TWI323263B - Novel acyclic nucleoside phosphonate derivatives, salts thereof and process for the preparation of the same - Google Patents

Description

1323263 Α7 _ Β7 Ministry of Economic Affairs Intellectual Property Bureau member H Consumer Cooperative Printed -! V. Description of Invention (1) [Technical Category I This invention relates to acyclic nucleoside phosphonate derivatives represented by the following formula (1):

Wherein ^^ represents a single bond or a double bond, and R1, R2, R3, R7 and R8 independently of each other represent hydrogen, arginyl, hydroxy, amine, C" to C7-alkyl, c2 to C6-alkenyl, C! To C5-alkylamino, C! to C5-aminoalkyl or q to C5-alkoxy, R4 and R5 independently of each other represent hydrogen, or means that (^ to C4•alkyl is required to pass one or more Substituents selected from the group consisting of halogen (especially fluorine), Ci to c4-alkoxy, phenoxy, C:7 to C|G-benzoicoxy and c2 to c5-decyloxy Substituted, or · represents q to c7-fluorenyl, (: 6 to c12-aryl or, if desired, substituted with a carbamoyl group, or represents _(CH2)m-OC(=)-R6 wherein m is from 1 to 12 Integer and R6 represent Ci to C12-alkyl, C2 to C7.alkenyl, Q to (V alkoxy, q to C7-alkylamino, bis(q to C7-alkyl)amine, C: a 3 to Cg-cycloalkyl group or a 3 to 6 membered heterocyclic ring having 1 or 2 hetero atoms selected from the group consisting of nitrogen and oxygen, and Y represents _0-, _S-, -CH(Z)-, =C(Z)-, -N(Z)-, =N·, -SiH(2:)- or = Si(Z)-' where z represents hydrogen, a meridine or a halogen, or is represented as (^ to ( V alkyl, q to c5-alkoxy, alkene a group, a hydroxy group to a c7-alkyl group, a C! to C7-aminoalkyl group or a phenyl group, Q represents a group having the formula: * 4* -71 0 C ua \ ° * * - i 1 92012 (please Read the notes on the back and fill out this page) ν·—Aw Order---------Line|Pain 1332263

Description of the invention

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The Intellectual Property Office of the Ministry of Economic Affairs, the Consumers' Cooperatives, prints 乂^^ and ... independently of each other to represent hydrogen or dentate, or as 〇, to alkyl, (^ to Cs_alkoxy, allyl hydroxy- ^ to alkyl, phenyl or alum, each of which is optionally substituted by nitro or q to c5 alkoxy or '(6 to C1G_arylthio which may optionally be via nitro, amine, C, To (6-alkyl or Ci to c4-alkoxy substituted, or represents 〇6 to c^-arylamino, 0! to CV alkylamino, bis(Cii c? alkyl)amine, C3 To a C0-cycloalkylamino group or structure is ten wherein n is an integer of 1 or 2 and Υΐ represents 0, CH2 or NR (R represents (^ to c7-alkyl or (:6 to C12-aryl), the non A cyclic nucleoside phosphonate derivative is a useful antiviral agent (particularly for hepatitis B virus). The invention also relates to a pharmaceutically acceptable salt of the acyclic nucleoside phosphonate derivative, stereo Isomers and preparation methods thereof [Background Art] Commercially available anti-cancer and anti-viral activities of cockroaches or biting derivatives, including AZT, 3TC and ACV, etc. Since the acyclic nucleoside phosphonate derivatives have shown their potent antiviral effects, cidopovir has been commercialized as an antiviral agent and many of the paper scales are applicable to the National Standard (CNS) A4. Specifications (2) 0x297 public)

SB 2 92012 (please read the notes on the back and fill out this page) .0 -----I—I order----;-----line” 1323263

