stirred for 5 days at room temperature. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was fractionated with SOmt, of water and 50ml of toluene to separate the organic layer. The aqueous layer was extracted twice with 50ml of toluene. The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography(eluent: methanol/dichloromethane= 1/20, v/v) to give 0.59g(Yield 32%) of the title compound as a white solid. 1H NMR(500MHZ, CDC13)  0.91 (m, 2H), 1.12 (m, 2H), 1.20 (m, 18H), 1.90 (brs,2H),3.90(d,2H),4.32(s,2H),5.65(m,4H),8.14(s, 1H), 8.31 (s. 1H) ESI: 528 (M+l)+, C22H34N508P Example 3 Synthesis of ({l-[(2-amino-6-chloro-9H-purin-9-yl)methyl]cyclopropyI} oxy)methyI phosphonic acid(Compound 3) The compound prepared in Example 1 (l.00g) was dissolved in 150ml of dry dimethylformamide, and 2.08g(7.32 mmol) of N,N'-dicyclohexyl-4-morpholine-carboxamidine and 2.75g(l8.3 mmol) of chloromethyl pivalate were added thereto. When the reaction mixture became homogeneous after about I hour, it was stirred for 5 days at room temperature. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was fractionated with 50ml of water and 50ml. of toluene to separate the organic layer. The aqueous layer was extracted twice with 50ml of toluene. The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (eluent: methanol/dichloromethane=l/20, v/v) to give 0.59g(Yield 32%) of the title compound as a white solid. 1H NMR(MeOH-d4)  1.00 (s, 2H), 1.07 (s, 2H), 3.94 (d. 2H), 4.52 (s, 2H), 9.50 (s, 1H) ESI: 334 (M+l)+ C10H13C1N5O4P Example 4 Synthesis of ({l-[(2-amino-6-hydroxy-9^-purin-9-yl)methyl]cyclopropyl}oxy) methylphosphonic acid(Compound 5) The compound prepared in Example 3 (41mg) was dissolved in 5ml of 2N hydrochloric acid and heated under reflux for 6 hours. Water was removed by distillation under reduced pressure to give 37mg(Yield 95%) of the title compound as a white solid. 1H NMR(MeOH-d4) 6 0.98 (m, 2H), 1.06 (m, 2H), 3.92 (d, 2H), 4.45 (s, 2H), 9.20 (s,lH) ESI: 316 (M+l)+, C10H14N5O5P Example 5 Synthesis of ({l-[(2-amino-9H-purin-9-yl)methyI]cyclopropyl}o.\y)rnethyl phosphonic acid(Compound 9) The compound prepared in Preparation 6 (150mg) was dissolved in 15ml of tetrahydrofuran, 15mg of 5% palladium/carbon was added thereto, and the compound was reduced under 1 atm of hydrogen atmosphere for 18 hours. After completion of reaction, palladium/carbon was removed by suction filtration and the filtrate was distilled under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/l, v/v) to give 130mg of diisopropyl compound(ESI: 3S4(M1)\ C16H26N504P). This compound was treated with trimethylsilylbromide according to the same procedure as Example 1 to give 91mg(Yield 90%) of the title compound. 1H NMR(MeOH-d4)  0.94 (m, 2H), 1.03 (m, 2H), 3.93 (d, 2H), 4.40 (s, 2H), S.66(s, lH),8.74(s, 1H) ESI: 300 (M+l)+ C10H14N5O4P Example 6 Synthesis of 3-[({l-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyll-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-385-phosphanon-l-yl pivalate(Compound 10) The compound prepared in Example 5 was reacted according to the same procedure as Example 2 to give the title compound. 1H NMR(CDCl3-d4) 6 0.90 (m, 2H), 1.05 (m, 2H), 1.20 (m, 18H), 3.96 (d, 2H), 4.22 (s, 2H), 5.65 (m, 4H), 8.03 (s, 1H), 8.69 (s, 1H) ESI: 528 (M+l)+, C22H34N508P Example 7 Synthesis of ({l-[(2-amino-6-cydopropyIamino-9H-purin-9-yl)methyi] cyclopropyl}oxy)methylphosphonic acid(Compound 11) The compound prepared in Preparation 6 (200mg) was dissolved in 20ml of ethanol, 53ml of triethylamine and 82mg of cyclopropylamine were added thereto, and the resulting mixture was heated under reflux for 18 hours. Water was added to stop the reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give 178mg(Yield 85%) of the diisopropyl compound. 1H NMR(CDC13)  0.59 (t, 2H), 0.83 (m, 4H), 1.00 (t, 2H), 1.24 (d, 6H), 1.29 (d, 6H). 3.0 (brs, 1H), 3.80 (d, 2H), 4.15 (s, 2H), 4.70 (m, 2H), 4.71 (brs. 2H), 5.71 (s, 1H), 7.68 (s, 1H) The compound thus obtained was treated with trimethylsilylbromide according to the same procedure as Example 1 to give 128mg(Yield 90%) of the title compound. 1H NMR(MeOH-d4)  0.86 (m, 2H), 0.94 (m, 2H), 1.02 (m, 2H),1.07 (m, 2H), 2.90 (br s, 1H), 3.93 (d, 2H), 4.39 (s, 2H), 8.43 (br s, 1H) ESI: 355 (M+l)+ C13H19N604P Example 8 Synthesis of ({l-((2-amino-6-ethylamino-9H-purin-9-yl)methyl]cyclopropyl} oxy) methylphosphonic acid(Compound 13) The compound prepared in Preparation 6 (115mg) was dissolved in 20ml of ethanol, 31 ml of triethylamine and 0.07ml of ethylamine were added thereto, and the resulting mixture was heated under reflux for 18 hours. Water was added to stop the reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give 104mg(Yield 89%) of the diisopropyl compound. 1H NMR(CDC13)  0.82 (m, 2H), 1.00 (m, 2H), 1.24 (d, 6H), 1.27 (t, 3H), 1.29 (d, 6H), 3.60 (brs, 2H), 3.81 (d, 2H), 4.15 (s, 2H), 4.65 (m, 4H), 5.50 (br s, 1H), 7.78 (s, 1H) The compound thus obtained was reacted according to the same procedure as Example 1 to give 75mg( Yield 90%) of the title compound. 1H NMR(MeOH-d4)  0.89 (m, 2H), 1.04 (m, 2H). 1.31 (t, 3H), 3.59 (br s, 2H;. 3.92 (d. 2H), 4.35 (s, 2H), 9.95 (br s, 1H) ESI: 343 (M+l)+, C13H19N604P Example 9 Synthesis of [(l-{[2-amino-6-(dimethyIamino)-9H-purin-9-yl]methyl} cyclopropyl)oxy\|methylphosphonic acid(Compound 15) The compound prepared in Preparation 6 (115mg) was dissolved in 20m? of ethanol. 38.6ml of triethylamine and 1.74ml of N,N-dimethylamine were added thereto, and the resulting mixture was heated under reflux for 18 hours. Water was acided to stop the reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give 1 l9mg(Yield 81%) of the diisopropyl compound. 1H NMR(CDC13) 6 0.75 (l, 2H), 0.93 (t, 2H), 1.16 (d, 6H), 1.22 (d, 6H), 3.3 (brs. 6H), 3.74 (d. 2H), 4.09 (s, 2H), 4.60 (m, 2H), 4.69 (brs, 2H), 7.68 (s, 1H) The compound thus obtained was reacted according to the same procedure as Example 1 to give 86mg( Yield 90%) of the title compound. 1H NMR(MeOH-d4)  0.89 (m, 2H), 1.05 (m, 2H). 3.30 (br s, 6H), 3.90 (d, 2H). 4.37 (s,2H), 7.92 (brs, 1H) ESI: 343 (M+l)+, C12H19N604P Example 10 Synthesis of [(l-{[2-amino-6-{isopropylamino)-9H-purin-9-.vl]methyl} cyclopropyl) oxy]methylphosphonic acid(Compound 17) The compound prepared in Preparation 6 (133mg) was dissolved in 20ml of ethanol, 0.049ml of triethylamine and 0.082ml. of isopropylamine were added thereto, and the resulting mixture was heated under reflux for 18 hours. Water was added to stop the reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give 95 mg( Yield 68%) of the diisopropyl compound. 1H NMR(CDC13)  0.83 (m, 2H), 0.98 (m, 2H), 1.28 (m. 18H), 3.79 (d, 2H), 4.15 (s, 2H), 4.60 (br s, 1H), 4.68 (s, 2H), 4.70 (m, 2H), 5.40 (br s, 1H), 7.77 (s, 1H) The compound thus obtained was reacted according to the same procedure as Example 1 to give 72mg(Yield 91%) of the title compound. 1H NMR(MeOH-d4) 6 0.89 (m, 2H), 1.05 (m, 2H), 1.34 id. 6H), 3.30 (br s. 1H). 3.90 (d, 2H), 4.36 (s, 2H), 8.01 (br s, 1H) ESI: 357 (M+l)+ C12H19N604P Example 11 Synthesis of ({l-{(2,6-diamino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl-phosphonic acid(Compound 19) The compound prepared in Preparation 4 (246mg) and 2.6-diaminopurine were reacted according to the same procedure as Preparation 5 to give 78.5mg(Yield 29%) of the diisopropyl compound. 1H NMR(CDC13)  0.85 (t, 2H), 1.00 (t, 2H), 1.25 (d, 6H). 1.29 (d, 6H), 1.83 (brs, 2H), 3.82 (d, 2H), 4.15 (s, 2H), 4.68 (m, 2H), 5.39 (d, 2H), 7.85 (s. 1H) introduced bit by bit under nitrogen atmosphere. 2ml of dry tetrahydrofuran was added dropwise thereto, the temperature was lowered to -78 , 0.08ml(20.238mmol) of methylmagnesium Grinard was added, and the resulting mixture was stirred for 1 hour. After the reaction mixture was warmed to room temperature, about 10mol% of palladiumtetrakistriphenylphosphine was added bit by bit. 50mg(0.119mmol) of the compound prepared in Preparation 6 in 1 ml of tetrahydrofuran was added to the above reaction solution dropwise. The resulting mixture was heated for 1 hour. The solvent was removed by distillation under reduced pressure, the residue was participated with water and ethyl, acetate, and the organic layer was concentrated by distillation under reduced pressure. The residue was purified by silica gel column chromatography(eluent: methylene chloride/methanol=90/10, v/v) to give 20mg(Yield 42%) of the diisopropyl compound. 1H NMR(MeOH-d4)  0.95 (m, 2H), 0.98(m, 2H), 1.17(d, 6H), 1.23 (d, 6H), 2.59(s, 3H), 4.02(s, 1H). 4.10(s, 1H), 4.32(s, 2H), 4.59(m, 2H), 8.12(s. 1H) ESI: 398 (M1)+. C17H28N504P The compound thus obtained was reacted according to the same procedure as Example 1 to give 8.0mg(Yield 50%) of the title compound. 1H NMR(D20)  0.87 (m, 2H), 1.02 (m, 2H), 3.79 (s, 1H). 3.81 (s. 1H), 4.53 (s. 2H),8.25(s, 1H) ESI: 314(M1)+.C11H16N504P Example 14 Synthesis of [(1 {[5-methyl-2,4-dioxo-3,4-dihydro-l(2H)-pyrimidinyll methyl} cyclopropyl)oxy\|methylphosphonic acid(Compound 31) The compound prepared in Preparation 7 (19mg) was reacted according to the same procedure as Example 1 to give 14mg( Yield 95%) of the title compound. ESI: 291 (M1)+.C10HllN2O6P 1H NMR(MeOH-d4)  0.82 (t, 2H), 0.97 (t, 2H), 1.87 (s, 3H), 3.83 (d. 2H), 3.97 (s, 2H), 7.55 (s, 1H) introduced bit by bit under nitrogen atmosphere. 2ml of dry tetrahydrofuran was added dropwise thereto, the temperature was lowered to -78 , 0.08ml(20.238mmol) of memylmagnesium bromide was added, and the resulting mixture was stirred for 1 hour. After the reaction mixture was wanned to room temperature, about 10mol% of palladiumtetrakistriphenylphosphine was added bit by bit. 50mg(0.119mmol) of the compound prepared in Preparation 6 in lot of tetrahydrofuran was added to the above reaction solution dropwise. The resulting mixture was heated for 1 hour. The solvent was removed by distillation under reduced pressure, the' residue was participated with water and ethyl acetate, and the organic layer was concentrated by distillation under reduced pressure. The residue was purified by silica gel column chromatography(eluem methylene chloride/methanol=90/10r v/v) to give 20mg(Yield 42%) of the diisopropyl compound. 1H NMR(MeOH-d4)  0.95 (m, 2H), 0.98(m, 2H), l.l7(d. 6H), r.23 (d, 6Hi. 2.59(s. 3H), 4.02(s, 1H), 4.l0(s, 1H), 4.32(s, 2H), 4.59(m, 2H), 8.12(s. 1H) ! ESI:398(M1)+,C17H28N504P The compound thus obtained was reacted according to the same procedure as Example 1 to give 8.0mg(Yield 50%) of the title compound. 1H NMR(D2O)  0.87 (m. 2H), 1.02 (m, 2H), 3.79 (s. 1H). 3.81 (s, 1H), 4.53 (s. 2H). 8.25 is. 1H) ESI:314(M1)+,CUH16N504P Example 14 Synthesis of ((l{{S-methyl-2,4-dioxo-3,4-dihydro-l(2H)-pyrimidinyl]methyl] cyclopropyl)oxy\|methylphosphonic acid(Compound 31) The compound prepared in Preparation 7 (19mg) was reacted according to the same procedure as Example 1 to give 14mg(Yield 95%) of the title compound. ESI: 291 (M1)+, C10H11N206P 1H NMR(MeOH-d4)  0.82 (t, 2H), 0.97 (t, 2H), 1 .87 (s. 3H), 3.83 (d, 2H), 3.97 (s. 2H), 7.55 (s, 1H) Example 15 Synthesis of [(l-{[2-amino-6-(4-morphoIinyl)-9Hr-purin-9-yI]methyl} cyclopropyl)oxy]methylphosphonic acid(Compound 37) The compound prepared in Preparation 6 (134mg) was dissolved in 20ml of ethanol, 0.049ml of triethylamine and 0.085 inf. of morpholine were added thereto, and the resulting mixture was heated under reflux for 18 hours. Water was added to stop the reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give 66mg(Yield 44%) of the diisopropyl compound. "H NMR(CDC13)  0.83 (m, 2H), 0.99 (m, 2H), 1.24 (d, 6H), 1,30 (d, 6H), 3.79 (m, 6H), 4.18 (s, 2H), 4.21 (br s, 4H), 4.67 (m. 2H), 4.80 (br s,.2H), 7.78 (s, 1H) ESI: 469 (M+l)+, C20H33N6O5P The compound thus obtained was treated with trimethylsilylbromide according to the same procedure as Example 1 to give 49mg( Yield 91%) of the title compound. 1H NMR(MeOH-d4)  0.89 (m, 2H). 1.07 (m, 2H), 3.81 (m, 4H), 3.92 (d, 2H), 4.40(brs,6H),7.87(s. 1H) ESI: 384 (M1)+, C14H21N605P Example 16 Synthesis of [(l-{[2-amino-6-(l-piperidinyl)-9H-purin-9-yl] methyl} cycIopropyl)oxy]methyIphosphonic acid(Compound 39) The compound prepared in Preparation 6 (154mg) was dissolved in 20ml of manol, 0 '049ml of triethylamine and 0.11 mK of amine were added thereto, and the resulting imxture was heated under reflux for 18 noms. Water was added to stop the reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give 123mg (Yield 72%) of the diisopropyl compound. 1H NMR(CDC13) 0.80 (m, 2H), 0.99 (m, 2H), 1.22 (d, 6H), 1.26 (d, 6H), 1.63 (m, 4H), 1.67 (m, 2H), 3.78 (d, 2H), 4.14 (s, 6H), 4.54 (br s, 2H), 4.65 (m, 2H), 7.72 (s, 1H) ESI: 467 (M+l)+, C21H35N604P The compound thus obtained was reacted according to the same procedure as Example 1 to give 87mg(Yield 91%) of the title compound. 1H NMR(MeOH-d4)  0.89 (m, 2H), 1.06 (m, 2H), 1.73 (m, 4H), 1.79 (m, 2H), 3.90 (d, 2H), 4.37 (s, 2H), 4.43(br s, 4H), 7.89 (s, 1H) ESI: 383 (M1)+, C15H23N604P Example 17 Synthesis of [(l-{[2-amino-6-(4-methyl-l-piperazinyl)-9H-purin-9-yl)methyl} cyclopropyl)oxy]methylphosphonic acid(Compound 41) The compound prepared in Preparation 6 (128mg) was dissolved in 20ml of ethanol, 0.10ml of 4-methyl-l-piperazine was added thereto, and the resulting mixture was heated under reflux for 18 hours. Water was added to stop the reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methano 1=20/1, v/v) to give l23mg(Yield 83%) of the diisopropyl compound. lH NMR(CDC13)  0.80 (m, 2H), 0.98 (m. 2H), 1.21 (d, 6H), 1.27 (d, 6H), 2.30 (s. 3H), 2.48 (m, 4H), 3.78 (d, 2H), 4.13 {z, 2H), 4.22 (br s, 4H), 4.57 (s, 2H), 4.66 (m, 2H), 7.73 (s, 1H) ESI: 482 (M+l)+, C21H36N704P The compound thus obtained was reacted accenting to the same procedure as Example 1 to give 87mg( Yield 85%) of the title compound. 1H NMR(MeOH-d4)  0.89 (m, 2H), 1.07 (m, 2H), 3.00 (s, 3H), 3.72 (m, 4H), 3.91 (d, 2H), 4.45 (s, 2H), 4.89 (m, 2H), 5.70 (br, 2H), 7.91 (s, 1H) ESI: 398 (M+l)+ C15H24N704P Example 18 Synthesis of [(l-{[2-amino-6-(l-pyrrolidinyl)-9H-purin-9-yl]methyl} cyclopropyl)oxy] methyl phosphonic acid (Compound 43) The compound prepared in Preparation 6 (122mg) was dissolved in 2ml of ethanol, 0.07ml of pyrrolidine was added thereio, and the resulting mixture was heated under reflux for 18 hours. Water was added to stop the reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/l. v/v) to give 110mg(Yield 83%) o f the diisopropyl compound. 1H NMR(CDC13)  0.78 (m, 2H), 0.96 (m, 2H), 1.20 (d, 6H), 1.26 (d, 6H), 2.00 (br s, 4H), 3.60 (br, 3H), 3.78 (d. 2H), 4.09 (br, 2H), 4.12 (s, 2H), 4.63 (m, 2H), 7.69 (s, 1H) ESI: 453 (M+l)+, C20H33N6O4P The compound thus obtained was reacted according to the same procedure as Example 1 to give 76mg( Yield 85%) of the title compound. 1H NMR(MeOH-d4)  0.94 (m. 2H), 1.03 (m. 2H), 2.15 (m, 4H), 3.76 (m, 2H). 3.91 (d, 2H), 4.18 (m, 2H), 4.40 (s, 2H), 5.70 (br, 2A), 8.42 (s, 1H) ESI: 369 (M1)+ C14H21N604P Example 19 Synthesis of 3-[({l-[(2-amino-9H-purin-9-yl)methyl)cyclopropyl}oxy) methyl] -9-methyl-3,7-dioxo-2,4,6-trioxa-385-phosphadec-l-yl 3-methyIbutanoate (Compound The compound prepared in Example 5 (l00mg) was dissolved in dimethylformamide (2ml) and then reacted with chloromethyl 3-methylbutyrate in the presence of triethylamine (3 equivalents) at room temperature for 24 hours. The resulting product was purified by silica gel column to give the title compound in a yield of 41%. 1H NMR(CDC13)  0.89 (t, 2H), 0.94 (d, 12H), 1.04 (t, 2H), 2.10 (m, 2H), 2.22 (d, 4H), 3.97 (d, 2H), 4.23 (s, 2H), 5.21 (s, 2H), 5.65 (m, 4H), 8.00 (s, 1H), 8.69 (s, 1H) ESI: 527 (M+l)+, C23H35N408P Example 20 Synthesis of 3-[({l-[(2-amino-9/7-purin-9-yl)methyI]cyclopropyl}oxy) The compound prepared in Example 5 was reacted with chloromethyl butyrate according to the same procedure as Example 19 at room temperature for 24 hours. The resulting product was purified by silica gel column to give the title compound in a yield of 24%. 1H NMR(CDC13)  0.88 (t, 2H), 0.92 (d, 6H), 1.60 (m, 4H), 2.32 (t, 4H), 3.96 id. 2H), 4.22 (s, 2H), 5.00 (s, 2H), 5.62 (m, 4H), 8.00 (s, 1H), 8.68 (s, 1H) ESI: 499 (M+l)+ C21H31N408P Example 21 Synthesis of 3-[({l-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy) methyl]- 8-methyI-3,7-dioxo-2,4,6-trioxa-385-phosphanon-l-yl 2-methylpropanoate (Compound 78) The compound prepared in. Example 5 was reacted with chloromethyl isobutyratc according to the same procedure as Example 19 at room temperature for 24 hours. The resulting product was purified by silica gel column to give the title compound in a yield of 21%. 1H NMR(CDC13)  0.84 (t, 2H), 0.97 (t, 2H), 1.11 (d, 12H), 2.52 (m, 2H), 3.91 (d. lr -.16 (s. 2H). 5.21 (s, 2H), 5.58 (m, 4H), 7.96 (s. l5 861(s, 1H) ESI: 499 (M+l)+, C21H31N408P Example 22 Synthesis of 3-[({l-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy) methyl] -3,7-dioxo-7-(l-pyrrolidinyl)-2,4,6-trioxa-385-phosphahept-1 -yl -pyrrotidtuecarboxylate (Compound 80) The compound prepared in Example 5 was reacted with chloromethyl 1-pyrrolidinecarboxylate according to the same procedure as Example 19 at room temperature for 24 hours. The resulting product was purified by silica gel column to give the title compound in a yield of 35%. 1H NMR(CDC13)  0.82 (t, 2H), 0.87 (m, 8H), 0.98 (t, 2H), 1.57 (d, 4H), 2.26 (t, 4H), 3.91 (d, 2H), 4.16 (s, 2H), 5.12 (s, 2H), 5.57 (m, 4H), 7.98 (s, 1H), 8.62 (s, 1H) ESI: 553 (M+l)+, C23H33N608P Example 23 Synthesis of 3-[({l-[(2-amino-9H-purin-9-yl)methylJcyclopropyl}oxy) methyl j-3,7-dioxo-7-(l-piperidinyl)-2.4,6-trioxa-385-phosphahept-l-yl l-piperidinecarboxylate(Compound 81); The compound prepared in Example 5 was reacted with chloromethyl I-piperidinecarboxylate according to the same procedure as Example 19 at room temperature for 24 hours. The resulting product was purified by silica gel column to give the title compound in a yield of 39%. 1H NMR(CDC13)  0.86 (t, 2H). 1.02 (t, 2H), 1.47-1.58 (brm. 12H), 3.40 (brm. 8H), 3.99 (d. 2H), 4.22 (s, 2H), 5.00 (s, 2H). 5.69 (m. 4H), 8.00 (s, 1H), 8.67 (s, 1H) ESI: 581 (M+l)+, C25H37N60SP Example 24 Synthesis of 3-[({l-((2-amino-9H-purin-9-yl)methyl]cycIopropyl}oxy) methyl]-7-(4-morphoIinyl)-3,7-dioxo-2,4,6-trioxa-385-phosphahept-l-yl 4-morphaliaecarboxylate(Compound 82) The compound prepared in Example 5 was reacted with chloromethyl 4-morpholinecarboxylate according to the same procedure as Example 19 at room temperature for 24 hours. The resulting product was purified by silica gel column to give the title compound in a yield of 40%. 1H NMR(CDC13) 6 0.89 (t, 2H), 1.03 (t, 2H), 3.47 (brm, 8H), 3.65 (brm, 8H), 4.00 (d, 2H), 4.24 (s, 2H), 5.04 (s, 2H), 5.70 (m, 4H), 8.07 (s, 1H), 8.69 (s, 1H) ESI: 586 (M+l)+, C23H33N6O10P Example 25 Synthesis of {[l-({2-amino-6-((4-methylphenyl)sulfanyl]-9H-purin-9-yl} methyl)cyciopropyl]oxy}methylphosphonic acid(Compound 66) 6-Chloroguanine derivative prepared in Preparation 6 (4.86g) was dissolved in 85 mlof methanol and 1.4g of triethylamine and 2.9g of 4-methyithiocresol were added. The reaction mixture was reacted under reflux condition for 24 hours. The reaction was stopped by adding 20ml of water, and the methanol was removed by distillation under reduced pressure. The reaction mixture was extracted with dichloromethane and purified by silica gel column to give a compound wherein 6-position of guanine was substituted by 4-methylphenylthio group. 1H NMR(CDCl3)  0.84 (t, 2H), 1.02 (t, 2H), 1.25-1.31 (m, 12H), 2.40 (s, 3H), 4.20 (d, 2H), 4.69 (m, 2H), 4.74 (s, 2H), 7.22(d. 2H), 7.50 (d, 2H), 8.00 (s, 1H) The compound thus obtained was reacted according to the same procedure as Example 1 and then recrystallized from a mixture of methanol-diethylether (1/20, v/v) to give the title compound. 1H NMR(MeOH-d4)  0.98 (t, 2H). 1.06 (t, 2H), 2.42 (s, 3H). 3.92 (d, 2H), 4.48 (s, 2H), 7.35 (d, 2H), 7.55 (d, 2H), 9.05 (s. 1H) ESI: 421 (M1)+, C18H21N404PS Example 26 Sywasss of {(l-({2-amino-6-[(4-methylphenyl) -9H-p«TB-9-yl} methyl)cyclicpyl]oxy ]methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-troxa-385-phosphanon-1-yl pivalate(Compound 68) The methylphosphonic acid prepared in Example 25 was reacted according to the same procedure as Example 2 to give the title compound. 1H NMR(CDC13)  0.82 (t, 2H), 0.98 (t, 2H), 1.18 (s, 18H), 2.36 (s, 3H), 3.93 (d, 2H), 4.15 (s, 2H), 4.93 (s, 2H), 5.60 (m, 4H), 7.18 (d, 2H), 7.48 (d, 2H), 7.88 (s, 1H) ESI: 649 (M+l)+, C30H41N4O8PS Example 27 Synthesis of {[l-({2-amino-6-[(4-metboxyphenyl)sulfanyl]-9H-purin-9-yl} methyl)cyclopropyl]oxy}methylphosphonic acid(Compound 96) 6-Chloroguanine derivative prepared in Preparation 6 (4.86g) was dissolved in 85 ml. of methanol and 1.4g of triethylamine and 2.9a of 4-methoxythiocresol were added. The reaction mixture was reacted under reflux condition for 24 hours. The reaction was stopped by adding 20ml of water, and the methanol was removed by distillation under reduced pressure. The reaction mixture was extracted with dichloroniethane and purified by silica gel column to give a compound wherein 6-position of guanine was substituted by 4-methoxyphenylthio group. The compound thus obtained was reacted according to the same procedure as Example 1 and then recrystallized from a mixture of methanol-diethylether (1/20, v/v) to give the title compound. lH NMR(MeOH-d4) 6 0.77 (m, 2H), 1.05 (m. 2H), 3.S7 (s, 3H), 3.92 (d, 2H). 