Compounds (including PMEA and PMPA) are now in clinical trials. However, the compounds developed in the early stage are not completely toxic or pharmaceutically active, and therefore it is still required to develop a compound which is nontoxic and has excellent activity. Previous studies on purine or pyrimidine derivatives or acyclic nucleoside phosphonate derivatives have been reported to date as follows. Patent Aspects: U.S. Patent No. 5,917,647; U.S. Patent No. 5,797, 061; U.S. Patent No. 5,886,179; U.S. Patent No. 5,837,871; U.S. Patent No. 6,069,249; W099/09031; W096/09307; WO95/22330; U.S. Patent No. 5,935,946 U.S. Patent No. 5,877,166; U.S. Patent No. 5,792,756; 'Internationai Jouftiai of yintimicr" 〇bial Agents 12 (1999), 81-95; Nature 323 (1986), 464; Heterocycles 31 (1990), 1571; J Med. Chem. 42 (1999), 2046; 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 〇 [Invention Disclosure] Therefore, the inventors have intensively studied And develop a biological activity (medical effect) with superior growth and a non-commercial or non-clinical stage Cyclic nucleoside phosphonate derivatives are also less toxic compounds. As a result, it was found that the compound of the above formula (1) is characterized by its unique chemistry (please read the notes on the back and then fill out this page) # --------订---------- Line" Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

92012 Α7 V. DESCRIPTION OF THE INVENTION (4) The structure and exhibiting effective pharmaceutical activity, thus completing the present invention. The purpose of this month is to provide a compound of formula (1), a pharmaceutically acceptable salt or an isomer thereof for use with a good antiviral agent. Another object of the present invention is to provide a process for the preparation of a compound of formula (1). A further object of the present invention is to provide an intermediate product which facilitates the preparation of the compound of formula (1). BEST MODE FOR CARRYING OUT THE INVENTION The compound of the formula (1) of the present invention, as shown below, has a natural base such as adenine, guanine, uracil, cytosine, thymine or a derivative thereof: 0 OR4 R1 (1) wherein two L represent a single bond or a double bond, and R1, R2, R3, R7 and R8 independently of each other represent hydrogen, dentate, hydroxyl, amine, to C7-alkyl, c2 to C6-lean a group, q to C5-alkylamino group, q to C5. aminoalkyl group or q to C5-alkoxy group, R4 and R5 independently of each other represent hydrogen, or represent (^ to alkyl group as needed by one or more Substituted from a substituent consisting of a group consisting of halogen (especially fluorine), Ci to c4-alkoxy, phenoxy, C7 to C]G-phenylalkoxy and q to c5-decyloxy Or means (^ to C7-fluorenyl, <:6 to C12-aryl or, if necessary, taken by carbamidyl, or _(CH2)m-OC(=)-R6 wherein m is 1 to An integer of 12 and R6 represent c! to ci2-alkyl, <:2 to C7-alkenyl, q to CV methoxy, C to C7-alkylamino 'di-C7-alkyl)amine ( Please read the notes on the back and fill out this page) -Γ . --------Book --------- Line. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 4 •••';,

92012 1323263

5. Description of the invention (5). A group, a C0-cycloalkyl group or a 3- to 6-membered heterocyclic ring having i or 2 hetero atoms selected from the group consisting of nitrogen and oxygen, Y represents -0, - S., -CH(Z)-, =C(Z)-, -N(Z)· ', _SiH(z)· or =si(z)- 'where z represents hydrogen, hydroxy or halogen, or c 1c7-alkyl, C to c5-alkoxy, propyl, thiol-Ci to c, alkyl to Ci to C7-aminoalkyl or stupid, Q represents a group having the formula:

or

(Jing Xian read the back of the note and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperatives printed again 1, 乂 2, \3 and 乂 4 independently of each other to represent hydrogen, amine 'trans-based or halogen, or Is C, to (:7-alkyl, Ci to c5-alkylindenyl, allyl, hydroxy-C! to. (:7.alkyl, phenyl or phenoxy each is optionally via a nitro group or Ci to alkoxy substituted, or 匕 to Ci. - arylthio which may optionally be substituted by nitro, amine, Ci to c6-alkyl or Ci to C4. alkoxy, or C6 to c12-aryl Amino, q to c7-alkylamino, di-c7-alkyl)amino, c3 to C6-cycloalkylamino or the structure is γΙ〇Η·wherein η is an integer of 1 or 2 and γι represents 〇 , CH2 or NR (R represents Ci to c7-alkyl or C6 to C12-aryl). Since the compound of the formula (1) of the present invention may have one or more asymmetric carbon atoms in the structure depending on the kind of the substituent. , which can be mirrored individually

92012 -- I I-----订 ------ 线. 3263 A7 ___B7 V. Description of the invention (6) The presence of a structure, a non-specular isomer or a mixture thereof containing a racemic compound. Further, when the structure contains a double bond, it may exist in the form of an E or z isomer. Accordingly, the present invention also encompasses all of these isomers and their chelates. Further, the compound of the formula (1) of the present invention can form a pharmaceutically acceptable salt. Such salts include non-toxic acid addition salts containing pharmaceutically acceptable anions such as mineral acid (eg, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrogen acid, argonic acid, etc.) addition salts, organic carboxylic acids ( Such as tartaric acid 'formic acid, citric acid, acetic acid, tri-acetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, anarubic acid, etc.) addition salt, or acid (such as smolderic acid An addition salt of benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid or the like, preferably sulfuric acid, hydrazine acid or hydrogen dentate. A compound having an effective pharmaceutically active activity is shown in the formula (1). Preferred compounds are those wherein = represents a single bond, and R1, R2, R3, R7 and R8 independently of each other represent hydrogen, fluorine, hydroxyl, c丨 to C7-alkane. a group, a c2 to c6-alkenyl group, a C! to C5-alkylamino group, a Ci to c5-aminoalkyl group or (^ to a c5-methoxy group, R4 and R5 independently of each other represent hydrogen, or represent (^ To the C4-alkyl group is optionally substituted with one or more substituents selected from the group consisting of fluorine, 1 to C4-alkoxy and phenoxy, or a methyl group substituted by q to C5-alkyl Indenyl, or represents -(CH2)m-OC(=)-R6 wherein m is an integer from 1 to 12 and R6 represents C! to C12-alkyl, C2 to C7-alkenyl, C丨 to C5-alkoxy Base, q to C7-alkylamino group, di(C! to C7-alkyl)amino group, C3 to C6- (please read the back note before refilling this page) — — — — — — — ---II---Line· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed This paper scale applies China National Standard (CNS) A4 specification (210 X 297 mm) 6 92012 1323263 A7

V. INSTRUCTION DESCRIPTION (7) A cycloalkyl group or a 3 to 6 membered heterocyclic ring having 1 or 2 hetero atoms selected from the group consisting of nitrogen and oxygen, and Y represents -0, -S-, -N ( Z)-, wherein Z represents a hydroalkyl group or a hydroxy group to a C7-alkyl group, and Q represents a group having the formula:

ΛΤ Λ~ Ji

or

(Jing Xian read the back of the note and fill out this page) -Γ. - Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed in which X1 represents hydrogen, amine, hydroxyl or halogen, or expressed as (^ to C7- Alkyl, q to cs-alkoxy, hydroxy-Ci to c:7-alkyl or phenoxy are each optionally substituted by nitro or Ci to c5-alkoxy, or by c6 to c1Q•aromatic sulfur It may optionally be substituted by nitro, amine, Ci to C6-alkyl or Ci to c4-alkoxy, or (6 to c12-arylamino, q to c7-alkylamino, di ( (^ to C7-alkyl)amino group, (:3 to c6-cycloalkylamino group or structure is ^〇*10 wherein η is an integer of 1 or 2 and Y! represents 〇, CH2 or NR (R represents C , to C7-alkyl), and X2, X3 and X4 independently of each other represent hydrogen, amine, mercapto, halogen, Cj to C7-alkyl, Ci to c5-alkoxy or Ci to c7-alkylamine The most preferred compound is wherein - represents a single bond, R1, R3, R7 and R8 independently of each other represent hydrogen, R2 represents hydrogen or methyl, and R4 and R5 independently of each other represent a third butylcarbonyloxy group. Base, isopropoxycarbonyloxymethyl or paper scale Use Chinese National Standard (CNS) A4 specification (210 x 297 mm) 7 92012