4.45 (s, 2H), 7.10 (d, 2H), 7.59 (d, 2H), 8.09 (s, 1H) ESI: 438 (M+l)+ C17H2CN505PS Example 28 Synthesis of {[l-({2-amino-6-[(4-nitrophenyl)sulfanyl]-9H-purin-9-yl}methyl) cyciopropyl]oxy}methylphosphonic acid(Compound 95) The comound prepared in Preparation 6 was reacted acceding to the same procedure as =.\ ample 27 except that 4-nitrothiocresol was sea. insteac of 4-methoxythiocresol to give the title compound. 1H NMR(MeOH-d4)  0.86 (m, 2H), 0.95 (m. 2H), 3.82 (d. 2H), 4.35 (s, 2H), 7.S 1 (d, 2H), 8.22 (d, 2H), 8.72 (s, 1H) ESI: 453 (M+l)+ C16H17N606PS Example 29 Synthesis of ({l-[(2-ammo-6-hydroxy-9i/-purin-9-yl)methyl]-2-methyl cyclopropyl}oxy)methylphosphonic acid(Compound 97) The 6-chloroguanine derivative prepared in Preparation 12 was consecutively reacted according to the same procedure as Examples 3 and 4 to give the title compound. 1H NMR(MeOH-d4)  0.73 (t, 1H), 1.15 (m. 1H), l.21(d, 3H), 1.38 (t, 1H), 1.48 (m, 1H), 3.85 (t, 1H), 3.96 (t, 1H), 4.42 (d, 1H), 4.69 (d. 1H), 9.12 (s. 1H) Example 30 Synthesis of {[l-({2-amino-{6-(4-methoxyphenyl)sulfanyl]-9H-purin-9-ylj methyl)-2-methylcycloprbpylloxy} methylphosphonic acid(Compound 99) The 6-chloroguanine derivative prepared in Preparation 12 was reacted according to the same procedure as Example 27 to give the title compound. 1H NMR(MeOH-d4)  0.67 (t, 1H), 1.13 (m. 2H), 1.20 (d. 3H), 1.45 (m, 1H), 3.S5 (m, 1H), 3.86 (s, 3H), 3.94 (m, 1H), 4.42 (d, 1H). 4.68 (d, 1H). 7.09 (d, 2H), 7.59 (d, 2H).9.00(s, 1H) ESI: 452 (M+l)+ C18H22N505PS Example 31 Synthesis of {[l-({2-amino-[6-(4-methylphenyl)sulfanyl]-9H-purin-9-yl} methyl)-2-methyIcyclopropyl]oxy}methylphosphonic acid(Compound 101) The 6-chloroguanine derivative prepared in Preparation 12 was reacted according to the same procedure as Examole 25 to give the title compound. 1H NMR(MeOH-d4)  0.68 (t, 1H), 1.15 (m. 2H), 1.20 (d, 3H), 1.45 (m, 1H), 2.42 (s, 3H), 3.84 (m, 1H), 3.96 (m, 1H), 4.43 (d, 1H). 4.68 (d. 1H), 7.36 (d. 2H), 7.55 (d, 2H),9.05(s, 1H) ESI: 436 (M+l)+ C18H22N504PS Example 32 Synthesis of {[l-({2-amino-[6-(4-nitrophenyl)suIfanyI]-9iy-purin-9-yl}methyl) -2-methylcyclopropyl]oxy}methylphosphonic acid(Compound 100) The 6-chloroguanine derivative prepared in Preparation 12 was reacted according to the same procedure as Example 28 to give the title compound. 1H NMR(MeOH-d4)  0.49 (t, 1H), 0.93 (m. 1H), 1.00 (d, 3H), 1.25 (m. 1H), 3.64 (m. 1H), 3.76 (m, 1H), 4.28 (d, 1H), 4.53 (d, 1H), 7.72 (d, 2H), 8.14 (d, 2H), 9.10 (s, 1H) ESI: 467 (M+l)+, C17H19N606PS Example 33 Synthesis of ({l-[(6-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl}oxy) methylphosphonic acid(Compound 103) The adenine derivative prepared in Preparation 11 was reacted according to the same procedure as Example 1 to give the title compound. !H NMR(MeOH-d4) 8 0.64 (t, 1H), 1.09 (m. !H), 1.20 (d, 3H), 1.43 (m. 1H). 3.83 (m. 1H), 3.95 (m, 1H), 4.49 (d, 1H), 4.75 (d, 1H). 5.49 (s, 2H). 8.39 (s, 1H), 8.55 is. 1H) ESI: 314 (M1)+, CI 1H16N504P Example 34 Synthesis of bis{[(t-butoxycarbonyl)oxy\|methyI}({l-[(2-amino-9H-purin-9-yl) methyi]cyclopropyl}oxy)methylphosphonate(CompouDd 69) The compound prepared in Example 5 (18~mg) was mixzc with 6ml of N-methyl-2-pyrro me. and 300mg of triethylamine and 150mg chloromemyl t-butylcarbonate were added. The reaction solution was stirred at room temperature for 4 hours. The reaction was stopped by adding I0ml of water, and the reaction mixture was extracted with ethyl acetate. The extract was distilled under reduced pressure and purified by silica gel column to give the title compound. 1H NMR(CDCl3) 0.86 (m, 2H), 1.06 (m, 2H), 1.47 (s, 18H), 4.01 (d, 4H), 4.22 (s, 2H), 5.00 (brs, 2H), 5.61 (m, 4H), 7.99 (s, 1H), 8.69 (s, 1H) ESP. 344 (M+l)+, C22H34N5O10P Example 35 Synthesis of bis{[(isopropoxycarbonyl)oxy]methyl}({1 -((2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate(Compound 70) The compound prepared in Example 5 (l00mg) was mixed with 5ml, of N-methyl-2-pyrrolidone, and 11Omg of triethylamine and 150mg of chloromethyl isopropylcarbonate were added. The reaction solution was stirred at 50 for 4 hours. The reaction was stopped by adding lOml of water, and the reaction mixture was extracted with ethyl acetate. The extract was distilled under reduced pressure and purified by silica gel column to give the title compound. 1H NMR(CDCl3)  0.88 (s, 2H), 1.06 (s, 2H). 1.29 (d, 2H), 1.31 (d, 2H), 4.01 (d. 4H), 4.21 (s. 2H), 4.92 (m, 2H), 5.01 (brs, 2H), 5.64 (m. 4H), 7.99 Example 36 Synthesis of ({l-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl)-2,2-dimethyl cyclopropyl}oxy)methylphosphonic acid(Compound 146) The compound prepared in Preparation 32 was consecutively reacted according to the same procedure as Examples 1 and 4 to give the title compound. 1H NMR(MeOH-d4) 0.78 (d, 1H), 0.82 (d. 1H). 1.21 (s, 3H), 1.27 (s, 3H), 3.90 (d. 1H). 3.91 (d, 1H), 4.58 (s, 2H), 9.12 (s. 1H) ESI: 344 (V - ". C12HISN505P Example 37 Synthesis of ({l-[(2-amino-9H-purin-9-yl)methyl]-2.2-dimethylcyclopropyl} oxy)methylphosphonic acid(Compound 147) The compound prepared in Preparation 32 was reacted according to the same procedure as Example 5 to give a compound wherein 6-position of guanine was reduced by hydrogen. lH NMR(CDC13)  0.60 (d, 1H), 0.82 (d, 1H), 1.21 (s, 3H), 1.22 (s, 3H), 1.22 (m, 15H), 3.73 (m, 1H), 3-87 (m, 1H), 4.13 (d, 1H), 4.49 (d, 1H), 4.67 (m, 2H), 4.98 (brs, 2H),8.09(s, lH),9.67(s, 1H) The compound thus obtained was reacted according to the same procedure as Example 1 to give the title compound. 1H NMR(MeOH-d4)  0.74 (d. 1H), 0.81 (d, 1H), 1.21 is. 3H). 1.26 (s, 3H). 3.91 (d, 2H).4.49(d, 1H), 4.57 (d, 1H), 8.63 (s, 1H), 8.74 (s. 1H) ESI: 328 (M1)+, C12H18N504P Example 38 Synthesis of ({l-[(6-amino-9H-purin-9-yl)methyl]-2.2-dimethylcycIopropyl} oxy)methylphosphonic acid(Compound 148) The compound prepared in Preparation 31 was reacted according to the same procedure as Example 1 to give the title compound. lH NMR(MeOH-d4)  0.77 (d, 1H), 0.79 (d, 1H), 1.25 (s. 3H). 1.28 (s, 3H). 3.90 (d, 2H), 4.61 (d, 1H), 4.70 (d, 1H), 8.38 (s, 1H), 8.51 (s. 1H) ESI: 328 (M+l)+, C12H18N504P Example 39 Synthesis of (E)-2-{l-l(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl} ethenylphosphonic acid(Compound 130) The compounc prepared ir. Preparation 26 was reacted according to the same procedure as Example 1 to give phosphonic acid derivative. 1H NMR(MeOH-d4) 6 1.07 (t, 2H), 1.33 (t. 1H), 4.41 (s. 2H), 5.76 (dd, 1H), 6.45 (dd, lH).9.1S(s, 1H) The compound thus obtained was reacted according to the same procedure as Example 4 to give die title compound. 1H NMR(MeOH-d4)  1.08 (t, 2H), 1.34 (t, 1H), 4.38 (s, 2H), 5.78 (dd, 1H), 6.46 (dd, 1H), 9.11 (s, 1H) ESI: 312 (M+l)+, CI 1H14N504P Example 40 Synthesis of 2-{l-[(2-amino-9H-purin-9-yl)methyl]cyclqpropyl}ethyl phosphonic acid(Compound 139) The compound prepared in Preparation 26 was reacted according to the same procedure as Example 5 to give the title compound. 1H NMR(MeOH-d4) 0.58 (t, 2H). 0.85 (t. 2H), 1.42 (m. 2H). 1.95 (m, 2H), 4.11 (s, 2H), 5.78 (dd, 1H), 8.55 (s, 1H), 8.75(s. 1H) ESI: 298 (M-l)+, CI 1H16N503P Example 41 Synthesis of (E)2-{ l-{(6-amino-9H-purin-9-yl)methyl]cyclopropyl}ethenyl phosphonic acid(Compound 132) The compound prepared to Preparation 25 was reacted according to the same procedure as Example 1 to give the title compound. 1H NMR(MeOH-d4) 0.94 (t, 2H). 1.20 (t, 2H), 4.36 (S. 2H). 5.63 (dd, 1H), 6.37 (dd, 1H). 8.30 (s. 1H), 8.31 (s, 1H) EST- 296 (M-l)+, C11H14N503P Example 42 Synthesis. of 2-{l-[(6-amino-9H-purin-9-yl)methyl]cyelopropyl}ethyl phosphonic acid(Compound 140) The compound prepared in Preparation 25 was reacted according to the 'same procedure as Example 5 to give the title compound. 1H NMR(MeOH-d4)  0.58 (t, 2H), 0.87 (t, 2H), 1.37 (m, 2H), 1.97 (m, 2H), 4.24 (s, 2H), 8.31 (s, 1H), 8.42 (s, 1H) ESI: 298 (M+l)+, C1 1H16N503P Example 43 Synthesis of 2-{l-((2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl} ethylpbosphonic acid(Compound 138) The compound prepared in Preparation 26 was reacted according to the same procedure as Example 12 to give a compound wherein 6-position of guanine was substituted by ethoxy group. 1H NMR(CDC13)  1.00 (t, 2H), 1.10 (t, 2H), 1.16-1.21 (m. 9H). 3.90 (m, 4H), 4.01 (m. 2H), 4.13 (s. 2H), 4.92 (s, 2H), 5.58 (dd. 1H), 6.49 (dd, 1H). 7.62 (s. 1H) The compound thus obtained (80mg) was dissolved in methanol and reacted under hydrogen atrmosphere in the presence of 20mg of 10% Pd/C to give a compound wherein double bond was reduced. 1H NMR(CDCl3)  0.49 (t, 2H), 0.66 (t. 2H), 1.21 (t, 6H). 1.42 (m. 2H). 2.01 (m. 2H), 3.99 (m, 6H), 4.96 (s. 2H), 7.59 (s, 1H) The compound thus obtained was reacted according to the same procedure as Example 1 to give the title compound. 1H NMR(MeOH-d4)  0.60 (t, 2H), 0.87 (t, 2H), 1.47 (m. 2H). 1.97 (m, 2H), 4.16 (s, 2H). 9.12 (s, 1H) ESI:314(M1)+. - H16N50-1 Example 44 Synthesis of 2-{l-i(2-amino-9H-purin-9-yl)methyl]cyclopropyl}propyl phosphonic acid(Compound 144) The compound prepared in Preparation 35 was consecutively reacted according to the same procedure as Preparations 24,26 and Example 5 to give the title compound. 1H NMR(MeOH-d4)  0.62-0.77 (m, 4H), 1.04 (d, 3H), 1.52 (m, 2H), 1.90 (m, 1H), 4.24 (m, 2H), 8.58 (s, 1H), 8.74 (s, 1H) ESI: 312 (M1)+, C12H18N503P Example 45 Synthesis of (E)-2-{l-[(6-amino-9H-purin-9-yl)methyl]cyclopropyI}-l-propenylphosphonic acid(Compound 137) The compound prepared in Preparation 35 was consecutively reacted according to the same procedure as Preparations 24, 25 and Example I to give the title compound. 1H NMR(MeOH-d4)  0.86 (t, 2H), 1.10 (t. 2H), 2.19 (d, 3H). 4.3S (s. 2H), 5.23 (d. lH),8.34(s. 1H), 8.3"(s, 1H) ESI:310(M-l)+.C12H16N5O3P Example 46 Synthesis of 2-{l-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}propyl phosphonic acid(Compound 143) The compound prepared in Preparation 35 was consecutively reacted according to the same procedure as Preparations 24, 25 and Example 5 to give the title compound. 1H NMR(MeOH-d4) 6 0.65 (t, 2H), 0.78 (t. 2H), 0.95 (m, 1H), 1.00 (d, 3H), 1.53 (s, 1H), 1.90 (m. 1H). 4.3 (q, 2H), 8.41 (s, lH).S.45(s, 1H) ESI:312(M1)\C12H18N503P Example 47 Synthesis of bis 2,2,2-trifluoroethyl) ({l-[(6-amino-9H-purin-9-yl),-methyl] cyclopropyl}oxy)methylphosphonate(Compound 48) To the methylphosphonic acid prepared in Example 1 (150mg) was added dropwise dichloromethane. 0.73ml of N,N-diethyltrimethylsilylamine was added dropwise thereto, and the resulting mixture was stirred at room temperature for 2 hours. Oxalyl 8 chloride (0.15ml) and 2 drops of dimethylformamide were added to the reaction vessel. The mixture was stirred for further 2 hours and the solvent was removed by distillation under reduced pressure. To the residue were added 10ml of pyridine and 2ml of trifluoroethanol, which was then reacted under stirring for 16 hours. The solvent was removed by distillation under reduced pressure and the residue was purified by silica gel column to give the title compound. 1H NMR(CD3OD) 1.02 (m, 4H), 4.30 (d, 2H), 4.53 (m, 6H), 8.40 (s, 1H), 8.46(s, 1H) ESI: 464 [M+H]+ C14H16F6N504P Example 48 Synthesis of bis(2,2,2-trifluoroethyl) ({l-[(2-amino-9H-purin-9-yl)methylJ cyclopropyI}oxy)methylphosphonate(Compound 49) The compound prepared in Example 5 was reacted according to the same procedure as Example 47 to give the title compound. 1H NMR(CDCl3)  0.88 (m, 2H), 1.04 (m, 2H). 4.07 (d, 2H). 4.22 (s. 2H), 4.33 (m. 4H), 5.06 (br.s. 2H), 7.92 (s, 1H), 8.68 (s. 1H) ESI: 464 [M+H]+ C14H16F6N504P Exampk 49 Synthesis of bis(2,2,2-trifluoroethyl) (l-({2-amino-(6-(4-methylphenyl) sulfanyl)-9H-purin-9-yl}methyl)cyclopropyl]oxy}methylphosphonate(Compound 62) The compound prepared in Example 25 was reacted according to the same procedure as Example 47 to give the title compound. 1H NMR(CDCl3)  0.88 (m, 2H), 1.03 (m, 2H). 2.39 (s, 3H). 4.06 (d, 2H), 4.19 (s, 2H), 4.33 (m, 4H), 4.76 (br.s, 2H), 7.22 (d, 2H), 7.50 (d. 2H), 7.82 (s. 1H) ESI: 586 [M+H].+ . C21H22F6N504PS Example 50 Synthesis of bis(2,12-rrifluoroethyl) [(l-{[2-amino-6-hydroxy-9H-purin-9-yl] methyl}cyclopropyl)oxy)methylphosphonate(Compound45) The compound prepared in Example 4 was reacted according to the same procedure as Example 47 to give the title compound. 1H NMR(CDC13)  0.91 (m, 2H), 1.05 (m, 2H), 4.08 (d, 2H), 4.17 (s, 2H), 4.35 (m, 4H), 4.70 (s, 2H), 7.69 (s, 1H) MW=478 [M+H]+ 479 C14H16F6N505P Example 51 Synthesis of bis(2,2,2-trifluoroethyl)(l-{[2-amino-6-cyclopropyIamino-9H-purin-9-yl]methyl}cyclopropyl)oxy]methylphosphonate(Compound 50) The compound prepared in Example 7 was reacted according to the same procedure as Example 47 to give the title compound. 1H NMR(CDC13)  0.60 (br.s, 2H), 0.84 (br.s. 4H), 1.01 (m. 2H), 2.98 (br.s, 1H), 4.05 (d. 2H), 4.14 (m, 4H), 4.70 (br.s. 2H), 5.67 (br.s. 1H). 7.60 (s. 1H) ESI: 519, [M+H]+, C17H21F6N604P Example 52 Synthesis of ({l-((2-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl}oxy) methylphosphonic acid(Compound 98) The 6-chloroguanine derivative prepared in Preparation 12 was reacted according to the same procedure as Example 5 to give the title compound. 1H NMR(MeOH-d4)  0.68 (t, 1H), 1.13 (m. 1H), 1.21 (d, 3H), 1.42 (t, 1H), 3.84 (i. 1H), 3.97 (t. 1H) 4.40 (d. 1H) 4.66 (d. 1H), 8.63 (s. i H), 8.73 (s. 1H) -ESI: 314 (M1)+. C1 1HI6X504P The compound of the present invention exhibits a potent pharmacological effect to a hepatitis B cell line, HepG2.2.15, and a transgenic mouse, widely used for development of a therapeutic agent against hepatitis B, when intravenously or orally adminis'iered. The experimental procedures and results are described below. Experiment 1 Measurement and Analysis of Inhibition Effect against Hepatitis B Virus (HBV) (1) Cell Culture and Treatment with Drugs HepG2.2.15 cell (M.A Shells et al., P.N.A.S. 84, 1005(1987)), a hepatocarcinoma cell line producing hepatitis B virus, was cultured in DMEM medium(GIBCO BRL. #430-22001 containing 10% FBS(Fetus bovine serum, GIBCO BRL. #16000-044). 1% ABAM (Antibiotic-Antimycotic, GIBCO BRL, #16000-028) and 400/µg/ml of geneticin( Sigma, #G-9516) in a T-75 flask under the conditions of 5% CO: incubator and 37ºC by dividing in a ratio of 1:3 at an interval of 3 days. The cells were distributed into a 96-well plate in the amount of 4x104/well and then when 80-90% of cell density was achieved, the old medium was changed with 200µl. of DMEM medium containing 2% FBS. 1% ABAM and 400µg/mlof geneticin. The drug solution was sequentially diluted five-fold each time, from 100 M to 0.16 M. In order to minimize an experimental error, each treatment was repeated 2-3 times for the respective drugs. The medium was changed every two days. On 10 days after the treatment with drug, 100µlof the medium was collected and the degree of inhibition of viral replication by drugs was determined through quantitative PCR (Polymerase Chain Reaction). (2) Determination of Cytotoxicity After 100µl of the medium was collected on 10th day from the treatment with drug, 7.5mginft of MTT (Thiazolyl Blue Tetrazolium Broide. Amresco. #0793-5G> solution was added to each well in the amount of 30µl/well and each cell was cultured for 2 hours in a 5% CO2 incubator at37ºC The solution was discarded, and an sopropanol solution containing 1 • Triton X-l-V. and 0.4µl. of c-HCI was added to ean. meil in the amount of 120µl/well. The cells thus dyed, were transferred to the isopropanol solution by shaking for 2 hours. Absorbance at 540nm was measured by Elisa Reader. (3) PCR Estimation of Inhibition Effect on Hepatitis B Virus Replication The degree of inhibition by drugs on the replication of hepatitis B virus was . determined using the cell culture solution collected on 10th day after the treatment with the drug. The cell culture solution treated with each drug was diluted ten-fold with distilled water and subjected to a pretreatment to destroy the cells by heating them for 15 minutes at 95 ºC. For the PCR amplification of the gene fragment of about 320bp, the 2001-base position that is conserved in all sub-strain of hepatitis B virus and 2319-base position that is between the core antigen gene and polymerase gene were used as 5'-end and 3'-end primer, respectively. Then, the amount of genomic DNA of hepatitis B virus was quantified, and the inhibitory effect by drugs on the replication of hepatitis B virus was determined on the basis thereof. First, the cell culture solution of hepatitis B virus that was not treated with drug was sequentially diluted and amplified through the PCR. The amplified DNA was subjected to electrophoresis on 2% agarose, gel and stained with ethidium bromide (EtBn to be analyzed by IS-1000 (Innotech Scientific Corporation) Digital Imaging System. Analysis of the cell culture solution treated with drug was then carried out using the dilution fold in the range where linearity is maintained. The DNA obtained from the group treated with drug was amplified through the same PCR method, subjected to electrophoresis on 2% agarose gel, stained with ethidium bromide, and analyzed by IS-1000. The degree of inhibition by drugs in the viral replication was quantified by calculating the ratio of test group to control group. Table S summarizes the inhibitory-effect (pharmaceutical activity and toxicity) of the typical compounds of the present invention. Table 8 (Table Removed) As can be seen from the results of Table 8, the compound according to the present invention exhibits 4 to 10-fold greater activity than the comparative compound PMEA that is on Phase III in clinical trials. Experiment 2 Pharmacological Test on Transgenic mouse (T/G mouse) The compounds were administered via subcutaneous and oral routes in the following animal test. The test compounds were administered to 4-5 weeks old HBV transgenic mice, which were obtained from FVB strain mice according to a method described in a reference (see, Jone D. Morrey. Kevin W. Bailey, Brent E. Korba, Robert W. Sidwell. "Utilization of transgenic mice replicating high levels of hepatitis B virus for antiviral evaluation of lamivudine" Antiviral research, 1999, 42, 97-108), subcutaneously for 9 days in the amount of 10mg/kg/day and orally for 9 days in the amount of 10, 2 and 0.4mg/kg/day, once a day, respectively (the same number of males and females were used). Blood was collected from the tail of the mouse and 5µl. of serum was obtained. To this serum was added 15ml of Genereleaser sol, which was then pretreated in different temperatures. HBV DNA was taken from the pretreated solution. The DNA was amplified by the PCR (Polymerase Chain Reaction) in the presence of 4µl of 10 x buffer (Perkin Elmer), 0.8µl. of l0mM dNTP, 500ng of the same HBV primers as used in Experiment 1. 2.125mM of MgCl2, DMSO and Taq polymerase. The amount of HBV DNA was analyzed by electrophoresis in order to evaluate a pharmacological effect of the compound of the present invention. The results are described in the following Table 9. In the following Table 9, mice showing pharmacological effect means the mice whose blood does not contain HBV DNA. Table 9 (Table Removed) * The result means ""number of mice showing pharmacological effect / number of total mice As can be seen in the above Table 9, the compound of the present invention shows a potent hepatitis B therapeutic effect in the tested animals when orally or subcutaneouslv administered. Particularly, since the compound of the present invention is superior to the comparative compound PMEA, which is on Phase III in clinical trials, it is expected that the compound of the present invention may be used very effectively for the tr atment of hepatitis B. We claim: l. A phosphonate compound represented by the following formula (2) (Formula Removed) Wherein, R1, R2, R3, R7 and R8 independently of one another represent hydrogen, halogen, hydroxy, amino, C1-C7-alkyl, C2-C6-alkenyl, C1-C5-alkylamino, C1-C5-aminoalkyl, or Cr C5-alkoxy, R4 and R5 independently of one another represent hydrogen, or represent C1-C4-alkyl optionally substituted by one or more substituents selected from the group consisting of halogen (particularly, fluorine), C1-C4-alkoxy, phenoxy, C7-C10-phenylalkoxy and C2-C5-acyloxy, or represent C1-C7-acyl, C6-C12-aryl or optionally substituted carbamoyl, or represent -(CH2)m-OC(=0)-R6 wherein m denotes an integer of 1 to 12 and R6 represents C1-C12-alkyl, C2-C7-alkenyl, C1-C5-alkoxy, C1-C7alkylamino, di(C1-C7-alkyl) amino, C3-C6-cycloalkyl, or 3 to 6-membered heterocyde having 1 or 2 hetero atoms selected from a group consisting of nitrogen and oxygen, Y represents -0-, -S-, -CH(Z)-, =C(Z)-, -N(Z)-, =N-,-SiH(Z)-, or =Si(Z)-, wherein Z represents hydrogen, hydroxy or halogen, or represents C1-C7-alkyl, C1-C5-alkoxy, allyl, hydroxy-C1-C7-alkyl, C1-C7aminoalkyl or phenyl, and L represents a leaving group 2. A phosphonate compound represented by the formula (2) substantially as herein described with reference to the foregoing description and the accompanying table and examples.