' IIIIIII * — — — 1 — — I — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — The group Y represents -Ο-, and Q represents wherein X1 represents hydrogen, hydroxy, ethoxy, 4-methoxyphenylthio or 4-nitrophenylthio, and X2 represents an amine group. Typical examples of the compound of the formula (1) of the present invention are described in the following Table 1 to the table (please read the precautions on the back side and then fill in the page), 0--------book-------- -Line" Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Printed on this paper scale Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 8 92012 1323263 A7 B7 V. Description of invention (9) Table 1 a Compound number structure Compound number structure NH N^^s·

OH

NH2 SN

Cl

O (Please read the notes on the back and fill out this page) OH〇 v ^xbk into Hi

HCV^q. I OH

OH

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed Clothes 7

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% This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 92012 1323263 A7 B7 V. Invention Description () Table lb

HO-p^*〇 I OH nh2

'A

H OH

*nh2 12

(Please read the notes on the back and fill out this page) -1 · 0

This paper scale applies to China National Standard (CNS) A4 specification (210 297 297 mm) 10 92012 ^•1 1323263 A7 B7 V. Invention Description (U) Table 1 c Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

17 Mjl person HO, Bu people NH: OH 18 t 19 ΝΗχ OH 20 nh2 21 OMe HO-b. OH 22 OMe 23 OEt H. Bu. OH 24 OB (please read the notes on the back and fill out this page) l·. -—Aw -------- order --------- line paper size applies to Chinese national standards (CNS ) A4 size (2) 0 χ 297 mm) 11 92012 1323263 A7 B7

Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

This paper scale applies to China National Standard (CNS) A4 specification (210 297 297 mm) 12 92012 1323263 A7 B7 V. Invention Description (13) Table 1 e Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative print ί..... 33 OH 34 nh2 °i 35 OH 36 4~ Bu Said H i 37 0 OH 38 0 39 1 ii [ 0 OH 40 ----^ I-----------Book----- ----Line (please read the notes on the back and fill in this page) This paper scale applies to China National Standard (CNS) A4 specification (210 297 297 mm) 13 92012 1323263 A7 B7 V. Invention Description (Μ) Table If

This paper scale applies to China National Standard (CNS) A4 specification (210 297 297 mm) 14 92012 1323263 A7 B7 V. Description of invention (l5 Table 2 a

Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed r5o, compound number X' X" R4 Rs 45 OH nh2 CH2CF3 CH2CF, 46 C1 nh2 CH2CF3 CH2CF3 47 nh2 nh2 CH2CF3 CH2CF3 48 NH2 H CHjCFa CH2CF3 49 Η nh2 CH2CF3 CH2CF3 50 ΝΗ- <] nh2 CH2CF3 ch2cf3 51 NHCzHj nh2 CH2CF3 CH2CF3 52 NCCHsh nh2 CH2CF3 CH2CF3 53 NH—<^ nh2 CH2CF3 CHzCFa 54 och3 nh2 CH2CF3 CH2CF3 55 ch3 nh2 CH2CF3 CHaCFs 56 CzHj NHz CH2CF3 CH2CF3 57 o NHz CH2CF3 CH2CF3 58 NO NHa CH2CT3 CH2CF3 59 r~~\ NN- nh2 CH2CF3 CH2CF3 (please read the notes on the back and fill out this page) # --------订---------Line · Mechanical scale applicable to China Standard (CNS) A4 specification (210 χ 297 mm) -4C • I7 -vt 15 92012 1323263 A7 B7 V4 -, invention description (I6t 2b Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 60 〇NHa CHsCFa ch2cf3 61 s ^O nh2 CH2CF3 CH2CF3 62 NHa ch2cf3 ch2cf3 63 S—“nh2 CH2CF3 CH2CF3 64 s*H〇~N〇2 nh2 CH2CF3 CH2CF3 65 nh2 HH 66 nh2 HH 67 NHz HH 68 nh2 69 H nh2 >0 person. ; 〇人. Seven (please read the note on the back and then fill out this page) Order --------- Line · Sheet of paper K degree applies China National Standard (CNS) A4 specification (210 χ 297 mm 16 92012 1323263 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing nuclear-V; V. Invention description (Π Table 2 c 70 Η νη2 71 Η νη2 72 Η μη2 >C^〇\^Y 73 Η νη2 person 0^|<>〇人74 Η νη2 冷从^Λλ 75 Η νη2 76 Η νη2 ^°\y 77 Η νη2 78 Η νη2 ο 79 S—^ ^OMc νη2 The scale applies to the Chinese National Standard (CNS) A4 Specifications (210 X 297 mil) 17 92012 (Read the phonetic on the back first? Matters fill out this page) - -------- order --------- line.