Full Text

1
NOVEL ACYCLIC NUCLEOSIDE PHOSPHONATE DERIVATIVES,
SALTS THEREOF AND PROCESS FOR THE PREPARATION OF
THE SAME
TECHNICAL FIELD
The present invention relates to an acyclic nucleoside phosphonate derivative represented by the following formula (1):
(Formula Removed)

in which
lii:: represents single bond or double bond,
R1. R2, R3, R7 and R8 independently of one another represent hydrogen, halogen, hydroxy, amino, C1-C7-alkyl, C2-C6-aIkenyl, C1-C5-alkylamino, C1-C5-aminoalkyl, or C1-C5-alkoxy.
R4 and R3 independently of one another represent hydrogen, or represent C1-G4-alkyl optionally substituted by one or more substituents selected from the group consisting of halogen (particularly, fluorine), CrGralkoxy, phenoxy, C7-C10-phenylalkoxy and C2-C5-acyloxy, or represent C1-C7-acyl, C6-C12-aryl or optionally substituted carbamoyl, or represent -(CH2)m-OC(=O)-R6 wherein m denotes an integer of 1 to 12 and R6 represents C1-C12-alkyl, C2-C7-alkenyl. C1-C5-aIkoxy, C1-C7-alkylamino, di(C1-C7-alkyl)amino, C3-C6-cycloalkyl, or 3 to 6-membered heterocycle having 1 or 2 hetero atoms selected from a group consisting of nitrogen and oxygen,
Y represents -0-, -S-, -CH(Z)-, =C(Z)-. -N(Z)-, =N-, -SiH(Z)-. or =Si(Z)-, wherein Z represents hydrogen, hydroxy or halogen, or represents C1-C-alkyl, C1-C5-alkoxy. allyl, hydroxy-C1-C7-alkyI, C1-C7-aminoalkyl or phenyl,
Q represents a group having the following formula:
(Formula Removed)
wherein
X1, X2, X3 and X4 independently of one another represent hydrogen, amino, hydroxy or halogen, or represent C1-C7-alkyl, C1-C5-alkoxy, allyl, hydroxy-C1-C7-alkyl, phenyl or phenoxy each of which is'optionally substituted by nitro or C1-C5-alkoxy, or represent C6-C10-arylthio which is optionally substituted by nitro, amino, C1-C6-alkyl or C1-C4-alkoxy, or represent C6-C12-arylamino, C1-C7-alkylamino, di(C1-C7-alkyl)amino.
o+
C3-C6-cycloalkylamino or a structure of ™ wherein n denotes an integer of 1 or 2 and Y1 represents O, CH2 or N-R (R represents C1-C7-alkyl or C6-C12-aryl),
which is useful as an antiviral agent (particularly, against hepatitis B virus).
pharmaceutically acceptable salts, stereoisomers, and a process for the preparation thereof.
BACKGROUND ART
Purine or pyrimidine derivatives have anti-cancer and antiviral activities, and more than 10 kinds of the compounds including AZT, 3TC and ACV have already been commercialized. Particularly, since acyclic nucleoside phosphonate derivatives show a potent antiviral effect, cidopovir has been commercialized as an antiviral agent and many compounds including PMEA and PMPA now entered into the step of clinical trials. However, the earlier developed compounds were not perfect in the aspects of toxicity or pharmaceutical activity, and thus, it is still desired to develop a compound having no toxicity as well as a superior activity. The prior researches for purine or pyrimidine derivatives or acyclic nucleoside phosphonate derivatives as reported heretofore are as follows. Patents: US 5817647; US 5977061; US5886179; US 5837871; US 6069249; WO 99/09031; WO96/09307; WO95/22330; US 5935946; US 5877166; US 5792756; Journals: International Journal of Antimicrobial Agents 12 (1999), 81-95; Nature 323 (1986), 464: Heterocycles 31(1990), 1571; J. Med. Chem. 42 (1999), 2064; Pharmacology & Therapeutics 85 (2000), 251; Antiviral Chemistry & Chemotherapy 5 (1994), 57-63.: Bioorganic & Medicinal Chemistry Letters 10 (2000) 2687-2690; Biochemical Pharmacology 60 (2000), 1907-1913; Antiviral Chemistry & Chemotherapy 8 (1997) 557-564; Antimicrobial Agent and Chemotherapy 42 (1999) 2885-2892.
DISCLOSURE OF INVENTION
Thus, the present inventors extensively studied to develop a compound having a superior biological activity (pharmaceutical effect) to as well as a lower toxicity than the existing acyclic nucleoside phosphonates commercialized or entered into the step of clinical trials. As a result, we found that the above compound of formula (1) characterized by its unique chemical structure exhibits a potent pharmaceutical activity, and then completed the present invention.
Therefore, one object of the present invention is to provide the compound of formula (I) having a good use of antiviral agent, pharmaceutically acceptable salts or isomers thereof.
It is another object of the present invention to provide a process for the preparation of the compound of formula (1).
It is still another object of the present invention to provide intermediates which are advantageously used for the preparation of the compound of formula (I).
BEST MODE FOR CARRYING OUT THE INVENTION
The compound of formula (1) according to the present invention, as represented below, is a type of acyclic nucleoside phosphonate derivative having a natural base, such as for example, adenine, guanine, uracil, cytosine, thymine or derivatives thereof:
(Formula Removed)

in which
—represents single bond or double bond.
R1, R2, R3, R7 and R8 independently of one another represent hydrogens halogen, hydroxy.

amino, C1-Cralkyl, C2-C6-alkenyl, C1-C5-alkylamino, C1-C5-aminoalkyl, or C1-C5-alkoxy,
R4and R5 independently of one another represent hydrogen, or represent C1-C4-alkyl optionally substituted by one or more substituents selected from the group consisting of halogen (particularly, fluorine), CrC4-alkoxy, phenoxy, C7-C10-phenylalkoxy and C2-C5-acyIoxy, or represent C1-C7-acyl, C6-C12-aryl or optionally substituted carbamoyl, or represent -(CH2)m-OC(=O)-R6 wherein m denotes an integer of 1 to 12 and R6 represents C1-C12-alkyl, C2-C7-alkenyl, C1-C5-alkoxy, C1-C7-alkylamino. di(C1-C7-alkyl)amino, C3-C6-cycloalkyl, or 3 to 6-membered heterocycle having 1 or 2 hetero atoms selected from a group consisting of nitrogen and oxygen,
Y represents -0-, -S-, -CH(Z)-, =C(Z)-, -N(Z)-, =N-, -SiH(Z)-, or =Si(Z)-, wherein Z represents hydrogen, hydroxy or halogen, or represents C1-C7-alkyl, C1-C5-alkoxy. allyl, hydroxy-C1-C7-alkyl, C1-C7-aminoaIkyI or phenyl,
Q represents a group having the following formula:
(Formula Removed)

wherein
X1, X2, X3 and X4 independently of one another represent hydrogen, amino, hydroxy or halogen, or represent C1-C7-alkyI, C1-C5-alkoxy, allyl, hydroxy-C1-C7-alkyl. phenyl or phenoxy each of which is optionally substituted by nitro or C1-C5-alkoxy, or represent C6-C10-arylthio which is optionally substituted by nitro, amino, C1-C6-alkyl or C1-C4-alkoxy, or represent C6-C12-arylamino. C1-C7-alkylamino. di(C1-C7-alkyl)amino.
C3-C6-cycloalkylamino or a structure of (Formula Removed) wherein n denotes an integer of 1 or 2 and Y1 represents O, CH2 or N-R (R represents C1-C7-alkyl or C6-C12-aryl).
Since the compound of formula (1) according to the present invention may have one or more asymmetric carbon atoms in the structure depending on the kind of substituents, it can be present in the form of the individual enantiomers, diastereomers, or mixtures thereof including racemate. Further, when a double bond is included in the structure, it can be present in the form of E or Z isomer. Thus, the present invention also includes all, of these isomers and their mixtures.
Also, the compound of formula (1) according to the present invention can form a pharmaceutically acceptable salt Such salt includes non-toxic acid addition salt containing pharmaceutically acceptable anion, for example a salt with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydriodic acid, etc., a salt with organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, etc., or a salt with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc., particularly preferably with sulfuric acid, methanesulfonic acid or hydrohalic acid, etc.
Among the compound of formula (1) showing a potent pharmaceutical activity, the
preferred compounds are those wherein
— represents single bond,
R1, R2, R3, R7 and R8 independently of one another represent hydrogen, fluorine, hydroxy, C1-C7-alkyl, C2-C6-alkenyl, C1-C5-alkylamino, C1-C5-aminoalkyl. or C1-C5-alkoxy,
R4 and R5 independently of one another represent hydrogen, or represent d-d-alky! optionally substituted by one or more substituenis selected from the group consisting of fluorine, C1-C4ralkoxy and phenoxy, or represent carbamoyl substituted by C1-C5-alkyl, or represent -(CH2)m-OC(=O)-R° wherein m denotes an integer of 1 to 12 and R6 represents C1-C12-alkyl, C2-C7-alkenyl, C1-C5-alkoxy, C1-C7-alkylamino, di(C1-C7-alkyl)amino, C1-C6-cycloalkyl, or 3 to 6-membered heterocycle having 1 or 2 hetero atoms selected from a group consisting of nitrogen and oxygen,
Y represents -0-, -S-, or -N(Z)-, wherein Z represents hydrogen, hydroxy, C1-C7-alkyl. or hydroxy-C1-C7-alkyl,
Q represents a group having the following formula:
(Formula Removed)
wherein
X1 represents hydrogen, amino, hydroxy or halogen, or represents C1-C7-alkyl, C1-C5-alkoxy, hydroxy-C1-C7-alkyl or phenoxy each of which is optionally substituted by nitro or C1-C5-alkoxy, or represents C6-C10-arylthio which is optionally substituted by nitro, amino, C1-C6flkyl or C1-C4-alkoxy, or represents C6-C12-arylamino. C1-C7-alkylamino, di(C1-C7-alkyl)amino, C3-C6cycloalkylamino or a structure of
an integer of 1 or 2 and Y1 represents O, CH2or N-R (R represents C1-C7-alkyl), and X2, X3 and X4 independently of one another represent hydrogen, amino, hydroxy, halogen, C1-Cr-alkyl, C1-C5-alkoxy, or C1-C7-alkylamino.
Most preferred compounds are those wherein — represents single bond, R1, R3, R7 and R8 independently of one another represent hydrogen, R2 represents hydrogen or methyl, R4 and R5 independently of one another represent t-butylcarbonyloxymethyl, isopropoxycarbonyloxymethyl or 2,2,2-trifluoroethyl, Y represents -0-, Q represents
-(Formula Removed)

wherein X1 represents hydrogen, hydroxy, ethoxy, 4-methoxyphenylthio or 4-nitrophenylthio, and X2 represents amino.
Typical examples of the compound of formula (1) according to the present invention are described in the following Tables 1 and 7.
(Table Removed)

1to23 Table
(Formula Removed)

More particularly preferable compounds among the compounds described in the
above Tables 1 and 7 are as follows:
."> ([ 1 -[(6-amino-9H-purin-9-yl)methyl]cyclopropylloxy)methylphosphonie acid
(Compound I);
3-[( 1 -[(6-amino-9H-purin-9-yl)methyl]cyclppropyl }oxy)methyl]-8,8-dimethyl-3.7-dioxo-2,4,6-rrioxa-3 5-phosphanon-1-yl pivalate(Compound 2);
([1 -[(2-amino-6-chloro-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonic

acid(Compound 3);
3-[( {1 -[(2-amino-6-cbloro-9H-purin-9-yl)methyl]cyclopropyl} oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3 5-phosphanonrl-yl pivalate(Compound 4);
({1 -[(2-amino-6-hydroxy-9H-purin-9-yl)methylJcyclopropyl }oxy)methyl phosphonic acid(Compound S):
3-[({1-[(2-amino-6-hydroxy-9H-purin-9-yl)methyI]cyclopropyl!oxy)methyl]-8.v dimethyl-3.7-dioxo-2,4,6-trioxa-3 5-phosphanon-1-yl pivaJate(Compound 6):
([ 1 -[(2-amino-6-fluoro-9H-purin-9-yl)methyl]cyclopropyl ; oxy)methylphosphonie acid(Compcund 7);
3-[( {1 -[(2-amirio-6-fluoro-9H-purin-9-yl)methyl]cyclopropyl J oxy )methyl]-X.S-dimethyl-3.7-dioxo-2.4,6-trioxa-3 -phosphanon-l-yl pivalate(Compound 8):
([1 -[(2-amino-9H-purin-9-yi imethyl]cyclopropyl! oxyjmethylphosphonic acid (Compound 9):
3-[( J l-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl]oxy(methyl]-.S.s-dimethyl- • 3.7-dioxo-2.4.6-trioxa-3 '5-phosphanon-l-yl pivalatc(Compound 10):
(! 1 -[(2-amino-6-cydopropyiamino-9H-purin-9-yl)meihyl]cyclopropyl: oxy) meth-ylphosphonio acid(Compound 11):
3-[(1-[(2-amino-6-cyclopropylamino-9H-purin-9-yl )methyl ]cyclopropyl i oxy) methyl]-8.8-dimethyl-3.7-dioxo-2.4..0-trioxa-3 5-phosphanon-1 -yl pi valate( Compound 12)
[(1 - {[2-amino-6-(dimethylamino)-9H-purin-9-yl]methyl; cyclopropyl loxy]methy. phosphonic acid(Compound 15):
3-![(1 - {[2-amino-6-ldimethylamino)-9H-purin-9-y|]methyl! cyclopropyl )oxy| methyl | -8.8-dimethyl-3,7-dioxo-2.4.o-trioxa-3 5-phosphanon-1 -yl pivalate(Compound 16);
[(1 [2-amino-6-(isopropylamino)-9H-purin-9-yl]methyI \ cyclopropyl )oxy]methy: phosphonic acid(Compound 17):
3-![(l-{[2-amino-6-(isopropyiamino)-9H-purin-9-y|]methyi;cyclopropyl)oxy] methyl }-8.8-dimethyl-3,7-dioxo-2.4.0-rrioxa-3 5-phosphanon-l-yl pivalate(Compound 18);
(! l-[(2,6-diamino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid(Compound 19);
3-[(1 1 -[(2.6-diamino-9H-punn-9-yl)methyl]cyclopropyl | oxy)methyl]-8.8-dimethyl-3.7-dioxo-2,4.6-trioxa-3 5-phosphanon-l-yl pivalate(Compound 20):
(; l-[(2-amino-6-methoxy-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl phosphonic acid (Compound 21):
3-[( {I-[(2-amino-6-methoxy-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8.8-
dimethyl-3,7-dioxo-2,4,6-trioxa-3 5-phosphanon-l-yI pivalate(Compound 22); ({1 -[(2-amino-6-ethoxy-9H-purin-9-yl)methyl]cycIopropyl} oxy)methyl phosphonic acid (Compound 23);
3-[( {l-[(2-amino-6-ethoxy-9H-purin-9-yl)methyl]cyclopropyl }oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3 5-phosphanon-l-yl pivalate(Compound 24);
({l-[(2-amino-6-methyl-9H-purin-9-yl)methyl]cycIopropyl; oxy)methyl phosphonic acid(Compound 25);
3-[(1 1 -[(2-amino-6-methyl-9H-purin-9-yl)methyl]cyclopropl] oxy)methyl]-8.8-dimethyl-3,7-dioxo-2,4,6-trioxa-3 3-phosphanon-l-yI pivalate(Compound 26):
[(1-{[5-methyl-2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]methyl J cyclopropyl )oxy ]methylphosphonic acid(Compound 31):
8,8-dimethyI-3- {[(1 -! [5-methyl-2.4-dioxo-3.4-dihydro-1 (2H )-pyrimidinyl ]methyl J cyclopropyl)oxy]methyl}-3.7-dioxo-2.4.6-trioxa-3 5-phosphanon-1 -yl pivalate (Compound 32):
[(1- [2-amino-6-(4-morpholinyl )-9H-purin-9-yl]methyl] cyclopropyl )oxy|merhyi phosphonic acid(Comp'ound 37);
3-![(l-{[2-amino-6-(4-morpholinyl)-9H-purin-9-yI]methyl | cyclopropyl )oxy] met-hyl} -8,8-dimethyl-3,7-dioxo-2.4,6-trioxa-3 5-phosphanon-1 -yl pivalate( Compound 38);
bis(2.2.2-trifluoroethyl) (! l-[(2amino-6-hydroxy-9H-purin-9-yl)methyl] cyclopropyl}oxy)methylphosphonate (Compound 45):
bis(2.2.2-trifluoroethyl) (! l-[(2-amino-6-chloro-9H-purin-9-yl)methyl] cyclopropyl | oxy)methylphosphonate(Compound 46):
bis(2.2.2-trifluoroediyl) ({1-[(2.6-diamino-9H-purin-9-yl)merhyl]cyclopropyl] oxy)methylphosphonate(Compound 47):
bis(2.2,2-trifluoroethyl) (| l-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl] oxy)methylphosphonate(Compound 48):
bis(2.2,2-trifluoroethyl) ([ l-[(2-amino-9H-purin-9-yl)methyljcyclopropyl] oxy)methylphosphonate(Compound 49);
bis(2.2,2-trifluoroethyl) ({l-[(2-amino-6-dimethylamino-9H-purin-9-yl)meth\ I] cyclopropyl }oxy)methylphosphonate( Compound 52);
bis(2.2,2-trifluoroethyl) ({1 -[(2-amino-6-isopropyIamino-9H-purin-9-yl) methyl)cycIopropyl}oxy)methylphosphonate(Compound 53);
bis(2,2,2-trifluoroethyl) ({t-[(2-amino-6-methoxy-9H-purin-9-yl)methyl] cyclopropyl }oxy)methylphosphonate(Compound 54):
bis(2.2.2-trifluoroethyl) [(l-{[2-amino-6-(4-morpholinyl)-9H-purin-9-yl]methyl; cyclopropyl)oxy]methylphosphonatc(Compound 58):
bis(2,2,2-trifluoroethyl) [(1 - {[2-amino-6-(phenylsuIfanyl)-9H-purin-9-yl] methyl} cyclopropyl)oxy]methylphosphonate(Compound 61);
bis(2,2,2-trifluoroethyl) {[1-({2-amino-6-[(4-methylphenyl)sulfanyl]-9H-purin-9-yl} methyl )cyclopropyl]oxy} methyIphosphonatc(Compound 62);
bis(2,2,2-trifluoroethyl) {[1-({2-amino-6-[(4-methoxyphenyl)sulfanyl]-9H-purin-9-yl} methyl)cyclopropyl]oxy} methylphosphonate(Compound 63): bis(2.2.2-trifluoroethyl) {[I-({2-amino-6-[(4-nitrophenyl)sulfanyl]-9H-purin-9-yl} methyl)cyclopropyl]oxy}methylphosphonate(Compound 64):
[(1 - {[2-amino-6-(phenylsulfanyl )-9H-purin-9-yl]methyl | cyclopropyl )oxy]methyl phosphonic acid(Compound 65);
{[ 1 -(12-amino-6-[(4-methylphenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl] oxyjmethylphosphonic acid(Compound 66);
3-( |[l-( 12-amino-6-[(4-methylphenyl)sultanyl]-9H-purin-9-yl]methyl)cyclo propyljoxyl methyl)-8.8-dimethyl-3.7-dioxo-2.4.6-trioxa-3 5-phosphanon-1-yl pivalate (Compound 68):
bis {[(t-butoxycarbonyl)oxy]methyl}(| l-[(2-amino-9H-purin-9-yl)methyl]cyclo propyl }oxy)methylphosphonate(Compound 69):
bis{[(isopropoxycarbonyl)oxy]methyl[(11-[(2-amino-9H-purin-9-yl)methyl]cyclo propyl! oxy)methylphosphonate (Compound 70):
bis J [(ethoxycarbonyl)oxy]methyl}({1 -[(2-amino-9H-purin-9-yl )methy 1 ]cyclo propyl ]oxy)methylphosphonate (Compound 71):
bis J[(isobutoxycarbonyl)oxy]methyl}(; l-[(2-amino-9H-purin-9-yl)mothyl]eyclo propyl foxy )methylphosphonate (Compound 72):
3-[( {1 -[(2-amino-9H-purin-9-yl)methyl]cyclopropyl }oxy)methyi]-9-methyl-3.7-dioxo-2.4,6-trioxa-3 5-phosphadec-I-yI 3-methylbutanoate(Compound 74);
3-[( {1 -[(2-amino-9H-purin-9-yl)methyl]cyclopropyl }oxy)methyl]-8-methyl-3.7-dioxo-2.4.6-trioxa-3 5-phosphanon-1-yl 2-methylpropanoate(Compound 78);
3-( [[ I-(12-amino-6-[(4-methoxyphenyl)sulfanyl]-9H-purin-9-yl i methyl)cyclo propyl]oxy| methyJ)-8.8-dimethyI-3.7-dioxo-2.4.6-trioxa-3 5-phosphanon-1-yl pivalate (Compound 79):
3-[(1 l-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-3.7-dioxo-7-( I-pyrrolidinyl)-2.4.6-trioxa-3 5-phosphahept-l-yl l-pyrrolidinecarboxylate(Compound SO): 3-[(1 l-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-3,7-dioxo-7-( I-piperidinyl)-2,4.6-rrioxa-3 5-phosphahept-l-yl 1-piperidinecarboxylate(Compound 81):
3-[(1 -[(2-amino-9H-purin-9-yl)methyl]cyclopropyl }oxy)methyl]-7-(4-morpholi-nyl)-3.7-dioxo-2,4,6-trioxa-3 5-phosphahept- 1-yl 4-morpholinecarboxylate(Compound 82):
is{[(t-butoxycarbonyl)oxy]methyl}[(l-{[2-amino-6-hydroxy-9H-purin-9-yl] methyl}cyclopropyl)oxy]methylphosphonate(Compound 83);
bis {[(isopropoxycarbonyl)oxy]methyl} [(1 - {[2-amino-6-hydroxy-9H-purin-9-yl] methyl} cyclopropyl)oxy]methylphosphonate(Compound 84);
bis {[(isopropoxycarbonyl)oxy]methyl} {[ 1 -({2-amino-[6-(4-methoxyphenyl) sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl]oxy}methylphosphonate(Compound 85);
3-[( {l-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-7-cyclopentyl-3,7-dioxo-2.4,6-trioxa-3 5-phosphahept-1-yl cyclopentanecarboxviate (Compound 86);
3-( {[ 1 -({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purin-9-yl} methyl )cyclopropyl] oxy] methyl)-8,8-dimethyl-3.7-dioxo-2,4,6-trioxa-3 5-phosphanon-1 -yl pivalate (Compound 87);
bis{[(isopropoxycarbonyl)oxy]methyl] [l-(12-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl]oxy}methylphosphonate(Compound 88):
bis {[(isopropoxycarbonyl)oxy]methyl} ({1 -[(6-amino-9H-purin-9-yl )methyl]cyclo-propyl }oxy)methylphosphonate(Compound 89);
3-[( {1 -[(6-amino-9H-purin-9-yl)methyl]cyclopropyl }oxy)methyl]-9-methyl-3.7-dioxo-2,4,6-trioxa-3 5-phosphadec-1-yl 3-methylbutanoate(Compound 90);
3-[( {1 -[(6-amino-9H-purin-9-yl)methyl]cyclopropyl }oxy)methyI]-7-cyclopentyl-3.7-dioxo-2,4.6-trioxa-3 5-phosphahept-l-yl cyclopentanecarboxylate(Compound 91):
bis {[(t-butoxycarbonyl )oxy]methyl}{[ 1-({2-amino-[6-(4-methoxyphenyl )sul fiinyl ] -9H-purin-9-yl} methyl)cyclopropyl]oxy,lmethylphosphonate(Compound 92):
bis{[(t-butoxycarbonyl)oxy]methyl} {[l-(;2-amino-[6-(4-hitrophenyl)sult*anyl]-9H -purin-9-yl} methyl)cyclopropyl]oxy} methylphosphonate(Compound 93);
{[ 1 -({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purin-9-yl} methyl)cyclopropyl]oxy i methylphosphonic acid(Compound 95);
{[l-({2-amino-[6-(4-methoxyphenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl] oxyj methylphosphonic acid(Compound 96);
({1 -[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]-2-methylcyclopropyl J oxy) methylphosphonic acidi(Compound 97);
({1 -[(2-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl }oxy)methylphosphonic acid( Compound 98);
J [ 1 -({2-amino-[6-(4-methoxyphenyl)sulfanyl]-9H-purin-9-yl }methyl)-2-methyl oyclopropyl]oxy} methylphosphonic acid(Compound 99):
| [ 1 -({2-amino-[6-(4-nitrophenyl)su;lfanyI]-9H-purin-9-yl \ methyl)-2-methylcyclo-propyl]oxy} methylphosphonic acid(Compound 100);
{[ 1-({2-amino-[6-(4-methylphenyl)sulfanyl]-9H-purin-9-yl} methyl )-2-methyl

cyclopropyl]oxy}methylphosphonic acid(Compound 101);
({1 -[(2,6-diamino-9H-purin-9-yl)methyI]-2-methylcyclopropyl} oxy)methyl phosphonic acid(Compound 102);
({1 -[(6-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl} oxy)methylphosphonic acid(Compound 103);
3-[( {1 -[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]-2-methylcyclopropyl J oxy) methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3 5-phosphanon-1-yl pivalate(Compound 105);
3-[({ 1 -[(2-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl}oxy)methyl]-8.8-dimethyl-3,7-dioxo-2.4.6-trioxa-3 5-phosphanon-1-yl pivalate(Compound 106):
3-[({1-[(6-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl!oxy)methyl]-8.8-dimethyl-3.7-dioxo-2.4.6-trioxa-3 5-phosphanon-1-yl pivalate(Compound 107):
3-({[l-( !2-amino-6-[(4-methoxyphenyl)sulfanyl;-9H-purin-9-yl } methyl )-2-methyl cyclopropyljoxy! methyl)-8.8-dimethyl-3.7-dioxo-2,4.6-irioxa-3 5-phosphanon-1 -yl pivalate (Compound 108):
bis{[(isopropoxycarbonyl)oxy]methyi; [(1- i[2-arnino-6-hydroxy-9H-purin-9-yl] methyl ]-2-methylcyclopropyl)oxy]methylphosphonate( Compound 109):
bis{[(isopropoxycarbonyl)oxy]methyl}({l-[(2-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl}oxy)rnethylphosphonate(Compound 110);
bis {[(isopropoxycarbonyl)oxy]methyl} {[ 1 -({2-amino-[6-(4-methoxypheny I) sulfanylj-9H-purin-9-yl} methyl)-2-methylcyclopropyl]oxy; methylphosphonate (Compound 112);
bis{[(t-butoxycarbonyl)oxy]methyl},'[1-(12-amino-[6-(4-methoxyphenyl)sulf'anyl] -9H-purin-9-yl }methyl)-2-methylcyclopropyl]oxy} methylphosphonate( Compound 113);
bis(2,2,2-trifluoroethyl){ [ l-( {2-amino-6-[(4-methoxyphenyl)sulfanylj-9H-purin-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate(Compound 114);
bis(2,2,2-trifluoroethyl) {[I-({2-amino-6-[(4-nitrophenyl)sulfanyl]-9H-purin-9-yl} methyl)-2-methylcyclopropyl] oxy}methylphosphonate( Compound 115):
bis{[(t-butoxycarbonyl)oxy]methyl] [1-(12-amino-[6-(4-nitrophenyl)sult'anyl]-9H -purin-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate(Compound 116):
bis{[(isopropoxycarbonyl)oxy]methyl] [ 1 -({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purin-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate( Compound 117); 3-( {[ 1 -({2-amino-6-[(4-nitrophenyl)suli'anyl]-9H-purin-9-yl} methyl)-2-methyl cyclopropyljoxy} methyl)-8.8-dimethyl-3.7-dioxo-2,4,6-trioxa-3 5-phosphanon-1-yl pivalate (Compound 118);
({1 -[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl} amino)methyl phosphonic acid( Compound 119);
{1 -[(2-amino-9H-purin-9-yl)methyl]cyclopropyl} amino)methylphosphonic acid(Compound 120);
({1 -[(6-amino-9H-purin-9-yl)methyI]cyclopropyl} amino)methylphosphonic acid(Compound 121);
[ {1 -[(2-amino-6-hydroxy-9H-purin-9-yl jmethyl]cyclopropyl (methyl)amino] methylphosphonic acid(Compound 122):
[ {1 -[(6-amino-9H-purin-9-yl)methyl]cyclopropyl {(ethyl)amino]methylphosphonic acid(Compound 125);
3-{[{(l-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl)( methyl )amino)methyl)-8.8-dimethyl-3.7-dioxo-2,4,6-trioxa-3 5-phosphanon-l-yl pivalate(Compound 126):
bis{[(isopropoxycarbonyl)oxy]methyl } [{1-[(6-amino-9H-purin-9-yl)methyl]cyclo propyl}( methyl )amino]methylphosphonate( Compound 127):
3-1[{ l-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl!(ethyl)amino]methyl} -.8.8-dimethyl-3,7-dioxo-2,4,6-trioxa-3 5-phosphanon-l-yl pivalate(Compound 129):
(E)-2-{I-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl}ethenyl phosphonic acid(Compound 130):
(E)-2-{l-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}ethenylphosphonic acid (Compound 131);
(E)-2-{I-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl]ethenylphosphonic acid (Compound 132);
3-((E)-2-{ l-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl]ethenyl)-.8.8-dimethyl-3,7-dioxo-2,4,6-trioxa-3 5-phosphanon-l-yl pivalate(Compound 133):
3-((E)-2-{l-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl]ethenyl)-8.8-dimethyl-3.7-dioxo-2,4,6-trioxa-3 5-phosphanon-1-yl pivalate(Compound 134):
(E)-2- {1 -[(6-amino-9H-purin-9-yl)methyl]cyclopropyl} -1 -propenylphosphonic acid(Compound 137):
2-{ l-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl | ethylphosphonic acid(Compound 138);
2- {1 -[(2-amino-9H-purin-9-yl)methyl]cyclopropyl} ethylphosphonic acid (Compound 139);
2- {1-[(6-amino-9H-purin-9-yl)methyl]eycIopropyl}ethylphosphonic acid (Compound 140);
2-[ 1 -({2-amino-6-[(4-methylphenyl)sulfanyl]-9H-purin-9-yl} methyl )cyclopropyl ] ethylphosphonic acid(Compound 141):
2-{ l-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl | propylphosphonic acid( Compound 142):
2- {1 -[(6-amino-9H-purin-9-yl)methyl]cyclopropyl j propylphosphonic acid
(Compound 143);
2-{1 -[(2-amino-9H-purin-9-yl)methyl]cyclopropyl }propylphosphonic acid (Compound 144);
3-(2-{l-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}propyl)-8,8-dimethyl-3,7-dioxo-2,4.6-trioxa-3 5-phosphanon-I-yl pivalate(Compound 145):
({l-[(2-amino-6-hydroxy-9H-purin-9-yl)methyI]-2,2-dimethylcyclopropyl j oxy) methylphosphonic acid(Compound 146);
({ l-[(2-amino-9H-purin-9-yl)methyl]-2,2-dimethylcyclopropyl }oxy)methyl phosphonic acid(Compound 147);
({1 -[(6-amino-9H-purin-9-yl)methyl]-2,2-dimethylcyclopropyl} oxy)methy] . phosphonic acid(Compound 148):
3-[(,' I-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]-2,2-dimethylcyclopropyl]oxy methyl]-8.8-dimethyl-3.7-dioxo-2.4.6-trioxa-3 5-phosphanon-1 -yl pivalate(Compound 149):
3-[({ l-[(2-amino-9H-purin-9-yl)methyl]-2.2-dimethyIcyclopropyl!oxy)methyl]-8.8 -dimethyl-3.7-dioxo-2.4,6-trioxa-3 .5-phosphanon-l-yl pivalate(Compound 150):
3-[(1 l-[(6-amino-9H-purin-9-yl)methyl]-2.2-dimethylcyclopropyl}oxy)methyl]-8.8
-dimethyl-3.7-dioxo-2,4,6-trioxa-3 5-phosphanon-1-yl pivalate(Compound 151);
bis {[(isopropoxycarbonyl)oxy]methyl} ({1 -[(6-amino-9H-purin-9-yl)methyl]-2.2-dimethylcyclopropyl}6xy)methylphosphonate(Cornpound 152); and
bis J [(isopropoxycarbonyl)oxy]methyl}[(1-{[2-amino-6-hydroxy-9H-purin-9-yl] methyl} -2.2-dimeth.ylcyclopropyl)oxy]methylphosphonate(Compound 153).
The compound of formula (l) according to the present invention can be prepared by a process as explained below, and thus, it is another object of the present invention to provide such a preparation process. However, conditions of the process, such as for example, reactants, solvents, bases, amounts of the reactants used. etc. are not restricted to those explained below. The compound of the present invention may also be conveniently prepared by optionally combining the various synthetic ways described in the present specification or known in the arts, and such a combination can be easily performed by one of ordinary skill in the art to which the present invention pertains.
The compound of formula (1) of the present invention can be prepared characterized in that
(a) a compound represented by the following formula (2):
(Formula Removed)

in which R1, R2. R3, R4, R5, R7, R8 and Y are defined as previously described, and L represents a leaving group, preferably methanesulfonyloxy. p-toluenesulfonyloxy or halogen, is reacted with a compound represented by the following formula (3):
QH (3)
in which Q is defined as previously described, to produce rhe compound of formula (1).
(b) a compound represented by the following formula (9):
(Formula Removed)

in which Rl, R2 R3 R7, R8 Y and L are defined as previously described, and R9 and R10 independently of one another represent optionally substituted alkyl. is reacted with the compound of formula (3) to produce a compound represented by the following formula (10):
(Formula Removed)

in which R1, R2. R3 R4 R5, Y, Q, R9 and R10are defined as previously described, and the resulting compound of formula (10) is hydrolyzed in the presence of a Lewis acid to produce a compound represented by the following formula (la):

(Formula Removed)

in which R1, R2, R3. R7. R8. Y and Q are defined as previously described, or
(c) groups R4 and R5 are introduced into the compound of formula (la) to produce a compound represented by the following formula (lb):
(Formula Removed)

in which R1, R2, R3, R7, R8, Y and Q are derlned as previously described, and R4 and R5 represent R4 and R3 with the exception of hydrogen, respectively, or further the compounds thus obtained are subjected to conventional conversions (see: USP 6.1)37.335. 5.935.946. and 5.792,756).
In the above process variants (a) to (c) for preparing the compound of formula (1). the reactions may be carried out in a solvent and in the presence of a base. As the solvent, one or more selected from a group consisting of dimethylformamide. dichloromethane. tetrahydrofuran. chloroform, l-methyl-2-pyrrolidinone and dimethylacetamide can be mentioned, and as the base one or more selected from a group consisting of sodium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium t-butoxide, hydrogen bis(trimethylsilyl)amide. sodium amide, cesium carbonate and potassium bis(trimethylsilyl)amide can be mentioned. The Lewis acid which can be used in the process variant (b) includes trimethylsilylhalide. Further, in the process variant (c) for introducing the groups R4 and R5 into the compound of formula (la), this compound is subjected to an ether-forming reaction with an alkylhalide in the, presence of a base, or is treated with thionyl chloride, oxalyl chloride or phosphorus pentachloride to produce a dichlorophosphonate derivative which is then reacted with a
'33 suitable alcohol or amine to give the desired compound.
The phosphonate compound of formula (2) used as a starting material in the above process is itself a novel compound. Therefore, it is another object of the present invention to provide the compound of formula (2).
The compound of formula (2) wherein Y is 0, R1 is hydrogen, and each of R2, R3. R7 and R8 is hydrogen or alkyl, that is, a compound of the following formula (8), can be prepared characterized in that ( i ) an ethylgiycolate. the alcohol group of which is protected, represented by the following formula (Formula Removed)

in which P1 represents an alcohol-protecting group, preferably benzyl(Bn). tetrahydropyranyl(THP), t-butyldiphenylsilyl(TBDPS), or t-butyldimethylsilyl(TBDMS), is reacted with ethyl magnesium bromide[C2H5MgBr] or the corresponding alkyl magnesium bromide or alkyl magnesium chloride in the presence of titanium tetraisopropoxide[Ti(OiPr)4], (ii) the resulting cyclopropanol represented by the following formula (5):
(Formula Removed)

in which P1 is defined as previously described and each of R2, R3, R4 and R'8 represents hydrogen or alkyl, is subjected to an ether-forming reaction in the presence of a base with a compound represented by the following formula {by.
(Formula Removed)
in which L, R4 and R5 are defined as previously described, to produce a phosphonate compound represented by the following formula (7):
(Formula Removed)

m which P1, R1:, R3, R7, R8', R4and R5are defined as previously described, and (in) the alcohol-protecting group of the resulting compound of formula (7) is removed and a leaving group(L) is introduced to produce a compound represented by the following formula (8):
(Formula Removed)

in which L. R2. R3. R7. R8. R4 and R5 are defined as previously described.
The process for preparing the simplest compound of formula (8) (that is. all of R2. R6. R7 and R8 are hydrogen) is briefly depicted in the following Reaction Scheme I.
Reaction Scheme 1
(Formula Removed)
The specific reaction conditions of the above process can be referred to the following Preparations and Examples.
Further, die compound of formula (2) wherein Y is -CH2-, and each of R1. R2. R3. R7 and R8 is hydrogen, that is a compound of the following formula (II):
(Formula Removed)

in which L. R4and R3are defined as previously described, can be prepared by a process as depicrd in the following Reaction Scheme 2:
Reaction Scheme 2
(Scheme Removed)
.
Reaction Scheme 2 is briefly explained below. ( i ) According to a known method isee: JOC. 1975, Vol.40, 2969-2970), dialkylmalonate is reacted with dihaloethane to give malonic acid wherein cyclopropyl group is introduced into its 2-position. (ii) The malonic acid is reduced to give diol compound, one hydroxy group of which is then

protected with a suitable protecting group (P1 is defined as previously described). Then, the other hydroxy group is oxidized to an aldehyde group, (iii) The resulting aldehyde compound is reacted with tetraalkylmethylenediphosphonate to give the desired phosphonate compound, (iv) The phosphonate compound thus obtained is reduced to give a compound having no unsaturated bond, alcohol-protecting group (P1) is removed, and a leaving group (L) is introduced to give the compound of formula (11).
Further, the compound of formula (2) wherein Y is -N(CH3)- and each of R1. R". R3. R7 and R8 is hydrogen, that is a compound of the following formula (12):
(Formula Removed)

in which L. R4 and R5 are defined as previously described, can be prepared by a process as depictd in the following Reaction Scheme 3:
Reaction Scheme 30