1323263 V. Description of invention (1S) Table 2d Printed by the Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative 80 Η nh2 > O人 O人 8丨 Η NH2 82 Η NHa 83 OH nh2 ♦0 person. Seven people. Seven 84 OH nh2 S3 S—“_”—ΟΜΰ nh2 々〇人. People 86 OH nh2 >〇ΧΌ 87 s~^y~v〇2 nh2 >TO^yC. 88 s_O~N〇i nh2 >r^〇人. People 89 nh2 H >r^〇人. People -------- Order -------- (Please read the notes on the back and fill out this page) - Line · "Applicable to China National Standard (CNS) A4 specification (210 χ 297 public) Meal 18 92012 1323263 V. Description of invention (19 ) Table 2 e Printed by the Intellectual Property Office of the Ministry of Economic Affairs

- Order --------- line. (Please read the notes on the back and fill out this page) 9. NH2 H 91 nh2 H 92 s_C^_〇Me NH2 > 〇人. Seven 93 s_^〇_n〇2 nh2 Again. Seven 94 nh2 H Η Η 95 s—^~~^-N〇2 nh2 Η Η 96 s-〇^°Me nh2 Η Η -Γ

This paper scale applies to Chinese national standards (CNS>A4 specifications (210 χ 297 mm 92012 1323263)

ο .X1 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

RsO, Bu y 1 . \ μ OR4 Compound No. X1 R4 R3 97 OH nh2 HH 98 Η nh2 HH 99 nh2 HH 100 S~{^)~N02 nh2 HH 101 S~{^}~CH3 NHz HH 102 nh2 NH2 HH 103 NHj HHH 104 OH HHH 105 OH nh2 ^0^]< 106 H nh2 nh2 H -------Γ------- Please read the notes on the back and fill out this page) ------- Line · "Applicable to China National Standard (CNS) A4 Specifications (2) 297 297) 20 92012 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

V. Description of invention (21) Table 3b 108 S—^ OMc nh2 109 OH nh2 110 Η nh2 Sichuan νη2 H 112 s_H0~〇Me nh2 113 s~^cy~〇uit nh2 Vo. Seven nh2 CH2CF3 CH2CF3 s_〇_N〇2 nh2 CHjCF? CH2CF3 116 s-〇_n〇2 nh2 Vo person 117 s-^ nh2 >0 person. Person 11S s_^3_n〇2 nh2 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public hair) 1323263 A7 V. Invention description (22) Table 4

Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Compound No. Z X1 X1 R4 Rs 119 Η OH nh2 HH 120 Η H nh2 HH 121 Η nh2 HHH 122 CHs OH NH2 HH 123 CH? H nh2 HH 124 ch3 nh2 HHH 125 c2h5 nh2 HHH 126 CHs nh2 H >CO^C 127 ch3 nh2 H 〇1 >0 people 0 people 128 C2H5 H NHa > 〇人. People > people. Person 129 1 C2H5 H nh2 >r^<-----!——l·-----#-1 (Please read the note on the back and fill out this page) Order to take 'not used曱圑囤,豕系早 (〇NS) A4 specification (210 χ 297 mm) « — — — — — — — — — — — — — — — — — — — — — — — — — — 92012 1323263 A7 B7