(Scheme Removed)
Reaction Scheme 3 is briefly explained below. ( i) Diethyl 1.1cylopropyl
dicarboxylate is selectively hydrolyzed to give a monocarboxylic acid, (ii) An amine group is introduced into the monocarboxylic acid according to the known Curtious Reaction (see: S. Linke, G. T. Tisue and W. Lowowski, J. Am. Chem. Soc. 1967, 89, 6308). (iii) The amine group is protected with a suitable protecting group [P2 may be carbamate or various benzyl protecting groups, or alkyl group (methyl, ethyl, etc.)]. (iv) The opposite ester group is reduced into a hydroxy group, which is then protected (P1 is defined as previously described), (v) The compound protected with protecting groups is reacted with methyl iodide in the presence of sodium hydride to introduce methyl group into the amine group. (vi) The amine-protecting group is removed and the resulting compound is reacted with dialkylbromomethylphosphonate to give the desired phosphonate compound, (vii) The alcohol-protecting group (P1) is removed from the phosphonate compound thus obtained and then a leaving group (L) is introduced to give the compound of formula (12).
The specific reaction conditions of the above processes can be referred to the following Preparations and Examples.
After the reaction is completed, the resulting product may be further separated and purified by usual work-up processes, such as for exampie. chromatography, recrystallization. etc.
The compound of formula (1) of the present invention can be effectively used as an antiviral agent. Therefore, it is another object of the present invention to provide a composition for the treatment of viral diseases, which comprises as an active ingredient the compound of formula (1), pharmaceutically acceptable salt, hydrate, solvate or isomer thereof together with the pharmaceutically acceptable carrier.
When the active compound according to the present invention is used for clinical purpose, it is preferably administered in an amount ranging generally from 0.1 to 10000mg. preferably from 0.5 to 100mg per kg of body weight a day. The total daily dosage may be administered in once or over several times. However, the specific administration dosage for the patient can be varied with the specific compound used, body weight, sex or hygienic condition of the subject patient, diet, time or method of administration, excretion rate, mixing ratio of the agent, severity of the disease to be treated, etc.
The compound of the present invention may be administered in the form of injections or oral preparations.
Injections, for example, sterilized aqueous or oily suspension for injection, can be prepared according to the known procedure using suitable dispersing agent, wetting agent, or suspending agent. Solvents which can be used for preparing injections include water, Ringer's fluid and isotonic NaCl solution, and also sterilized fixing oil may be conveniently used as the solvent or suspending media. Any non-stimulative fixing oil including mono-, di-glyceride may be used for this purpose. Fatty acid such as oleic acid may also be used for injections.
As the solid preparation for oral administration, capsules, tablets, pills, powders and granules, etc., preferably capsules and tablets can be mentioned. It is also desirable for tablets and pills to be formulated into enteric-coated preparation. The solid preparations may be prepared by mixing the active compound of formula (1) according to the present invention with at least one carrier selected from a group consisting of inactive diluents such as sucrose, lactose, starch, etc., lubricants such as magnesium stearate. disintegrating agent and binding agent.
When the compound according to the present invention is clinically applied for obtaining the desired antiviral effect, the active compound of formula (I) can be administered in combination with one or more substances selected from the known anti-cancer or antiviral agents. As the anti-cancer or antiviral agents which can be administered together with the compound of the present invention in such a manner. 5-Fluorouracil, Cisplatin, Doxorubicin, Taxol. Gemcitabine, Lamivudine. etc. can be mentioned.
However, preparations comprising the compound of the present invention are not restricted to those explained above, but may contain any substances useful for the treatment or prevention of cancers or viral diseases.
The present invention will be more specifically explained in the following Examples and Experiments. However, it should be understood that these Examples and Experiments are intended to illustrate the present invention but not in any manner to limit the scope of the present invention.
Preparation 1
Synthesis of l-({|t-butyl(diphenyl)silyl]oxy}methyl)cvciopropanol
According to the description in a reference (see: Syn. Lett. 07, 1053-1054, 1999), the title compound was prepared as follows. 12g(35 mmole) of ethyl 2-{[t-butyl(diphenyl)silyl]oxy} acetate was dissolved in 200ml of tetrahydrofuran(THF) and 2.2ml of titaniumtetraisopropoxide was added thereto. To the mixture was slowly added 29.2mlof ethylmagnesiumbromide(3.0M in THF), and the reaction solution was stirred for 12 hours at room temperature. 20ml of saturated ammonium chloride was added to stop the reaction. About 150ml of tetrahydrofuran (THF) used as a solvent was removed by distillation under reduced pressure, and the reaction mixture was extracted twice with 200ml of ethyl acetate. The ethyl acetate extract was distilled under reduced pressure to give 11.4g( Yield 100%) of the title compound as a white solid.
1H NMR(CDCl3) 5 0.44 (q. 2H), 0.7S (q, 2H). 1.09 Is. 9H). 3.6 is. 2H). 7.41 (m.6H),7.70(m.4H)
ESI: 344 (M+NH4)+, C20H26O2Si
Preparation 2
Synthesis of diisopropyl {[l-({|t-buryl(diphenyl)silyl]oxy}metliyl)cydopropyl] oxy} methylphosphonate
The compound prepared in Preparation 1 (6.5g) was dissolved in lOml' of dimethylformamide(DMF), 32ml of lithium t-butoxide( 1.0M in THF) was added thereto, and the resulting mixture was stirred for 10 minutes. To the mixture was added 7.0g of diisopropyl bromomethylphosphonate, and then the temperature was raised to 40 C and the mixture was stirred for 4 hours. Dimethylformamide(DMF) was removed by distillation under reduced pressure, 40ml of saturated ammonium chloride was added to the residue, which was then extracted with ethyl acetate. The ethyl acetate extract was distilled under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane= 1 /1. v/v) to give G.8g( Yield 70%) of the title compound.
1H NMR(CDCl3) 6 0.53 (m, 2H), 0.88 (m. 2H). 1.07 (s. 9H), 1.29 (t. 12H), 3.78 (s, 2H). 3.98 (d, 6H), 475 (m, 2H), 7.40(m. 611). 7.67(m. 4H)
Preparation 3
Synthesis of diisopropyI{l-f(hydroxymethyl)cyclopropyl]oxy}methyl phosphonate
The compound prepared in Preparation 2 (8.3g) was dissolved in l00ml. of methanol, 3.1g of ammonium fluoride was added thereto, and the resulting mixture was heated under reflux for 2 hours. After the reaction was completed, methanol was removed by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichloromethane/'methanol=20/I, v\v) to give 3.6g(Yield 82%) of the title compound.
1H NMR(CDC13) 5 0.60 (t, 2H), 0.87 (t, 2H), 1.28 (d, 12H), 2.5 (br s. 1H). 3.65 (s. 2H).3.83(d,2H),4.82(m.2H)
ESI:267(M-rl)".CllH2304P
Preparation 4
Synthesis of )l-[(diisopropoxyphosplioryl)methoxy|cyclopropyl[methyl methane- sulfonate
The compound prepared in Preparation 3 (1.5g) was dissolved in 50ml' of dichloromethane, 0.85ml! of triethylamine and 0.84g of methanesulfonylchioride were added thereto, and the resulting mixture was stirred for 30 minutes at room temperature. Saturated ammonium chloride was added to stop the reaction. The product was extracted with dichloromethane. and the dichloromethane extract was concentrated by distillation under reduced pressure. The residue was purified by silica ge! column chromatography(eluent: ethyl acetate/n-hexane=l/l, v/v) to give 1.63g( Yield 81%) of the title compound.
1H NMR(CDCl3) 5 0.77 (m, 2H), 1.09 (m. 2H). 1.32 (m. 12H). 3.10 (s. 3H). 3.82 (m. 2H), 4.33 (s, 2H). 4.71 (m, 2H)
Preparation 5
Synthesis of diisopropyl({l-[(6-amino-9H-purin-9-yl)methyl]cyclopropy!}oxy) methylphosphonate
(Formula Removed)

The compound prepared in Preparation 4 (430mg) was dissolved in 18ml of dimethylformamide, 57.6mg (60% purity) of sodium hydride and 162mg of adenine were added thereto, and the resulting mixture was heated under reflux over 4 hours. Saturated ammonium chloride was added to stop the reaction. The product was extracted with ethyl acetate, and the ethyl acetate extract was distilled under reduced pressure. The residue was purified by silica gel column chromatography!eluent: dichloromethane/methanol=20 I. v, v) to give 20 lmg( Yield 44%) of the title compound.
H NMR(CDC13) 6' 0.86 (t, 2H), 1.01 (t. 2H), 1.24 (d. 6H), 1.34 (d. 6H). 3.NA .d. 2H). 4.34 (s,2H), 4.71 (m, 2H). 5.97 (br s, 2H). 8.32 (s. lH).8.58(s. 1H) ESI: 384 (M+l)+, C16H25N504P
Preparation 6
Synthesis of diisopropyI({l-{(2-amino-6-chloro-9H-purin-9-vl)mcfliy|| cyclopropyl} oxy)methyIphosphonate
(Formula Removed)

The compound prepared in Preparation 4 (l.64g) was dissolved in "Onn of dimethylformamide. 219mg(60% purity) of sodium hydride and 7~3mg of 2-amino-C1-Chloro-9H-purine were added thereto, and the resulting mixture was stirred for 4 hours while heating at a temperature of up to 80 °C. Saturated ammonium chloride was added to stop the reaction. The product was extracted with ethyl acetate, and the ethyl acetate extract was distilled under reduced pressure. The residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol-20/I, v/v) to give 765mg(Yield 40%) of the title compound.
1H NMR(CDCl3) ' 0.80 (t, 2H), 1.02 (t. 2H), 1.27 id. 6H), 1.28 (d, 6H). 3.82 id. 2H).4.21 (s.2H).4.68(m,2H),5.13(brs,2H).8.15(s. 1H)

' 42 ESI: 418 (M+l)+, C16H25CIN504P
Preparation 7
Synthesis of diisopropyl[(l {[5-methyI-2,4-dioxo-3,4-dihydro-l(2H)-
pyrimidinyl]methyl} cyclopropyl)oxy|methylphosphonate
(Formula Removed)

The compound prepared in Preparation 4 (118mg) and thymine were reacted according to the same procedure as Preparation 6 to give 26mgi Yield 2l%)of the title compound.
1H NMR(CDCl3)  0.82 (t, 2H). 0.95 (t, 2H). 1.31 (m 12H), 1.92(s. 311). 3.74 (d. 2H), 3.89 (s. 2H), 4.71 (m. 2H), 7.62 (s. 1H), 9.15 (s, 1H) ESI:375(M+I) C16H27N206P
Preparation 8
Synthesis of l-({[t-butyl(diphenyl)silyl]oxy}methyl)-2-methylcyclopropanol
(Formula Removed)

According to the description in a reference (see: Syn. Let:. 07. 1053-1054, 1999). the title compound was prepared as follows. 50g(146 mmole) of ethyl 2- i[t-butyl(diphenyl)silyl]oxy}acetate was dissolved in 700mC of tetrahydrofuran(THF) and 30.0ml of titaniumtetraisopropoxide was added thereto. To the mixture was slowly added 290ml of propylmagnesiumchloride(2.0M in THF) at -10ºC. and the reaction solution was stirred for. 12 hours at room temperature. 200ml of saturated ammonium chloride was added to stop the reaction. The tctiahydrofuran (THF) used as a solvent was removed by distillation under reduced pressure, and the reaction mixture was extracted
twice with 2000ml of n-hexane. The n-hexane extract was distilled under reduced pressure and purified by silica gel column to give 42g of the title compound.
1H NMR(CDC13)  0.06 (t, 1H), 0.88 (dd, 2H), 0.97 (d, 3H). 1.09 (s, 9H) 1.1 (mr 1H), 2.78 (s, 1H), 3.70 (d, 1H), 3.86 (d, 1H), 7.41 (m. 6H), 7.70 (m. 4H) ESI: 363 (M+Na)+, C21H2802Si
Preparation 9
Synthesis of diisopropyl {[l-({[t-butyl(diphenyl)silyl]oxy}methyl)-2-methyl cyclopropyl]oxy}methylphosphonate
(Formula Removed)

The compound prepared in Preparation 8 (4.2g) was reacted according to the same procedure as Preparation 2 to give 3.3g of the title compound.
1H NMR(CDC13) ' 0.04 (t, 1H). 0.96 (dd. 1H), 0.97 (d. 3H. 1.05 (m. 1H). 1.06 (s, 9H), 1.23 (t. I2H). 3.72 (d. 1H), 3.95 (d. 2H). 3.98 (d. 1H). 4.75 (m. 211). ".40 (m. 611), 7.68 (m, 4H)
Preparation 10
Synthesis of diisopropyl{ l-[(hydroxymethyl)-2-methylcyclopropyl]oxy} methylphosphonate
(Formula Removed)

The compound prepared in Preparation 9 (3.3g) was reacted according to the same procedure as Preparation 3 to give l.7g of the title compound.
1H NMR(CDCL3) ' 0.03 (t. 1H). 0.95 (dd. 1H), 0.96 (m. 1 H). I.N (d.. 3H), 1.35 (d, 12H),2.l7(brs. 1H). 3.80 (d, 2H). 3.96 (d. 1H). 4.80 (m. 211)

ESI: 303 (M+Na)+, C12H22504
Preparation 11
Synthesis of diisopropyl({l-f(6-amino-9H-purin-9-yl)methyl]-2-methyl cycIopropyl}oxy)methylphosphonate
(Formula Removed)

The compound prepared in Preparation 10 (I.5g) was dissolved in 50ML of dichloromethane. O.85ml of triethylamine and 0.84g of methanesulfonylehloride were added thereto, and the resulting mixture was stirred for 30 minutes at room temperature. Saturated ammonium chloride was added to stop the reaction. The product was extracted with dichloromethane and the dichloromethane extract was concentrated by distillation under reduced pressure. The residue was used in the next reaction without any purification.
1H NMR(CDCl3)  0.42 (m, 1H). 1.12 (d. 3H). 1.25 (m. 1H). 1.32 (m. 12H). 1.33 (m. 1H). 3.10 (S.3H), 3.76 (m,2H). 4.31 (d. 1H). 4.71 (d. 1H). 4.76 (m. 2H)
The methanesulfonate thus obtained (430mg) was dissolved in 18ml' of dimethylformamide, and 57.6mg (60% purity) of sodium hydride and 162mg of adenine were added thereto. The reaction mixture was refluxed under heating over 4 hours. Saturated ammonium chloride was added to stop the reaction. The product was extracted with ethyl acetate and the ethyl acetate extract was concentrated by distillation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/l, v/v) to give 201mg(Yield 44%) of the title compound.
lHNMR(CDCl3)  0.53 (t/lH), 1.13 (d,3H), 1.15 (m. 1H). 1.30 (m. 12H). 1.41 (m, 1H), 1.85 (brs, 2H). 3.81 (m, 2H), 4.43 (m. 2H). 4.70 (m, 2H). 5.65 (br s. 2H), 8.26 (s. 1H).8.34(s.1H)
ESI: 398 (M1). C17H28N504P
Preparation 12
Synthesis of diisopropyl({l-[(2-amino-6-chloro-9H-purin-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonate
(Formula Removed)

The compound prepared in Preparation 10 was reacted according to the same procedure as Preparation 11 except that 6-chloroguanine (2-amino-6-chloro-9H-purine) was used instead of adenine to give the title compound.
1H NMR(CDCl3)_  0.47 (t, J=6.4Hz, 1H), 1.12 (m, 4H), 1.24 (dd. J= 2.8Hz. .4Hz.oH). 1.28 (t. J=6.0Hz. 6H). 1.38 (m, 1H), 3.80 (m. 2H),.4.28 (m. 2H). 4.68 (m. 2H). 5.13 (brs. 2H), 8.15 (s, 1H)
ESI: 432 (M+l)+. C17H27C1N504P
Preparation 13
Synthesis of diisopropyl[(l{|5-methyl-2,4-dioxo-3,4-dihydro-l(2H)-
pyrimidinyl]methyl}-2-methylcyclopropyl)oxy|methylphosphonate
(Formula Removed)

The compound prepared in Preparation 10 was reacted according to the same procedure as Preparation 11 except that thymine was used instead of adenine to give the title compound.
1H NMR(CDCL3) 0.48 (t, 1H), 1.10 (m, 4H), 1.24 (dd, 6H), 1.28 (t. J= 6H). 1.38 (m, 1H), 1.92 (s, 3H). 3.80 (m, 2H), 4.28 (m, 2H), 4.68 (m, 2H), 7.62 (s. 1H). 9.15 (s. 1H)
ESI: 389 (M1)+ C17H29N206P
Preparation 14
Synthesis of (-(ethoxycaibonyl)cyclopropanecarboxylie acid
(Formula Removed)

Diethyl 1,1-cyclopropane dicarboxylate (20g) was hydrolyzed in IN NaOH (107 ml.) and ethanol (220ml) for 16 hours, and the ethanol was removed by distillation under reduced pressure. The remaining starting material was removed by using ethyl acetate and the aqueous layer was acidified by IN HC1. The reaction mixture was extracted with ethyl acetate and distilled under reduced pressure. The residue was purified by silica gel column to give the title compound in a yield of 94%.
1HNMR(CDCI3)  1.06 (t.3H), 1.53 (m.2H). 1.62 (m. 2H). 4.21 (q. 2H ESI: 159(M-I)~C7HI0O4
Preparation 15
Synthesis of ethyl l-{((benzyIoxy)carbonyl]amino}cyclopropanecarboxylate
(Formula Removed)

The carboxylic acid prepared in Preparation 14 (16g) was dissolved ;n dichloromethane, l0.8ml of oxalyl chloride was added dropwise, and 2 drops of dimethylformamide was added. The reaction mixture was stirred at room temperature for 3 hours and distilled under reduced pressure to give ethoxycarbonyl 1,1 -cyclopropane carbonylchloride. This compound, not purified, was dissolved in 30im' of dimethylformamide and the resulting solution was cooled with water-ice. 36g of NaV. was added and the reaction was carried out at room temperature for 3 hours. The reaction solution was extracted with 100ml of water and 200ml' of diethylether, and the diethylether extract was concentrated to give crude compound which was purified by silica gel column to give an azide compound.
1H NMR(CDC13)  1.28 (t, 3H), 1.54 (m, 4H), 4.19 (q, 2H)
To the azide compound thus obtained (13g) was added dropwise 11ml of benzyl alcohol and the reaction mixture was heated to 100ºC. by which the reactants were vigorously reacted with each other with the generation of gas. The-reaction mixture was
heated at lOOºC for further 1 hour, cooled to room temperature, and distilled under reduced pressure to remove benzyl alcohol. The residue was purified by silica gel column to give the title compound.
1H NMR(CDC13)  1.19 (m, 5H), 1.54 (m, 2H), 4.11 (m, 2H), 5.15 (br.s, 2H), 7.32 (m. 5H)
Preparation 16
Synthesis of benzyl l-{[t-butyl(diphenylsilyl)oxy|methylcyclopropylJ (methyl)carbamate
(Formula Removed)

The carboxylate prepared in Preparation 15.(13.2g) was dissolved in diethylether. to which 1.3g of LiBH4 dissolved in diethylether was slowly added dropwise. The reaction misture was stirred at room temperature for 16 hours, and 50mC of methanol and 5 ml, of IN HC1 were added dropwise thereto. The reaction mixture was stirred for 2 hours, the precipitate was removed by suction filtration, and the solvent in the filtrate was removed by distillation under reduced pressure. The residue was purified by silica gel column to give benzyl l-(hydroxymethyl)cyclopropylcarbamate.
This compound (9.3g) was dissolved in dichloromethane. and 4.2g of imidazole and 13.5ml(' of t-butyldiphenylsilylchloride were added in order. The reaction mixture was stirred at room temperature for 4 hours and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column to give benzyl l-({[t-butyl(diphenyl)silyl]oxy}methyl)cyclopropylcarbamate.
1H NMR(CDCL3)S 0.71-1.19 (m. 4H). 1.04 (s, 9H). 3.68 (br.s. 2H), 5.04 (s. 211). 7.25-7.45 (m. 11H), 7.62 (d,4H)
The carbamate thus obtained (5.5g) was dissolved in THF. 3.5ml of methane iodide (Mel) was added dropwise and then 1g of NaH was added. The reaction mixture was stirred at room temperature for 4 hours and then extracted with 100ml of diethylether
and lOOml of water. The diethylether extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column to give the title compound.
1H NMR(CDC13)  0.78-0.84 (m, 4H), 1.03 (s, 9H), 3.03 (s, 3H). 3.55- 3.80 (m, 2H), 5.10 (s, 2H), 7.24-7.45 (m, 11H), 7.61 (m, 4H)
Preparation 17
Synthesis of diisopropyl[l-({|t-butyl(diphenyl)silyl]oxy}methyl)cyclopropyl) (methyl)amino|methylphosphonate
(Formula Removed)

The carbamate prepared in Preparation 16 (1.0g) was dissolved in erhanol. lOOmg of 10% Pd/C was added, and the reaction mixture was subjected to a hydrogenation under hydrogen atmosphere. After the reaction was completed, the solvent was removed by-distillation under reduced pressure. The residue was purified by silica gel column to give I -({[t-butyl(diphenyl)silyl]oxy} methyl )-N-methylcyclopropancamine.
1H NMR(CDC13)  0.36 (m. 2H). 0.65 (m, 2H), 1.05 (s. 9H). 2.36 (s. 3H). 3.57 (s, 2H), 7.37-7.45 (m, 11H), 7.66 (d. 4H)
The methylcyclopropaneamine thus obtained (l.Og) was dissolved in dichloromethane, to which l.03mC of diisopropylethylamine and 1.3ml' of (diisopropyl phosphoryl)methyl trifluoromethansulfonate were added dropwise. The reaction mixture was reacted under stirring at room temperature for 4 hours, and then extracted with l00ml' of diethylether and l00ml. of water. The solvent in the diethylether extract was removed by distillation under reduced pressure and the residue was purified by silica gel column to give the title compound.
1H NMR(CDCL3)  0.42 (m. 2H). 0.69 (m, 2H), 1.04 (s. 9H). 1.25 (d, 6H), 1.30, (d, 6H), 2.62 (s, 3H), 3.25 (d, 2H), 3.64 (s. 2H), 4.68 (m, 2H), 7.39 (m. 611), 7.65 (d. 4H)
Preparation 18
Synthesis of diisopropyl(l-{((6-amino-9i/-purin-9-yl)methyl)cyclopropyl} (methyl)amino)methylphosphonate

The compound prepared in Preparation 17 (0.32g; was dissolved in methanol and 1.5g of ammonium fluoride was added dropwise. The reaction mixture was reacted under stirring at 60ºC) for 24 hours and then the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column to give methylaminediisopropylmethylphosphone 1.1-cyclopropane ethyl alcohol.
1H NMR(CDC13)  0.56 (m. 2H). 0.73 (m, 2H). 1.31 (m. 1211). 2.56 (s. 311). 3.11 (d, 2H), 3.55 (s, 2H), 4.70 (m. 2H)
The compound thus obtained was consecutively reacted according to the same procedure as Preparations 4 and 5 to give the title compound.
1H NMR(CDCL3)  0.78 (m, 2H). 0.S6 (m, 2H). 1.25 (m. I2H). 2.35 (s. 311). 4.10 (s. 2H), 4.68 (m 2H), 5.13 (m. 2H), 8.32 (s. 1H). 8.58 (s. 1H) ESI:397(M1)+.C17H29N603P
Preparation 19
Synthesis of diisopropyl(l-{[(2-amino-6-chloro-9H-:puriii-9-yl)methyl] cyclopropyl}(methyl)amino)methylphosphonate
(Formula Removed)

The compound prepared in Preparation 17 (0.32g) was dissolved in methanol and 1.5g of ammonium fluoride was added dropwise. The reaction mixture was reacted under stirring at 60ºC for 24 hours and then the solvent was removed by distillation under
reduced pressure. The residue was purified by silica gel column to give methylaminediisopropylmethylphosphone 1,1-cyclopropane ethyl alcohol.
1H NMR(CDCl3)  0.56 (m, 2H), 0.73 (m, 2H), 1.31 (m, 12H), 2.56 (s. 3H), 3.11 (d, 2H), 3.55 (s, 2H), 4.70 (m, 2H)
The compound thus obtained was consecutively reacted according to the same procedure as Preparations 4 and 6 to give the title compound.
1H NMR(400MHz. CD3OD):  0.79 (m. 2H). 0.89 (m. 2H), 1.26 (m. 12H). 2.38 (s. 3H), 2.76 (d. 2H, 7=7Hz), 4.11 (s, 2H), 4.65 (m. 2H), 5.13 (m, 2H), 8.02 (s. 1H ) ESI: 431(M1)+C17H28C1N603P
Preparation 20
Synthesis of diisopropyl((l-{[5-methyl-2,4-dioxo-3,4-dihydro-l(2H)-
pyrimidinyl]methyl}cyclopropyl)(metliyl)amino|methylphosphonate
(Formula Removed)

The compound prepared in Preparation 17 (0.32g) was dissolved in methanol and 1.5g of ammonium fluoride was added dropwise. The reaction mixture was reacted under stirring at 60 T? for 24 hours and then the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column to give methylaminediisopropylmethylphosphone 1.1-cyclopropane ethyl alcohol.
1H NMR(CDCl3) " 0.56 (m, 2H). 0.73 (m. 2H), 1.31 (m, 12H), 2.5o (s. 3H), 3.11 (d, 2H), 3.55 (s, 2H), 4.70 (m, 2H)
The compound thus obtained was consecutively reacted according to the same procedure as Preparations 4 and 7 to give the title compound.
1H NMR(CDC13) 79 (m, 2H), 0.90 (m. 2H), 1.31 (m, 12H), 1.92 (s. 3H). 2.38 (s, 3H), 3.75 (d, 2H). 4.10 (s, 2H), 4.65 (m, 2H). 7.62 (s, 1H), 9.1,5 (s. 1 H)
Preparation 21
Synthesis of 1,1-cyclopropanedicarboxylic acid
(Formula Removed)

In 50% NaOH 187ml was dissolved 15g of diethylmalonate at room temperature. Benzyltriethylammoniumchloride (21.3g) was added and the resulting mixture was stirred for 10 minutes. 1,2-Dibromoethane (12.3g) was added to the reaction solution and the resulting mixture was stirred for more than 18 hours at room temperature. The reaction mixture was neutralized by adding dropwise cone, sulfuric acid and then extracted with ethyl acetate. The extract was distilled under reduced pressure to give j.2g of the title compound as a white solid.
1H NMR(CDCl3)  1.88 (s, 4H)
Preparation 22
Synthesis of [l-({[t-butyl(diphenyl)silyl]oxy}methyl)cyclopropyljmethanol
(Formula Removed)

Lithium aluminum hydride (LAH) 15.3g was dissolved in 39g of tetrahydrofuran, and 11.7g of the carboxylic acid prepared in Preparation 21 was slowly added dropwise at 0T. The reaction solution was refluxed for 17 hours. The reaction was stopped by adding 10% HC1 at room temperature and the mixture was extracted with ethyl acetate. The extract was distilled under reduced pressure and the residue was purified by silica gel column to give 8.2g of diol compound.
1H NMR(CDC13)  0.56 (s, 4H), 2.22 (s, 2H), 3.63 (s, 4H) •
The compound thus obtained (400mg) was dissolved in 12ml. of THF, 184mg of
NaH and 1.16g of t-butyldiphenylsilylchloride (TBDPSC1) were added, and the resulting mixture was refluxed for 6 hours. The reaction was stopped by adding 10ml of water and the mixture was extracted with ethyl acetate. The extract was distilled under reduced pressure and the residue was purified by silica gel column to give l.lg of the title compound.
1H NMR(CDC13)  0.33 (t, 2H), 0.48 (t, 2H), 1.23 (s, 9H), 3.59 (d, 4H), 7.42 (m, 6H), 7.68 (m, 4H)
Preparation 23
Synthesis of diethyI(E)-2-[l-({[t-butyl(diphenyl)silyl]oxy}methyl)cyclopropyl] ethenylphosphonate
(Formula Removed)

; 53 by silica gel column to give 2.32g of the title compound.
1H NMR(CDC13)  0.76 (t, 2H), 0.81 (t, 2H), 1.04 (s, 9H), 1.31 (t, 6H), 3.71 (s, 2H), 4.05 (m, 4H), 5.70 (m, 1H), 6.42 (m, 1H), 7.43 (m, 6H), 7.64 (d, 4H) ESI: 501 (M+l)+C28H4104PSi
Preparation 24
Synthesis of diethyl 2-[l-(hydroxymethyl)cyclopropyl]ethenylphosphonate
(Formula Removed)

The compound prepared in Preparation 23 was reacted according to the same procedure as Preparation 3 to give the title compound.
1H NMR(CDC13)  0.76 (t, 2H), 0.81 (t, 2H), 1.04 (s, 9H), 1.31 (t, 6H), 3.71 (s. 2H), 4.05 (m, 4H), 5.70 (m, 1H), 6.42 (m, 1H), 7.43 (m, 6H), 7.64 (d, 4H) ESI: 501 (M+l)+C28H4104PSi
Preparation 25
Synthesis of diethyl 2-{l-[(6-amino-9H-purin-9-yl)methyi|cyclopropyl} ethenylphosphonate
(Formula Removed)

The compound prepared in Preparation 24 was reacted according to the same procedure as Preparations 4 and 5 to gi\ e the title compound.
1H NMR(CDC13)  1.07 (t, 2H), 1.19 (t, 2H), 1.22 (t, 6H), 3.93 (s, 4H), 4.33 (s. 2H). 5.55 (s, 2H), 5.63 (m, 1H), 6.49 (m, 1H), 7.88 (s, 1H), 8.37 (s, 1H) ESI:352 (M1)+C15H22N503P
Preparation 26
Synthesis of diethyl 2-{l-[(2-amino-6-chloro-9^-purin-9-yl)methyl] cyc!opropyI}ethenylphosphonate
(Formula Removed)

The compound prepared in Preparation 24 was reacted according to the same procedure as Preparations 4 and 6 to give the title compound.
1H NMR(CDC13)  1.06 (t, 2H). 1.15 (t, 2H), 1.23 (t, 6H). 3.93 (s, 4H), 4.18 (s, 2H), 5.12 (s, 2H), 5.59 (m, 1H), 6.58 (m, 1H), 7.81 (s, 1H) ESI:386(M1)+'C15H21CIN503P
Preparation 27
Synthesis of diethyl 2-(l-{(5-methyl-2,4-dioxo-3,4-dihydro-l(2H)-pyrimidinyl] methyl}cyclopropyl)ethenylphosphonate
(Formula Removed)

The compound prepared in Preparation 24 was reacted according to the same procedure as Preparations 4 and 7 to give the title compound.
1H NMR(CDC13)  0.93 (t, 2H). 1.01 (t, 2H), 1.24 (t, 6H), 1.92 (s, 3H), 3.91 (s, 2H). 3.96 (m, 4H). 5.49 (m, lH),5.87(m. 1H). 7.62 (s, 1H). 9.15 (s. 1H) ESI:343 (M1)+,C15H23N205P
Preparation 28
Synthesis of l-({[t-butyl(diphenyl)silyl]oxy}methyl)-2,2-dimethylcyclo-
(Formula Removed)

According to the description in a reference (see: Syn. Lett. 07, 1053-1054, 1999), the title compound was prepared as follows. 10g(29 mmole) of ethyl 2- {[t-butyl(diphenyl)silyl]oxy}acetate was dissolved in 100ml of tetrahydroftiran (THF) and 6.0ml of titaniumtetraisopropoxide was added thereto. To the mixture was slowly added 37ml of isobutylmagnesiumbromide(2.0M in THF) at -10 ºC, and the reaction solution was stirred for 12 hours at room temperature.50ml of saturated ammonium chloride was added to stop the reaction. The tetrahydroftiran (THF) used as a solvent was removed by distillation under reduced pressure, and the reaction mixture was extracted twice with 500mlof n-hexane. The n-hexane extract was distilled under reduced pressure-and purified by silica gel column to give 5.0g of the title compound.
1H NMR(CDC13) 0.25 (d, 1H), 0.51 (d. 2H), 0.99 (s. 3H), 1.07 (s. 9H), 1.22 (s, 3H), 3.71 (d, 1H), 3.91 (d. 1H), 7.41 (m, 6H), 7.70 (m. 4H) ESI: 355 (M+l)+ C22H30O2Si
Preparation 29
Synthesis of diisopropyl {{l-({[t-buryl(diphenyl)silyl]oxy}methyl)-2.2-dimethyl cyclopropyl]oxy}methylphosphonate
(Formula Removed)

The compound prepared in Preparation 2S was reacted according to the same procedure as Preparation 2 to give the title compound..
1H NMR(CDCl3)  0.29 (d, 1H), 0.60 (d. 1H), 1.06 (s, 3H), 1.09 (s. 9H), 1.27 (s, 3H), 1.30 (m, 12H), 3.75 (m. 2H), 3.92 (m, 2H). 4.72 (m, 2H), 7.41 (m,-6H), 7.67 (m, 4H) ESI: 519 (M1)+, C28H4305PSi
Preparation 30
Synthesis of diisopropyl{l-l(hydroxymethyl)-2,2-dimethylcyclopropyl]oxy} methylphosphonate
(Formula Removed)

The compound prepared in Preparation 29 was reacted according to the same procedure as Preparation 3 to give the title compound.
1H NMR(CDC13)  0.39 (d. 1H), 0.59 (d, 1H). 1.13 (s. 3H), 1.21 (s, 3H), 1.33 (d, 12H), 3.76 (m, 2H), 3.86 (m, 2H), 4.76 (m, 2H) ESI: 295 (M+l)+ C13H2704P
Preparation 31
Synthesis of diisopropyl({l-[(6-amino-9H-purin-9-yl)methyIl-2,2-dimcthyI cyclopropyl}oxy)methylphosphonate
(Formula Removed)

The compound prepared in Preparation 30 was reacted according to the same procedure as Preparation 11 to give the title compound.
1H NMR(500MHZ, CDC13):  0.62 (d, J=5.9Hz, 1H), 0.81 (d, J=5.9Hz. 1H), 1.10 (s,3H), 1.23 (m, 15H), 3.72 (dd, J= 15.1, 11.0Hz. 1H), 3.85 (dd, J=l5.1, 5.5Hz, 1H), 4.28 (d, J=15.1Hz, 1H), 4.58 (d, J=15.1Hz, 1H), 4.68 (m. 2H), 5.79 (bs, 2H), 8.19 (s, 1H), 8.32 (s,lH)
ESI: 412 (M+l)+, C18H30N5O4P
Preparation 32
Synthesis of diisopropyl({l-{(2-amino-6>iodo-9H-purin-9-yl)inethyl]-2,2-dimethylcyclopropyl}oxy)methylphosphonate

(Formula Removed)

The compound prepared in Preparation 30 was reacted according to the same procedure as Preparation 12 except mat 6-iodoguanine was used instead of 6-chloroguanine to give the title compound.
1H NMR(500MHZ, CDCl3): 0.58 (d, J=6.4Hz, 1H), 0.80 (d, J=6.4Hz, 1H), 1.10 (s, 3H), 1.24 (m, 8H), 3.72 (dd, J=13.0, 11.0Hz. 1H), 3.88 (dd, J=13.0, 9.3Hz, 1H) 4.08 (d,J=l5.1Hz, lH),4.47(d,J=15.1Hz, 1H), 4.67 (m, 2H), 5.05 (bs, 1H), 8.10 (s. 1H)
ESI: 538 (M+l)+, C18H29IN504P
Preparation 33
Synthesis of diisopropyl[(l {(5-methyl-2,4-dioxo-3,4-dihydro-l(2H)-
pyrimidinyl]methyI}-2,2-dimethylcyclopropy!)oxy|methylphosphonate
(Formula Removed)

The compound prepared in Preparation 30 was reacted according to the same procedure as Preparation 13 to give the title compound.
1H NMR(CDC13)  0.58 (d, 1H), 0.80 (d, 1H), 1.10 (s, 3H), 1.24 (dd. 6H), 1.28 (t. 6H), 1.58 (s, 3H), 1.92 (s, 3H), 3.72 (dd. 1H), 3.88 (dd, 1H), 4.08 (d, 1H), 4.47 (d, 1H), 4.67 (m, 2H), 7.62 (s, 1H), 9.15 (s, 1H)
ESI: 403 (M1)+- C18H31N206P
Preparation 34
Synthesis of l-[l-({|t-butyl(diphcnyl)silyl]oxy}methyl)cyclopropyl]-l-methyl alcohol
(Formula Removed)
6g of the compound prepared in Preparation 22 was dissolved in 150ml of dichloromethane. 3.0g of N-oxide and 103mg of tetrapropylammoniumperruthenate (TPAP) were added thereto at room temperature. The reaction mixture was stirred for about 1 hour at room temperature and quenched by adding 20ml of water. The reaction mixture was extracted with dichloromethane and the extract was concentrated under reduced pressure to give 6.0g of aldehyde compound which went to next reaction without further purification.
5.23g of the aldehyde was dissolved in 350ml of THF. The solution was cooled to -78 ºC and 10.3ml of methylmagnesiumbromide (3.0M solution) was slowly added to the solution and then, stirred for 1 hour at room temperature. The reaction mixture was quenched by 0.5ml of water and O.5ml of methanol and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=l/8, v/v) to 3.57g of title compound.
■H NMR(CDC13)  0.22 (m, 1H), 0.39 (m, 2H), 0.61 (m, 1H), 1.06 (s, 9H), 1.24 (d, 3H), 3.3 (d, 1H), 3.47 (s, 2H), 3.9 (d, 1H), 7.43 (m, 6H), 7.64 (m, 6H)
Preparation 35
Synthesis of diethyl (E)-2-l-(l-({(t-buryl(diphenyl)siIyl]oxy}methyl)cyclopropyl]-1-propenylphosphonate
(Formula Removed)