V. Description of invention (23) Table 5 R*0-

Compound No. ZX* X2 R4 R5 130 Η OH nh2 HH 131 Η H nh2 HH 132 Η nh2 HHH 133 Η OH nh2 ^〇^]< 134 Η nh2 H o 135 CH3 OH nh2 HH 136 CH3 H nh2 HH 137 ch3 nh2 HHH Zhang scale applies to China National Standard (CNS) A4 specification (210 χ 297 public) 23 92012

1323263 A7 _____B7 V. Description of invention (24) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Printed Table 6 OR4 Ζ Ν<γΝ Compound No.Ζ X1 X1 R4 R5 138 Η OH ΝΗ2 Η Η 139 Η Η νη2 Η Η 140 Η νη2 Η Η 141 141 Η s-〇-cHi νη2 Η 142 142 CH, OH νη2 Η 143 143 CH? νη2 Η Η 144 144 ch3 Η νη2 Η Η 145 CHj νη2 Η (Please read the notes on the back and fill in this page) Order .. --Line · This paper scale applies to China National Standard (CNS) A4 specification (210 297 297 mm) 24 92012 1323263 A7 ------: _ B7 V. Description of invention (25 ) Table 7 Compound number X1 R4 R3 146 OH νη2 Η 147 147 Η νη2 Η Η 148 νη2 Η Η Η 149 OH νη2 150 Η νη2 151 νη2 Η 152 νη2 Η > People ^ΛΛ 153 ΟΗ νη2 " ----J >*〇·〇人. ^'''' /^0 meaning is described in the above table! The preferred compounds to Table 7 are the following combinations

({1-[(6-Amino-9//-嘌呤-9-yl)methyl]cyclopropyl})-yl)methylphosphonic acid (Compound 1); A-amino-9β-嘌呤-9- Base) methyl]cyclopropyl}oxy) A paper size applicable to the national standard (CNS) A4 specifications (210 X 297 public love) 92012 (please read the back of the note before you fill out this page) Ministry of Economics wisdom Property Bureau employee consumption cooperative printed matter: --------tx----------^--------------------- -- 25 1323263 Α7 Β7 V. Description of the invention (26) yl]-8,8-dimethyl-3,7-dioxo-2,4,6-tris-3 λ 5-phosphonium-1- Base phthalate (compound 2); ({1-[(2-amino-6-a-9-/-fluoren-9-yl)methyl]cyclopropyl}oxy) decylphosphonic acid ( Compound 3); 3-[({1-[(2-amino-6-chloro-9孖-嘌呤-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-di Methyl-3,7-dioxo-2,4,6-tris-3 and 5-phosphonium-1-yl pivalate (Compound 4); ({1-[(2-Amino-) 6-hydroxy-9open·indol-9-yl)methyl]cyclopropyl}oxy)decylphosphonic acid (compound 5); 3-[({1-[(2-amino-6-hydroxy-) 9孖-嘌呤-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6- Tris-3 λ 5-phosphonium-1-yl pivalate (compound 6); ({1-[(2-amino-6-fluoro-9//-fluoren-9-yl)methyl] Cyclopropyl}oxy) decylphosphonic acid (compound 7); 3-[({1-[(2-amino-6-fluoro-9/f-嘌呤-9-yl)methyl]cyclopropyl) }oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-triazine-3; 15-phosphonium-1-yl pivalate (compound 8 ({1-[(2·Amino-9//-嘌呤-9-yl)methyl]cyclopropyl}oxy)methyllinic acid (Compound 9); 3-[({1-[ (2-Amino-9//-嘌呤-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4, 6-tris-3 λ 5-phosphonium-1-yl pivalate (compound 10); ({1-[(2-amino-6-cyclopropylamino-9//--9) -yl)methyl]cyclopropyl}oxy)methylphosphonic acid (Compound 11); This paper scale applies to Chinese national standards (CNS>A4 specification (210 X 297 mm) 92012 (Please read the back of the note first) Matters fill out this page) Printed by the Intellectual Property Office of the Ministry of Economic Affairs