4g of the compound prepared in preparation 34 was dissolved in 10ml of dichloromethane. 2.1g of n-morpholine N-oxide and 209mg of tetrapropylammoniumperruthenate (TPAP) were added thereto at room temperature. The reaction mixture was stirred for about 1 hour at room temperature and quenched by adding 20ml. of water. The reaction mixture was extracted with dichloromethane and the extract was concentrated under reduced pressure to give 4.0g of compound which went to next reaction without further purification.
Tetraethylmethylene diphosphonate (2.7g) was dissolved in 30ml of tetrahydrofuran (THF) at -78 and 4ml of n-butyllithium was added. The resulting mixture was stirred for 20 minutes, and then 1.0 g of the ketone compound as obtained above was added. The reaction mixture was stirred at room temperature for 1 hour and was stopped by adding 20ml of water. The reaction mixture was extracted with ethyl acetate and concentrated under reduced pressure. The residue was purified by silica gel column to give 654mg of the title compound.
1H NMR(CDCl3)  0.58 (m, 1H), 0.69 (m, 2H), 1.02 (s, 9H), 1.20 (t, 6H), 2.09 (d, 3H), 3.59 (s, 2H), 4.05 (m, 4H), 5.61 (d, 1H), 7.38 (m, 6H), 7.63 id, 4H)
Example 1
Synthesis of ({l-[(6-amino-9H-purin-9-yl)methyljcyclopropyl}oxy)methyl phosphonic acid (Compound 1)
The compound prepared in Preparation 5 (159mg) was dissolved in 15ML. of dichloromethane, 1.27g of trimethylsilylbromide was added thereto, and the resulting mixture was heated under reflux for 18 hours. After the completion of reaction, the reaction mixture was extracted with water, and the water extract was distilled under reduced pressure. The residue was purified by high performance liquid chromatography (HPLC) to give 0.89g(Yield 90%) of the title compound as a white powder.
lH NMR(MeOH-d4)  1.02 (d, 4H), 3.95 (d. 2H), 4.55 (s, 2H), 8.40 (s, 1H). 8.55 (s, 1H)
ESI: 300 (M+l)+, C10H14N5O4P
Example 2
Synthesis of 3-l({l-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-385-phosphanon-l-yl pivalate (Compound 2)
The title compound was prepared according to the method known in a reference(see: J. Med. Chem., 37(12), 1857 (1994)) and USP 5,663,159 (1998).
The compound prepared in Example 1 (1.00g) was dissolved in 150ml of dry dimethylformamide, and 2.08g(7.32 mmol) of N,N'-dicyclohexyl-4-morpholine-
carboxamidine and 2.75g(18.3 mmol) of chloromethyl pivalate were added thereto.
When the reaction mixture became homogeneous after about 1 hour, it was stirred for 5
days at room temperature. The reaction solution was filtered, the filtrate was
concentrated under reduced pressure, and the residue was fractionated with SOmt, of water
and 50ml of toluene to separate the organic layer. The aqueous layer was extracted twice
with 50ml of toluene. The combined organic layers were concentrated under reduced
pressure. The residue was purified by column chromatography(eluent:
methanol/dichloromethane= 1/20, v/v) to give 0.59g(Yield 32%) of the title compound as a white solid.
1H NMR(500MHZ, CDC13)  0.91 (m, 2H), 1.12 (m, 2H), 1.20 (m, 18H), 1.90 (brs,2H),3.90(d,2H),4.32(s,2H),5.65(m,4H),8.14(s, 1H), 8.31 (s. 1H) ESI: 528 (M+l)+, C22H34N508P
Example 3
Synthesis of ({l-[(2-amino-6-chloro-9H-purin-9-yl)methyl]cyclopropyI} oxy)methyI phosphonic acid(Compound 3)
The compound prepared in Example 1 (l.00g) was dissolved in 150ml of dry dimethylformamide, and 2.08g(7.32 mmol) of N,N'-dicyclohexyl-4-morpholine-carboxamidine and 2.75g(l8.3 mmol) of chloromethyl pivalate were added thereto. When the reaction mixture became homogeneous after about I hour, it was stirred for 5 days at room temperature. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was fractionated with 50ml of water and 50ml. of toluene to separate the organic layer. The aqueous layer was extracted twice with 50ml of toluene. The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (eluent: methanol/dichloromethane=l/20, v/v) to give 0.59g(Yield 32%) of the title compound as a white solid.
1H NMR(MeOH-d4)  1.00 (s, 2H), 1.07 (s, 2H), 3.94 (d. 2H), 4.52 (s, 2H), 9.50 (s, 1H)
ESI: 334 (M+l)+ C10H13C1N5O4P
Example 4
Synthesis of ({l-[(2-amino-6-hydroxy-9^-purin-9-yl)methyl]cyclopropyl}oxy) methylphosphonic acid(Compound 5)
The compound prepared in Example 3 (41mg) was dissolved in 5ml of 2N hydrochloric acid and heated under reflux for 6 hours. Water was removed by distillation under reduced pressure to give 37mg(Yield 95%) of the title compound as a white solid.
1H NMR(MeOH-d4) 6 0.98 (m, 2H), 1.06 (m, 2H), 3.92 (d, 2H), 4.45 (s, 2H), 9.20 (s,lH)
ESI: 316 (M+l)+, C10H14N5O5P
Example 5
Synthesis of ({l-[(2-amino-9H-purin-9-yl)methyI]cyclopropyl}o.\y)rnethyl phosphonic acid(Compound 9)
The compound prepared in Preparation 6 (150mg) was dissolved in 15ml of tetrahydrofuran, 15mg of 5% palladium/carbon was added thereto, and the compound was reduced under 1 atm of hydrogen atmosphere for 18 hours. After completion of reaction, palladium/carbon was removed by suction filtration and the filtrate was distilled under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/l, v/v) to give 130mg of diisopropyl compound(ESI: 3S4(M1)\ C16H26N504P). This compound was treated with trimethylsilylbromide according to the same procedure as Example 1 to give 91mg(Yield 90%) of the title compound.
1H NMR(MeOH-d4)  0.94 (m, 2H), 1.03 (m, 2H), 3.93 (d, 2H), 4.40 (s, 2H), S.66(s, lH),8.74(s, 1H)
ESI: 300 (M+l)+ C10H14N5O4P
Example 6
Synthesis of 3-[({l-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyll-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-385-phosphanon-l-yl pivalate(Compound 10)
The compound prepared in Example 5 was reacted according to the same procedure as Example 2 to give the title compound.
1H NMR(CDCl3-d4) 6 0.90 (m, 2H), 1.05 (m, 2H), 1.20 (m, 18H), 3.96 (d, 2H), 4.22 (s, 2H), 5.65 (m, 4H), 8.03 (s, 1H), 8.69 (s, 1H) ESI: 528 (M+l)+, C22H34N508P
Example 7
Synthesis of ({l-[(2-amino-6-cydopropyIamino-9H-purin-9-yl)methyi] cyclopropyl}oxy)methylphosphonic acid(Compound 11)
The compound prepared in Preparation 6 (200mg) was dissolved in 20ml of ethanol, 53ml of triethylamine and 82mg of cyclopropylamine were added thereto, and the resulting mixture was heated under reflux for 18 hours. Water was added to stop the reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give 178mg(Yield 85%) of the diisopropyl compound.
1H NMR(CDC13)  0.59 (t, 2H), 0.83 (m, 4H), 1.00 (t, 2H), 1.24 (d, 6H), 1.29 (d, 6H). 3.0 (brs, 1H), 3.80 (d, 2H), 4.15 (s, 2H), 4.70 (m, 2H), 4.71 (brs. 2H), 5.71 (s, 1H), 7.68 (s, 1H)
The compound thus obtained was treated with trimethylsilylbromide according to the same procedure as Example 1 to give 128mg(Yield 90%) of the title compound.
1H NMR(MeOH-d4)  0.86 (m, 2H), 0.94 (m, 2H), 1.02 (m, 2H),1.07 (m, 2H), 2.90 (br s, 1H), 3.93 (d, 2H), 4.39 (s, 2H), 8.43 (br s, 1H) ESI: 355 (M+l)+ C13H19N604P
Example 8
Synthesis of ({l-((2-amino-6-ethylamino-9H-purin-9-yl)methyl]cyclopropyl} oxy) methylphosphonic acid(Compound 13)
The compound prepared in Preparation 6 (115mg) was dissolved in 20ml of ethanol, 31 ml of triethylamine and 0.07ml of ethylamine were added thereto, and the resulting mixture was heated under reflux for 18 hours. Water was added to stop the
reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give 104mg(Yield 89%) of the diisopropyl compound.
1H NMR(CDC13)  0.82 (m, 2H), 1.00 (m, 2H), 1.24 (d, 6H), 1.27 (t, 3H), 1.29 (d, 6H), 3.60 (brs, 2H), 3.81 (d, 2H), 4.15 (s, 2H), 4.65 (m, 4H), 5.50 (br s, 1H), 7.78 (s, 1H)
The compound thus obtained was reacted according to the same procedure as Example 1 to give 75mg( Yield 90%) of the title compound.
1H NMR(MeOH-d4)  0.89 (m, 2H), 1.04 (m, 2H). 1.31 (t, 3H), 3.59 (br s, 2H;. 3.92 (d. 2H), 4.35 (s, 2H), 9.95 (br s, 1H) ESI: 343 (M+l)+, C13H19N604P
Example 9
Synthesis of [(l-{[2-amino-6-(dimethyIamino)-9H-purin-9-yl]methyl} cyclopropyl)oxy|methylphosphonic acid(Compound 15)
The compound prepared in Preparation 6 (115mg) was dissolved in 20m? of ethanol. 38.6ml of triethylamine and 1.74ml of N,N-dimethylamine were added thereto, and the resulting mixture was heated under reflux for 18 hours. Water was acided to stop the reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give 1 l9mg(Yield 81%) of the diisopropyl compound.
1H NMR(CDC13) 6 0.75 (l, 2H), 0.93 (t, 2H), 1.16 (d, 6H), 1.22 (d, 6H), 3.3 (brs. 6H), 3.74 (d. 2H), 4.09 (s, 2H), 4.60 (m, 2H), 4.69 (brs, 2H), 7.68 (s, 1H)
The compound thus obtained was reacted according to the same procedure as Example 1 to give 86mg( Yield 90%) of the title compound.
1H NMR(MeOH-d4)  0.89 (m, 2H), 1.05 (m, 2H). 3.30 (br s, 6H), 3.90 (d, 2H).
4.37 (s,2H), 7.92 (brs, 1H)
ESI: 343 (M+l)+, C12H19N604P
Example 10
Synthesis of [(l-{[2-amino-6-{isopropylamino)-9H-purin-9-.vl]methyl} cyclopropyl) oxy]methylphosphonic acid(Compound 17)
The compound prepared in Preparation 6 (133mg) was dissolved in 20ml of ethanol, 0.049ml of triethylamine and 0.082ml. of isopropylamine were added thereto, and the resulting mixture was heated under reflux for 18 hours. Water was added to stop the reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give 95 mg( Yield 68%) of the diisopropyl compound.
1H NMR(CDC13)  0.83 (m, 2H), 0.98 (m, 2H), 1.28 (m. 18H), 3.79 (d, 2H), 4.15 (s, 2H), 4.60 (br s, 1H), 4.68 (s, 2H), 4.70 (m, 2H), 5.40 (br s, 1H), 7.77 (s, 1H)
The compound thus obtained was reacted according to the same procedure as Example 1 to give 72mg(Yield 91%) of the title compound.
1H NMR(MeOH-d4) 6 0.89 (m, 2H), 1.05 (m, 2H), 1.34 id. 6H), 3.30 (br s. 1H). 3.90 (d, 2H), 4.36 (s, 2H), 8.01 (br s, 1H) ESI: 357 (M+l)+ C12H19N604P
Example 11
Synthesis of ({l-{(2,6-diamino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl-phosphonic acid(Compound 19)
The compound prepared in Preparation 4 (246mg) and 2.6-diaminopurine were reacted according to the same procedure as Preparation 5 to give 78.5mg(Yield 29%) of the diisopropyl compound.
1H NMR(CDC13)  0.85 (t, 2H), 1.00 (t, 2H), 1.25 (d, 6H). 1.29 (d, 6H), 1.83 (brs, 2H), 3.82 (d, 2H), 4.15 (s, 2H), 4.68 (m, 2H), 5.39 (d, 2H), 7.85 (s. 1H)
introduced bit by bit under nitrogen atmosphere. 2ml of dry tetrahydrofuran was added dropwise thereto, the temperature was lowered to -78 , 0.08ml(20.238mmol) of methylmagnesium Grinard was added, and the resulting mixture was stirred for 1 hour. After the reaction mixture was warmed to room temperature, about 10mol% of palladiumtetrakistriphenylphosphine was added bit by bit. 50mg(0.119mmol) of the compound prepared in Preparation 6 in 1 ml of tetrahydrofuran was added to the above reaction solution dropwise. The resulting mixture was heated for 1 hour. The solvent was removed by distillation under reduced pressure, the residue was participated with water and ethyl, acetate, and the organic layer was concentrated by distillation under reduced pressure. The residue was purified by silica gel column chromatography(eluent: methylene chloride/methanol=90/10, v/v) to give 20mg(Yield 42%) of the diisopropyl compound.
1H NMR(MeOH-d4)  0.95 (m, 2H), 0.98(m, 2H), 1.17(d, 6H), 1.23 (d, 6H), 2.59(s, 3H), 4.02(s, 1H). 4.10(s, 1H), 4.32(s, 2H), 4.59(m, 2H), 8.12(s. 1H) ESI: 398 (M1)+. C17H28N504P
The compound thus obtained was reacted according to the same procedure as Example 1 to give 8.0mg(Yield 50%) of the title compound.
1H NMR(D20)  0.87 (m, 2H), 1.02 (m, 2H), 3.79 (s, 1H). 3.81 (s. 1H), 4.53 (s. 2H),8.25(s, 1H)
ESI: 314(M1)+.C11H16N504P
Example 14
Synthesis of [(1 {[5-methyl-2,4-dioxo-3,4-dihydro-l(2H)-pyrimidinyll methyl} cyclopropyl)oxy|methylphosphonic acid(Compound 31)
The compound prepared in Preparation 7 (19mg) was reacted according to the same procedure as Example 1 to give 14mg( Yield 95%) of the title compound.
ESI: 291 (M1)+.C10HllN2O6P
1H NMR(MeOH-d4)  0.82 (t, 2H), 0.97 (t, 2H), 1.87 (s, 3H), 3.83 (d. 2H), 3.97 (s, 2H), 7.55 (s, 1H)
introduced bit by bit under nitrogen atmosphere. 2ml of dry tetrahydrofuran was added dropwise thereto, the temperature was lowered to -78 , 0.08ml(20.238mmol) of memylmagnesium bromide was added, and the resulting mixture was stirred for 1 hour. After the reaction mixture was wanned to room temperature, about 10mol% of palladiumtetrakistriphenylphosphine was added bit by bit. 50mg(0.119mmol) of the compound prepared in Preparation 6 in lot of tetrahydrofuran was added to the above reaction solution dropwise. The resulting mixture was heated for 1 hour. The solvent was removed by distillation under reduced pressure, the' residue was participated with water and ethyl acetate, and the organic layer was concentrated by distillation under reduced pressure. The residue was purified by silica gel column chromatography(eluem methylene chloride/methanol=90/10r v/v) to give 20mg(Yield 42%) of the diisopropyl compound.
1H NMR(MeOH-d4)  0.95 (m, 2H), 0.98(m, 2H), l.l7(d. 6H), r.23 (d, 6Hi.
2.59(s. 3H), 4.02(s, 1H), 4.l0(s, 1H), 4.32(s, 2H), 4.59(m, 2H), 8.12(s. 1H)
! ESI:398(M1)+,C17H28N504P
The compound thus obtained was reacted according to the same procedure as Example 1 to give 8.0mg(Yield 50%) of the title compound.
1H NMR(D2O)  0.87 (m. 2H), 1.02 (m, 2H), 3.79 (s. 1H). 3.81 (s, 1H), 4.53 (s. 2H). 8.25 is. 1H)
ESI:314(M1)+,CUH16N504P
Example 14
Synthesis of ((l{{S-methyl-2,4-dioxo-3,4-dihydro-l(2H)-pyrimidinyl]methyl] cyclopropyl)oxy|methylphosphonic acid(Compound 31)
The compound prepared in Preparation 7 (19mg) was reacted according to the same procedure as Example 1 to give 14mg(Yield 95%) of the title compound.
ESI: 291 (M1)+, C10H11N206P
1H NMR(MeOH-d4)  0.82 (t, 2H), 0.97 (t, 2H), 1 .87 (s. 3H), 3.83 (d, 2H), 3.97 (s. 2H), 7.55 (s, 1H)
Example 15
Synthesis of [(l-{[2-amino-6-(4-morphoIinyl)-9Hr-purin-9-yI]methyl} cyclopropyl)oxy]methylphosphonic acid(Compound 37)
The compound prepared in Preparation 6 (134mg) was dissolved in 20ml of ethanol, 0.049ml of triethylamine and 0.085 inf. of morpholine were added thereto, and the resulting mixture was heated under reflux for 18 hours. Water was added to stop the reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give 66mg(Yield 44%) of the diisopropyl compound.
"H NMR(CDC13)  0.83 (m, 2H), 0.99 (m, 2H), 1.24 (d, 6H), 1,30 (d, 6H), 3.79 (m, 6H), 4.18 (s, 2H), 4.21 (br s, 4H), 4.67 (m. 2H), 4.80 (br s,.2H), 7.78 (s, 1H) ESI: 469 (M+l)+, C20H33N6O5P
The compound thus obtained was treated with trimethylsilylbromide according to the same procedure as Example 1 to give 49mg( Yield 91%) of the title compound.
1H NMR(MeOH-d4)  0.89 (m, 2H). 1.07 (m, 2H), 3.81 (m, 4H), 3.92 (d, 2H), 4.40(brs,6H),7.87(s. 1H)
ESI: 384 (M1)+, C14H21N605P
Example 16
Synthesis of [(l-{[2-amino-6-(l-piperidinyl)-9H-purin-9-yl] methyl}
cycIopropyl)oxy]methyIphosphonic acid(Compound 39)
The compound prepared in Preparation 6 (154mg) was dissolved in 20ml of manol, 0 '049ml of triethylamine and 0.11 mK of amine were added thereto, and the resulting imxture was heated under reflux for 18 noms. Water was added to stop the reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give 123mg (Yield 72%) of the diisopropyl compound.
1H NMR(CDC13) 0.80 (m, 2H), 0.99 (m, 2H), 1.22 (d, 6H), 1.26 (d, 6H), 1.63 (m, 4H), 1.67 (m, 2H), 3.78 (d, 2H), 4.14 (s, 6H), 4.54 (br s, 2H), 4.65 (m, 2H), 7.72 (s, 1H)
ESI: 467 (M+l)+, C21H35N604P
The compound thus obtained was reacted according to the same procedure as Example 1 to give 87mg(Yield 91%) of the title compound.
1H NMR(MeOH-d4)  0.89 (m, 2H), 1.06 (m, 2H), 1.73 (m, 4H), 1.79 (m, 2H),
3.90 (d, 2H), 4.37 (s, 2H), 4.43(br s, 4H), 7.89 (s, 1H)
ESI: 383 (M1)+, C15H23N604P
Example 17
Synthesis of [(l-{[2-amino-6-(4-methyl-l-piperazinyl)-9H-purin-9-yl)methyl} cyclopropyl)oxy]methylphosphonic acid(Compound 41)
The compound prepared in Preparation 6 (128mg) was dissolved in 20ml of ethanol, 0.10ml of 4-methyl-l-piperazine was added thereto, and the resulting mixture was heated under reflux for 18 hours. Water was added to stop the reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methano 1=20/1, v/v) to give l23mg(Yield 83%) of the diisopropyl compound.
lH NMR(CDC13)  0.80 (m, 2H), 0.98 (m. 2H), 1.21 (d, 6H), 1.27 (d, 6H), 2.30 (s. 3H), 2.48 (m, 4H), 3.78 (d, 2H), 4.13 {z, 2H), 4.22 (br s, 4H), 4.57 (s, 2H), 4.66 (m, 2H), 7.73 (s, 1H)
ESI: 482 (M+l)+, C21H36N704P
The compound thus obtained was reacted accenting to the same procedure as Example 1 to give 87mg( Yield 85%) of the title compound.
1H NMR(MeOH-d4)  0.89 (m, 2H), 1.07 (m, 2H), 3.00 (s, 3H), 3.72 (m, 4H),
3.91 (d, 2H), 4.45 (s, 2H), 4.89 (m, 2H), 5.70 (br, 2H), 7.91 (s, 1H)
ESI: 398 (M+l)+ C15H24N704P
Example 18
Synthesis of [(l-{[2-amino-6-(l-pyrrolidinyl)-9H-purin-9-yl]methyl}
cyclopropyl)oxy] methyl phosphonic acid (Compound 43)
The compound prepared in Preparation 6 (122mg) was dissolved in 2ml of ethanol, 0.07ml of pyrrolidine was added thereio, and the resulting mixture was heated under reflux for 18 hours. Water was added to stop the reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/l. v/v) to give 110mg(Yield 83%) o f the diisopropyl compound.
1H NMR(CDC13)  0.78 (m, 2H), 0.96 (m, 2H), 1.20 (d, 6H), 1.26 (d, 6H), 2.00 (br s, 4H), 3.60 (br, 3H), 3.78 (d. 2H), 4.09 (br, 2H), 4.12 (s, 2H), 4.63 (m, 2H), 7.69 (s, 1H)
ESI: 453 (M+l)+, C20H33N6O4P
The compound thus obtained was reacted according to the same procedure as Example 1 to give 76mg( Yield 85%) of the title compound.
1H NMR(MeOH-d4)  0.94 (m. 2H), 1.03 (m. 2H), 2.15 (m, 4H), 3.76 (m, 2H). 3.91 (d, 2H), 4.18 (m, 2H), 4.40 (s, 2H), 5.70 (br, 2A), 8.42 (s, 1H) ESI: 369 (M1)+ C14H21N604P
Example 19
Synthesis of 3-[({l-[(2-amino-9H-purin-9-yl)methyl)cyclopropyl}oxy) methyl] -9-methyl-3,7-dioxo-2,4,6-trioxa-385-phosphadec-l-yl 3-methyIbutanoate (Compound
The compound prepared in Example 5 (l00mg) was dissolved in dimethylformamide (2ml) and then reacted with chloromethyl 3-methylbutyrate in the presence of triethylamine (3 equivalents) at room temperature for 24 hours. The resulting product was purified by silica gel column to give the title compound in a yield of 41%.
1H NMR(CDC13)  0.89 (t, 2H), 0.94 (d, 12H), 1.04 (t, 2H), 2.10 (m, 2H), 2.22 (d, 4H), 3.97 (d, 2H), 4.23 (s, 2H), 5.21 (s, 2H), 5.65 (m, 4H), 8.00 (s, 1H), 8.69 (s, 1H) ESI: 527 (M+l)+, C23H35N408P
Example 20
Synthesis of 3-[({l-[(2-amino-9/7-purin-9-yl)methyI]cyclopropyl}oxy) The compound prepared in Example 5 was reacted with chloromethyl butyrate according to the same procedure as Example 19 at room temperature for 24 hours. The resulting product was purified by silica gel column to give the title compound in a yield of 24%.
1H NMR(CDC13)  0.88 (t, 2H), 0.92 (d, 6H), 1.60 (m, 4H), 2.32 (t, 4H), 3.96 id. 2H), 4.22 (s, 2H), 5.00 (s, 2H), 5.62 (m, 4H), 8.00 (s, 1H), 8.68 (s, 1H) ESI: 499 (M+l)+ C21H31N408P
Example 21
Synthesis of 3-[({l-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy) methyl]-
8-methyI-3,7-dioxo-2,4,6-trioxa-385-phosphanon-l-yl 2-methylpropanoate
(Compound 78)
The compound prepared in. Example 5 was reacted with chloromethyl isobutyratc according to the same procedure as Example 19 at room temperature for 24 hours. The resulting product was purified by silica gel column to give the title compound in a yield of 21%.
1H NMR(CDC13)  0.84 (t, 2H), 0.97 (t, 2H), 1.11 (d, 12H), 2.52 (m, 2H), 3.91 (d. lr -.16 (s. 2H). 5.21 (s, 2H), 5.58 (m, 4H), 7.96 (s. l5 861(s, 1H) ESI: 499 (M+l)+, C21H31N408P
Example 22
Synthesis of 3-[({l-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy) methyl] -3,7-dioxo-7-(l-pyrrolidinyl)-2,4,6-trioxa-385-phosphahept-1 -yl -pyrrotidtuecarboxylate (Compound 80)

The compound prepared in Example 5 was reacted with chloromethyl 1-pyrrolidinecarboxylate according to the same procedure as Example 19 at room temperature for 24 hours. The resulting product was purified by silica gel column to give the title compound in a yield of 35%.
1H NMR(CDC13)  0.82 (t, 2H), 0.87 (m, 8H), 0.98 (t, 2H), 1.57 (d, 4H), 2.26 (t, 4H), 3.91 (d, 2H), 4.16 (s, 2H), 5.12 (s, 2H), 5.57 (m, 4H), 7.98 (s, 1H), 8.62 (s, 1H) ESI: 553 (M+l)+, C23H33N608P
Example 23
Synthesis of 3-[({l-[(2-amino-9H-purin-9-yl)methylJcyclopropyl}oxy)
methyl j-3,7-dioxo-7-(l-piperidinyl)-2.4,6-trioxa-385-phosphahept-l-yl l-piperidinecarboxylate(Compound 81);
The compound prepared in Example 5 was reacted with chloromethyl I-piperidinecarboxylate according to the same procedure as Example 19 at room temperature for 24 hours. The resulting product was purified by silica gel column to give the title compound in a yield of 39%.
1H NMR(CDC13)  0.86 (t, 2H). 1.02 (t, 2H), 1.47-1.58 (brm. 12H), 3.40 (brm. 8H), 3.99 (d. 2H), 4.22 (s, 2H), 5.00 (s, 2H). 5.69 (m. 4H), 8.00 (s, 1H), 8.67 (s, 1H) ESI: 581 (M+l)+, C25H37N60SP
Example 24
Synthesis of 3-[({l-((2-amino-9H-purin-9-yl)methyl]cycIopropyl}oxy)
methyl]-7-(4-morphoIinyl)-3,7-dioxo-2,4,6-trioxa-385-phosphahept-l-yl 4-morphaliaecarboxylate(Compound 82)
The compound prepared in Example 5 was reacted with chloromethyl 4-morpholinecarboxylate according to the same procedure as Example 19 at room temperature for 24 hours. The resulting product was purified by silica gel column to give the title compound in a yield of 40%.
1H NMR(CDC13) 6 0.89 (t, 2H), 1.03 (t, 2H), 3.47 (brm, 8H), 3.65 (brm, 8H), 4.00 (d, 2H), 4.24 (s, 2H), 5.04 (s, 2H), 5.70 (m, 4H), 8.07 (s, 1H), 8.69 (s, 1H) ESI: 586 (M+l)+, C23H33N6O10P
Example 25
Synthesis of {[l-({2-amino-6-((4-methylphenyl)sulfanyl]-9H-purin-9-yl} methyl)cyciopropyl]oxy}methylphosphonic acid(Compound 66)
6-Chloroguanine derivative prepared in Preparation 6 (4.86g) was dissolved in 85 mlof methanol and 1.4g of triethylamine and 2.9g of 4-methyithiocresol were added. The reaction mixture was reacted under reflux condition for 24 hours. The reaction was stopped by adding 20ml of water, and the methanol was removed by distillation under reduced pressure. The reaction mixture was extracted with dichloromethane and purified by silica gel column to give a compound wherein 6-position of guanine was substituted by 4-methylphenylthio group.
1H NMR(CDCl3)  0.84 (t, 2H), 1.02 (t, 2H), 1.25-1.31 (m, 12H), 2.40 (s, 3H), 4.20 (d, 2H), 4.69 (m, 2H), 4.74 (s, 2H), 7.22(d. 2H), 7.50 (d, 2H), 8.00 (s, 1H)
The compound thus obtained was reacted according to the same procedure as Example 1 and then recrystallized from a mixture of methanol-diethylether (1/20, v/v) to give the title compound.
1H NMR(MeOH-d4)  0.98 (t, 2H). 1.06 (t, 2H), 2.42 (s, 3H). 3.92 (d, 2H), 4.48 (s, 2H), 7.35 (d, 2H), 7.55 (d, 2H), 9.05 (s. 1H) ESI: 421 (M1)+, C18H21N404PS
Example 26
Sywasss of {(l-({2-amino-6-[(4-methylphenyl) -9H-p«TB-9-yl} methyl)cyclicpyl]oxy ]methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-troxa-385-phosphanon-1-yl pivalate(Compound 68)
The methylphosphonic acid prepared in Example 25 was reacted according to the same procedure as Example 2 to give the title compound.
1H NMR(CDC13)  0.82 (t, 2H), 0.98 (t, 2H), 1.18 (s, 18H), 2.36 (s, 3H), 3.93 (d, 2H), 4.15 (s, 2H), 4.93 (s, 2H), 5.60 (m, 4H), 7.18 (d, 2H), 7.48 (d, 2H), 7.88 (s, 1H) ESI: 649 (M+l)+, C30H41N4O8PS
Example 27
Synthesis of {[l-({2-amino-6-[(4-metboxyphenyl)sulfanyl]-9H-purin-9-yl} methyl)cyclopropyl]oxy}methylphosphonic acid(Compound 96)
6-Chloroguanine derivative prepared in Preparation 6 (4.86g) was dissolved in 85 ml. of methanol and 1.4g of triethylamine and 2.9a of 4-methoxythiocresol were added. The reaction mixture was reacted under reflux condition for 24 hours. The reaction was stopped by adding 20ml of water, and the methanol was removed by distillation under reduced pressure. The reaction mixture was extracted with dichloroniethane and purified by silica gel column to give a compound wherein 6-position of guanine was substituted by 4-methoxyphenylthio group.
The compound thus obtained was reacted according to the same procedure as Example 1 and then recrystallized from a mixture of methanol-diethylether (1/20, v/v) to give the title compound.
lH NMR(MeOH-d4) 6 0.77 (m, 2H), 1.05 (m. 2H), 3.S7 (s, 3H), 3.92 (d, 2H). 4.45 (s, 2H), 7.10 (d, 2H), 7.59 (d, 2H), 8.09 (s, 1H) ESI: 438 (M+l)+ C17H2CN505PS
Example 28
Synthesis of {[l-({2-amino-6-[(4-nitrophenyl)sulfanyl]-9H-purin-9-yl}methyl) cyciopropyl]oxy}methylphosphonic acid(Compound 95)
The comound prepared in Preparation 6 was reacted acceding to the same procedure as =.\ ample 27 except that 4-nitrothiocresol was sea. insteac of 4-methoxythiocresol to give the title compound.
1H NMR(MeOH-d4)  0.86 (m, 2H), 0.95 (m. 2H), 3.82 (d. 2H), 4.35 (s, 2H), 7.S 1 (d, 2H), 8.22 (d, 2H), 8.72 (s, 1H)
ESI: 453 (M+l)+ C16H17N606PS

Example 29
Synthesis of ({l-[(2-ammo-6-hydroxy-9i/-purin-9-yl)methyl]-2-methyl cyclopropyl}oxy)methylphosphonic acid(Compound 97)
The 6-chloroguanine derivative prepared in Preparation 12 was consecutively reacted according to the same procedure as Examples 3 and 4 to give the title compound.
1H NMR(MeOH-d4)  0.73 (t, 1H), 1.15 (m. 1H), l.21(d, 3H), 1.38 (t, 1H), 1.48 (m, 1H), 3.85 (t, 1H), 3.96 (t, 1H), 4.42 (d, 1H), 4.69 (d. 1H), 9.12 (s. 1H)
Example 30
Synthesis of {[l-({2-amino-{6-(4-methoxyphenyl)sulfanyl]-9H-purin-9-ylj methyl)-2-methylcycloprbpylloxy} methylphosphonic acid(Compound 99)
The 6-chloroguanine derivative prepared in Preparation 12 was reacted according to the same procedure as Example 27 to give the title compound.
1H NMR(MeOH-d4)  0.67 (t, 1H), 1.13 (m. 2H), 1.20 (d. 3H), 1.45 (m, 1H), 3.S5 (m, 1H), 3.86 (s, 3H), 3.94 (m, 1H), 4.42 (d, 1H). 4.68 (d, 1H). 7.09 (d, 2H), 7.59 (d, 2H).9.00(s, 1H)
ESI: 452 (M+l)+ C18H22N505PS
Example 31
Synthesis of {[l-({2-amino-[6-(4-methylphenyl)sulfanyl]-9H-purin-9-yl} methyl)-2-methyIcyclopropyl]oxy}methylphosphonic acid(Compound 101)
The 6-chloroguanine derivative prepared in Preparation 12 was reacted according to the same procedure as Examole 25 to give the title compound.
1H NMR(MeOH-d4)  0.68 (t, 1H), 1.15 (m. 2H), 1.20 (d, 3H), 1.45 (m, 1H), 2.42 (s, 3H), 3.84 (m, 1H), 3.96 (m, 1H), 4.43 (d, 1H). 4.68 (d. 1H), 7.36 (d. 2H), 7.55 (d, 2H),9.05(s, 1H)
ESI: 436 (M+l)+ C18H22N504PS
Example 32
Synthesis of {[l-({2-amino-[6-(4-nitrophenyl)suIfanyI]-9iy-purin-9-yl}methyl) -2-methylcyclopropyl]oxy}methylphosphonic acid(Compound 100)
The 6-chloroguanine derivative prepared in Preparation 12 was reacted according to the same procedure as Example 28 to give the title compound.
1H NMR(MeOH-d4)  0.49 (t, 1H), 0.93 (m. 1H), 1.00 (d, 3H), 1.25 (m. 1H), 3.64 (m. 1H), 3.76 (m, 1H), 4.28 (d, 1H), 4.53 (d, 1H), 7.72 (d, 2H), 8.14 (d, 2H), 9.10 (s, 1H)
ESI: 467 (M+l)+, C17H19N606PS
Example 33
Synthesis of ({l-[(6-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl}oxy) methylphosphonic acid(Compound 103)
The adenine derivative prepared in Preparation 11 was reacted according to the same procedure as Example 1 to give the title compound.
!H NMR(MeOH-d4) 8 0.64 (t, 1H), 1.09 (m. !H), 1.20 (d, 3H), 1.43 (m. 1H). 3.83 (m. 1H), 3.95 (m, 1H), 4.49 (d, 1H), 4.75 (d, 1H). 5.49 (s, 2H). 8.39 (s, 1H), 8.55 is. 1H)
ESI: 314 (M1)+, CI 1H16N504P
Example 34
Synthesis of bis{[(t-butoxycarbonyl)oxy|methyI}({l-[(2-amino-9H-purin-9-yl) methyi]cyclopropyl}oxy)methylphosphonate(CompouDd 69)
The compound prepared in Example 5 (18~mg) was mixzc with 6ml of
N-methyl-2-pyrro me. and 300mg of triethylamine and 150mg chloromemyl
t-butylcarbonate were added. The reaction solution was stirred at room temperature for 4 hours. The reaction was stopped by adding I0ml of water, and the reaction mixture was extracted with ethyl acetate. The extract was distilled under reduced pressure and purified by silica gel column to give the title compound.
1H NMR(CDCl3) 0.86 (m, 2H), 1.06 (m, 2H), 1.47 (s, 18H), 4.01 (d, 4H), 4.22 (s, 2H), 5.00 (brs, 2H), 5.61 (m, 4H), 7.99 (s, 1H), 8.69 (s, 1H) ESP. 344 (M+l)+, C22H34N5O10P
Example 35
Synthesis of bis{[(isopropoxycarbonyl)oxy]methyl}({1 -((2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate(Compound 70)
The compound prepared in Example 5 (l00mg) was mixed with 5ml, of N-methyl-2-pyrrolidone, and 11Omg of triethylamine and 150mg of chloromethyl isopropylcarbonate were added. The reaction solution was stirred at 50 for 4 hours. The reaction was stopped by adding lOml of water, and the reaction mixture was extracted with ethyl acetate. The extract was distilled under reduced pressure and purified by silica gel column to give the title compound.
1H NMR(CDCl3)  0.88 (s, 2H), 1.06 (s, 2H). 1.29 (d, 2H), 1.31 (d, 2H), 4.01 (d. 4H), 4.21 (s. 2H), 4.92 (m, 2H), 5.01 (brs, 2H), 5.64 (m. 4H), 7.99 Example 36
Synthesis of ({l-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl)-2,2-dimethyl cyclopropyl}oxy)methylphosphonic acid(Compound 146)
The compound prepared in Preparation 32 was consecutively reacted according to the same procedure as Examples 1 and 4 to give the title compound.
1H NMR(MeOH-d4) 0.78 (d, 1H), 0.82 (d. 1H). 1.21 (s, 3H), 1.27 (s, 3H), 3.90 (d. 1H). 3.91 (d, 1H), 4.58 (s, 2H), 9.12 (s. 1H) ESI: 344 (V - ". C12HISN505P
Example 37
Synthesis of ({l-[(2-amino-9H-purin-9-yl)methyl]-2.2-dimethylcyclopropyl} oxy)methylphosphonic acid(Compound 147)
The compound prepared in Preparation 32 was reacted according to the same
procedure as Example 5 to give a compound wherein 6-position of guanine was reduced by hydrogen.
lH NMR(CDC13)  0.60 (d, 1H), 0.82 (d, 1H), 1.21 (s, 3H), 1.22 (s, 3H), 1.22 (m, 15H), 3.73 (m, 1H), 3-87 (m, 1H), 4.13 (d, 1H), 4.49 (d, 1H), 4.67 (m, 2H), 4.98 (brs, 2H),8.09(s, lH),9.67(s, 1H)
The compound thus obtained was reacted according to the same procedure as Example 1 to give the title compound.
1H NMR(MeOH-d4)  0.74 (d. 1H), 0.81 (d, 1H), 1.21 is. 3H). 1.26 (s, 3H). 3.91 (d, 2H).4.49(d, 1H), 4.57 (d, 1H), 8.63 (s, 1H), 8.74 (s. 1H) ESI: 328 (M1)+, C12H18N504P
Example 38
Synthesis of ({l-[(6-amino-9H-purin-9-yl)methyl]-2.2-dimethylcycIopropyl} oxy)methylphosphonic acid(Compound 148)
The compound prepared in Preparation 31 was reacted according to the same procedure as Example 1 to give the title compound.
lH NMR(MeOH-d4)  0.77 (d, 1H), 0.79 (d, 1H), 1.25 (s. 3H). 1.28 (s, 3H). 3.90 (d, 2H), 4.61 (d, 1H), 4.70 (d, 1H), 8.38 (s, 1H), 8.51 (s. 1H) ESI: 328 (M+l)+, C12H18N504P
Example 39
Synthesis of (E)-2-{l-l(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl} ethenylphosphonic acid(Compound 130)
The compounc prepared ir. Preparation 26 was reacted according to the same procedure as Example 1 to give phosphonic acid derivative.
1H NMR(MeOH-d4) 6 1.07 (t, 2H), 1.33 (t. 1H), 4.41 (s. 2H), 5.76 (dd, 1H), 6.45 (dd, lH).9.1S(s, 1H)
The compound thus obtained was reacted according to the same procedure as Example 4 to give die title compound.
1H NMR(MeOH-d4)  1.08 (t, 2H), 1.34 (t, 1H), 4.38 (s, 2H), 5.78 (dd, 1H), 6.46 (dd, 1H), 9.11 (s, 1H)
ESI: 312 (M+l)+, CI 1H14N504P
Example 40
Synthesis of 2-{l-[(2-amino-9H-purin-9-yl)methyl]cyclqpropyl}ethyl
phosphonic acid(Compound 139)
The compound prepared in Preparation 26 was reacted according to the same procedure as Example 5 to give the title compound.
1H NMR(MeOH-d4) 0.58 (t, 2H). 0.85 (t. 2H), 1.42 (m. 2H). 1.95 (m, 2H), 4.11 (s, 2H), 5.78 (dd, 1H), 8.55 (s, 1H), 8.75(s. 1H) ESI: 298 (M-l)+, CI 1H16N503P
Example 41
Synthesis of (E)2-{ l-{(6-amino-9H-purin-9-yl)methyl]cyclopropyl}ethenyl phosphonic acid(Compound 132)
The compound prepared to Preparation 25 was reacted according to the same procedure as Example 1 to give the title compound.
1H NMR(MeOH-d4) 0.94 (t, 2H). 1.20 (t, 2H), 4.36 (S. 2H). 5.63 (dd, 1H), 6.37 (dd, 1H). 8.30 (s. 1H), 8.31 (s, 1H)
EST- 296 (M-l)+, C11H14N503P
Example 42
Synthesis. of 2-{l-[(6-amino-9H-purin-9-yl)methyl]cyelopropyl}ethyl
phosphonic acid(Compound 140)
The compound prepared in Preparation 25 was reacted according to the 'same procedure as Example 5 to give the title compound.
1H NMR(MeOH-d4)  0.58 (t, 2H), 0.87 (t, 2H), 1.37 (m, 2H), 1.97 (m, 2H), 4.24 (s, 2H), 8.31 (s, 1H), 8.42 (s, 1H)
ESI: 298 (M+l)+, C1 1H16N503P
Example 43
Synthesis of 2-{l-((2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl} ethylpbosphonic acid(Compound 138)
The compound prepared in Preparation 26 was reacted according to the same procedure as Example 12 to give a compound wherein 6-position of guanine was substituted by ethoxy group.
1H NMR(CDC13)  1.00 (t, 2H), 1.10 (t, 2H), 1.16-1.21 (m. 9H). 3.90 (m, 4H), 4.01 (m. 2H), 4.13 (s. 2H), 4.92 (s, 2H), 5.58 (dd. 1H), 6.49 (dd, 1H). 7.62 (s. 1H)
The compound thus obtained (80mg) was dissolved in methanol and reacted under hydrogen atrmosphere in the presence of 20mg of 10% Pd/C to give a compound wherein double bond was reduced.
1H NMR(CDCl3)  0.49 (t, 2H), 0.66 (t. 2H), 1.21 (t, 6H). 1.42 (m. 2H). 2.01 (m. 2H), 3.99 (m, 6H), 4.96 (s. 2H), 7.59 (s, 1H)
The compound thus obtained was reacted according to the same procedure as Example 1 to give the title compound.
1H NMR(MeOH-d4)  0.60 (t, 2H), 0.87 (t, 2H), 1.47 (m. 2H). 1.97 (m, 2H), 4.16 (s, 2H). 9.12 (s, 1H)
ESI:314(M1)+. - H16N50-1*
Example 44
Synthesis of 2-{l-i(2-amino-9H-purin-9-yl)methyl]cyclopropyl}propyl phosphonic acid(Compound 144)
The compound prepared in Preparation 35 was consecutively reacted according to
the same procedure as Preparations 24,26 and Example 5 to give the title compound.
1H NMR(MeOH-d4)  0.62-0.77 (m, 4H), 1.04 (d, 3H), 1.52 (m, 2H), 1.90 (m, 1H), 4.24 (m, 2H), 8.58 (s, 1H), 8.74 (s, 1H) ESI: 312 (M1)+, C12H18N503P
Example 45
Synthesis of (E)-2-{l-[(6-amino-9H-purin-9-yl)methyl]cyclopropyI}-l-propenylphosphonic acid(Compound 137)
The compound prepared in Preparation 35 was consecutively reacted according to the same procedure as Preparations 24, 25 and Example I to give the title compound.
1H NMR(MeOH-d4)  0.86 (t, 2H), 1.10 (t. 2H), 2.19 (d, 3H). 4.3S (s. 2H), 5.23 (d. lH),8.34(s. 1H), 8.3"(s, 1H)
ESI:310(M-l)+.C12H16N5O3P
Example 46
Synthesis of 2-{l-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}propyl phosphonic acid(Compound 143)
The compound prepared in Preparation 35 was consecutively reacted according to the same procedure as Preparations 24, 25 and Example 5 to give the title compound.
1H NMR(MeOH-d4) 6 0.65 (t, 2H), 0.78 (t. 2H), 0.95 (m, 1H), 1.00 (d, 3H), 1.53 (s, 1H), 1.90 (m. 1H). 4.3 (q, 2H), 8.41 (s, lH).S.45(s, 1H) ESI:312(M1)\C12H18N503P
Example 47
Synthesis of bis 2,2,2-trifluoroethyl) ({l-[(6-amino-9H-purin-9-yl),-methyl] cyclopropyl}oxy)methylphosphonate(Compound 48)
To the methylphosphonic acid prepared in Example 1 (150mg) was added dropwise dichloromethane. 0.73ml of N,N-diethyltrimethylsilylamine was added dropwise thereto, and the resulting mixture was stirred at room temperature for 2 hours. Oxalyl
8
chloride (0.15ml) and 2 drops of dimethylformamide were added to the reaction vessel. The mixture was stirred for further 2 hours and the solvent was removed by distillation under reduced pressure. To the residue were added 10ml of pyridine and 2ml of trifluoroethanol, which was then reacted under stirring for 16 hours. The solvent was removed by distillation under reduced pressure and the residue was purified by silica gel column to give the title compound.
1H NMR(CD3OD) 1.02 (m, 4H), 4.30 (d, 2H), 4.53 (m, 6H), 8.40 (s, 1H), 8.46(s, 1H)
ESI: 464 [M+H]+ C14H16F6N504P
Example 48
Synthesis of bis(2,2,2-trifluoroethyl) ({l-[(2-amino-9H-purin-9-yl)methylJ cyclopropyI}oxy)methylphosphonate(Compound 49)
The compound prepared in Example 5 was reacted according to the same procedure as Example 47 to give the title compound.
1H NMR(CDCl3)  0.88 (m, 2H), 1.04 (m, 2H). 4.07 (d, 2H). 4.22 (s. 2H), 4.33 (m. 4H), 5.06 (br.s. 2H), 7.92 (s, 1H), 8.68 (s. 1H) ESI: 464 [M+H]+ C14H16F6N504P
Exampk 49
Synthesis of bis(2,2,2-trifluoroethyl) (l-({2-amino-(6-(4-methylphenyl) sulfanyl)-9H-purin-9-yl}methyl)cyclopropyl]oxy}methylphosphonate(Compound 62)
The compound prepared in Example 25 was reacted according to the same procedure as Example 47 to give the title compound.
1H NMR(CDCl3)  0.88 (m, 2H), 1.03 (m, 2H). 2.39 (s, 3H). 4.06 (d, 2H), 4.19 (s, 2H), 4.33 (m, 4H), 4.76 (br.s, 2H), 7.22 (d, 2H), 7.50 (d. 2H), 7.82 (s. 1H) ESI: 586 [M+H].+ . C21H22F6N504PS
Example 50
Synthesis of bis(2,12-rrifluoroethyl) [(l-{[2-amino-6-hydroxy-9H-purin-9-yl]
methyl}cyclopropyl)oxy)methylphosphonate(Compound45)
The compound prepared in Example 4 was reacted according to the same procedure as Example 47 to give the title compound.
1H NMR(CDC13)  0.91 (m, 2H), 1.05 (m, 2H), 4.08 (d, 2H), 4.17 (s, 2H), 4.35 (m, 4H), 4.70 (s, 2H), 7.69 (s, 1H)
MW=478 [M+H]+ 479 C14H16F6N505P
Example 51
Synthesis of bis(2,2,2-trifluoroethyl)(l-{[2-amino-6-cyclopropyIamino-9H-purin-9-yl]methyl}cyclopropyl)oxy]methylphosphonate(Compound 50)
The compound prepared in Example 7 was reacted according to the same procedure as Example 47 to give the title compound.
1H NMR(CDC13)  0.60 (br.s, 2H), 0.84 (br.s. 4H), 1.01 (m. 2H), 2.98 (br.s, 1H), 4.05 (d. 2H), 4.14 (m, 4H), 4.70 (br.s. 2H), 5.67 (br.s. 1H). 7.60 (s. 1H) ESI: 519, [M+H]+, C17H21F6N604P
Example 52
Synthesis of ({l-((2-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl}oxy) methylphosphonic acid(Compound 98)
The 6-chloroguanine derivative prepared in Preparation 12 was reacted according to the same procedure as Example 5 to give the title compound.
1H NMR(MeOH-d4)  0.68 (t, 1H), 1.13 (m. 1H), 1.21 (d, 3H), 1.42 (t, 1H), 3.84 (i. 1H), 3.97 (t. 1H) 4.40 (d. 1H) 4.66 (d. 1H), 8.63 (s. i H), 8.73 (s. 1H) -ESI: 314 (M1)+. C1 1HI6X504P
The compound of the present invention exhibits a potent pharmacological effect to a hepatitis B cell line, HepG2.2.15, and a transgenic mouse, widely used for development of a therapeutic agent against hepatitis B, when intravenously or orally adminis'iered. The experimental procedures and results are described below.
Experiment 1
Measurement and Analysis of Inhibition Effect against Hepatitis B Virus
(HBV)
(1) Cell Culture and Treatment with Drugs
HepG2.2.15 cell (M.A Shells et al., P.N.A.S. 84, 1005(1987)), a hepatocarcinoma cell line producing hepatitis B virus, was cultured in DMEM medium(GIBCO BRL. #430-22001 containing 10% FBS(Fetus bovine serum, GIBCO BRL. #16000-044). 1% ABAM (Antibiotic-Antimycotic, GIBCO BRL, #16000-028) and 400/µg/ml of geneticin( Sigma, #G-9516) in a T-75 flask under the conditions of 5% CO: incubator and 37ºC by dividing in a ratio of 1:3 at an interval of 3 days. The cells were distributed into a 96-well plate in the amount of 4x104/well and then when 80-90% of cell density was achieved, the old medium was changed with 200µl. of DMEM medium containing 2% FBS. 1% ABAM and 400µg/mlof geneticin. The drug solution was sequentially diluted five-fold each time, from 100 M to 0.16 M. In order to minimize an experimental error, each treatment was repeated 2-3 times for the respective drugs. The medium was changed every two days. On 10 days after the treatment with drug, 100µlof the medium was collected and the degree of inhibition of viral replication by drugs was determined through quantitative PCR (Polymerase Chain Reaction).
(2) Determination of Cytotoxicity
After 100µl of the medium was collected on 10th day from the treatment with drug, 7.5mginft of MTT (Thiazolyl Blue Tetrazolium Broide. Amresco. #0793-5G> solution was added to each well in the amount of 30µl/well and each cell was cultured for 2 hours in a 5% CO2 incubator at37ºC The solution was discarded, and an sopropanol solution containing 1 • Triton X-l-V. and 0.4µl. of c-HCI was added to ean. meil in the amount of 120µl/well. The cells thus dyed, were transferred to the isopropanol solution by shaking for 2 hours. Absorbance at 540nm was measured by Elisa Reader.
(3) PCR Estimation of Inhibition Effect on Hepatitis B Virus Replication
The degree of inhibition by drugs on the replication of hepatitis B virus was . determined using the cell culture solution collected on 10th day after the treatment with the drug. The cell culture solution treated with each drug was diluted ten-fold with distilled water and subjected to a pretreatment to destroy the cells by heating them for 15 minutes at 95 ºC. For the PCR amplification of the gene fragment of about 320bp, the 2001-base position that is conserved in all sub-strain of hepatitis B virus and 2319-base position that is between the core antigen gene and polymerase gene were used as 5'-end and 3'-end primer, respectively. Then, the amount of genomic DNA of hepatitis B virus was quantified, and the inhibitory effect by drugs on the replication of hepatitis B virus was determined on the basis thereof.
First, the cell culture solution of hepatitis B virus that was not treated with drug was sequentially diluted and amplified through the PCR. The amplified DNA was subjected to electrophoresis on 2% agarose, gel and stained with ethidium bromide (EtBn to be analyzed by IS-1000 (Innotech Scientific Corporation) Digital Imaging System. Analysis of the cell culture solution treated with drug was then carried out using the dilution fold in the range where linearity is maintained. The DNA obtained from the group treated with drug was amplified through the same PCR method, subjected to electrophoresis on 2% agarose gel, stained with ethidium bromide, and analyzed by IS-1000. The degree of inhibition by drugs in the viral replication was quantified by calculating the ratio of test group to control group. Table S summarizes the inhibitory-effect (pharmaceutical activity and toxicity) of the typical compounds of the present invention.

Table 8

(Table Removed)
As can be seen from the results of Table 8, the compound according to the present
invention exhibits 4 to 10-fold greater activity than the comparative compound PMEA that is on Phase III in clinical trials.
Experiment 2
Pharmacological Test on Transgenic mouse (T/G mouse)
The compounds were administered via subcutaneous and oral routes in the following animal test.
The test compounds were administered to 4-5 weeks old HBV transgenic mice, which were obtained from FVB strain mice according to a method described in a reference (see, Jone D. Morrey. Kevin W. Bailey, Brent E. Korba, Robert W. Sidwell. "Utilization of transgenic mice replicating high levels of hepatitis B virus for antiviral evaluation of lamivudine" Antiviral research, 1999, 42, 97-108), subcutaneously for 9 days in the amount of 10mg/kg/day and orally for 9 days in the amount of 10, 2 and 0.4mg/kg/day, once a day, respectively (the same number of males and females were used). Blood was collected from the tail of the mouse and 5µl. of serum was obtained. To this serum was added 15ml of Genereleaser sol, which was then pretreated in different temperatures. HBV DNA was taken from the pretreated solution. The DNA was amplified by the PCR (Polymerase Chain Reaction) in the presence of 4µl of 10 x buffer (Perkin Elmer), 0.8µl. of l0mM dNTP, 500ng of the same HBV primers as used in Experiment 1. 2.125mM of MgCl2, DMSO and Taq polymerase. The amount of HBV DNA was analyzed by electrophoresis in order to evaluate a pharmacological effect of the compound of the present invention. The results are described in the following Table 9. In the following Table 9, mice showing pharmacological effect means the mice whose blood does not contain HBV DNA.
Table 9

(Table Removed)

* The result means ""number of mice showing pharmacological effect / number of total mice
As can be seen in the above Table 9, the compound of the present invention shows a potent hepatitis B therapeutic effect in the tested animals when orally or subcutaneouslv administered. Particularly, since the compound of the present invention is superior to the comparative compound PMEA, which is on Phase III in clinical trials, it is expected that the compound of the present invention may be used very effectively for the tr atment of hepatitis B.

We claim:
l. A phosphonate compound represented by the following formula (2)

(Formula Removed)

Wherein,
R1, R2, R3, R7 and R8 independently of one another represent hydrogen, halogen, hydroxy, amino, C1-C7-alkyl, C2-C6-alkenyl, C1-C5-alkylamino, C1-C5-aminoalkyl, or Cr C5-alkoxy,
R4 and R5 independently of one another represent hydrogen, or represent C1-C4-alkyl optionally substituted by one or more substituents selected from the group consisting of halogen (particularly, fluorine), C1-C4-alkoxy, phenoxy, C7-C10-phenylalkoxy and C2-C5-acyloxy, or represent C1-C7-acyl, C6-C12-aryl or optionally substituted carbamoyl, or represent -(CH2)m-OC(=0)-R6 wherein m denotes an integer of 1 to 12 and R6 represents C1-C12-alkyl, C2-C7-alkenyl, C1-C5-alkoxy, C1-C7alkylamino, di(C1-C7-alkyl) amino, C3-C6-cycloalkyl, or 3 to 6-membered heterocyde having 1 or 2 hetero atoms selected from a group consisting of nitrogen and oxygen,
Y represents -0-, -S-, -CH(Z)-, =C(Z)-, -N(Z)-, =N-,-SiH(Z)-, or =Si(Z)-, wherein Z represents hydrogen, hydroxy or halogen, or represents C1-C7-alkyl, C1-C5-alkoxy, allyl, hydroxy-C1-C7-alkyl, C1-C7aminoalkyl or phenyl,
and L represents a leaving group
2. A phosphonate compound represented by the formula (2) substantially as herein described with reference to the foregoing description and the
accompanying table and examples.

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Patent Number

279726

Indian Patent Application Number

7792/DELNP/2008

PG Journal Number

05/2017

Publication Date

03-Feb-2017

Grant Date

30-Jan-2017

Date of Filing

16-Sep-2008

Name of Patentee

LG LIFE SCIENCES LTD

Applicant Address

20, YOIDO-DONG, YOUNGDUNGPO-KU, SEOUL 150-010, REPUBLIC OF KOREA

Inventors:

#	Inventor's Name	Inventor's Address
1	KIM, GYOUNG-WON	R & D PARK, LG LIFE SCIENCES LTD.,104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIC OF KOREA
2	CHOI, JONG-RYOO	R & D PARK, LG LIFE SCIENCES LTD.,104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIC OF KOREA
3	KIM, JEONG-MIN	R & D PARK, LG LIFE SCIENCES LTD.,104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIC OF KOREA
4	ROH, KEE-YOON	R & D PARK, LG LIFE SCIENCES LTD.,104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIC OF KOREA
5	CHO, DONG-GYU	R & D PARK, LG LIFE SCIENCES LTD.,104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIC OF KOREA
6	LIM, JAE-HONG	R & D PARK, LG LIFE SCIENCES LTD.,104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIC OF KOREA
7	HWANG, JAE-TAEG	R & D PARK, LG LIFE SCIENCES LTD.,104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIC OF KOREA
8	CHO, WOO-YOUNG	R & D PARK, LG LIFE SCIENCES LTD.,104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIC OF KOREA
9	JANG, HYUN-SOOK	R & D PARK, LG LIFE SCIENCES LTD.,104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIC OF KOREA
10	LEE, CHANG-HO	R & D PARK, LG LIFE SCIENCES LTD.,104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIC OF KOREA
11	CHOI, TAE-SAENG	R & D PARK, LG LIFE SCIENCES LTD.,104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIC OF KOREA
12	KIM, CHUNG-MI	R & D PARK, LG LIFE SCIENCES LTD.,104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIC OF KOREA
13	KIM YONG-ZU	R & D PARK, LG LIFE SCIENCES LTD.,104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIC OF KOREA
14	KIM, TAE-KYUN	R & D PARK, LG LIFE SCIENCES LTD.,104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIC OF KOREA
15	CHO, SEUNG-JOO	R & D PARK, LG LIFE SCIENCES LTD.,104-1, MOONGI-DONG, YUSEONG-GU, TAEJEON 305-380, REPUBLIC OF KOREA

PCT International Classification Number

C07F 9/6561

PCT International Application Number

PCT/KR2002/00086

PCT International Filing date

2002-01-18

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	2001-3087	2001-01-19	Republic of Korea