> 1^1 ϋ n IB^i ϋ n I n —rn iai ^1· nnn I 26 !> η ν 1323263 Α7 Β7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (27) 3- [({1-[(2-Amino-6-cyclopropylamino-9-heptan-9-yl)indolyl]cyclo)yloxy}methyl)-8,8-dimethyl -3,7-dioxo-2,4,6-tris-3 into 5-phosphonium-1-yl pivalate (Compound 12); [(1-{[2-Amino- 6- (Dimethylamino)-9//-嗓吟-9-yl]methyl}cyclo(yl)oxy]methylphosphonic acid (Compound 15); 3-{[(1-{[2- Amino-6-(dimethylamino)-9 ugly-indol-9-yl]methyl} propyl propyl)oxy]methyl}-8,8-dimethyl-3,7-dioxo Generation-2,4,6-tris-3 into 5-phosphonium-1-yl pentyl ester (compound 16); [(1-{[2-amino-6-(isopropylamino) )-9//-嗓吟-9-yl]methyl}cyclo(yl)oxy]methylphosphonic acid (Compound 17); 3-{[(1-{[2-Amino-6-(iso) Propylamino)-9 ugly-fluoren-9-yl]methyl} propyl propyl)oxy]methyl}-8,8-dimethyl-3,7-dioxo-2,4,6 -Triflf-3 into 5-phosphonium-1_ pentate valerate (Compound 18), · ({1_[(2,6-Diamino-9//-嘌呤-9-yl)methyl] Cyclopropyl}oxy) Phosphonic acid (compound 19); 3-[({1-[(2,6-diamino-9H-indol-9-yl)methyl]cyclopropyl}indolyl) fluorenyl]-8,8 -Dimethyl-3,7-dioxo-2,4,6-tris-345-phosphonium-1-pentetate (Compound 20); ({1-[(2-Amino-) 6-methoxy·9//·嘌呤-9-yl)methyl]cyclopropyl}oxy)methylphosphonium ruthenium (Compound 21); 3-[({1-[(2-Amino-6) -曱oxy-9/f-嘌呤-9-yl)methyl]cyclopropyl}oxy)indolyl]-8,8-dimethyl-3,7-dioxo-2,4,6 -trim-3 λ 5, scale 壬 1 - pentate valerate (compound 22); ({1-[(2-amino-6-ethoxy-9 ugly-oxime-9-yl)) Cyclopropyl}oxy

27 92012 ώ° 0:> iPlease read the notes on the back and fill out this page) #

H .1 nnn ^-OJ n ^ ^ n II n I ·1 ml ϋ ϋ ϋ II ϋ n I ϋ n 1 ϋ II i I ^^263 ^^263 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumption Cooperation Du Printing 28 A7 ____ B7__: _ V. Description of the invention (28) yl) methylphosphonic acid (Compound 23); 3-[({1-[(2-Amino-6-ethoxy-9//-嘌呤-9-) Methyl]cyclopropyl}yl)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-tris--3乂5-phosphonium-kitt Valerate (Compound 24); ({1-[(2-Amino-6-methyl-9//-嘌呤-9-yl)methyl]cyclopropyl decyloxy) f-phosphonic acid (compound) 25); 3-[({1-[(2-Amino-6-methyl-9//-嘌呤-9-yl)methyl]cyclopropyl} fluorenyl) fluorenyl]-8,8- Dimercapto-3,7-dioxo-2,4,6-tris-3-λ 5-phosphonium-l-pivalate (compound 26); [(1-{[5-methyl- 2,4-dioxo-3,4-diindole-1(2Η)-pyrimidinyl]methyl}cyclopropyl)oxy]methylphosphonic acid (Compound 31); 8,8-Dimethyl_ 3-{[(l_{[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]indolyl}cyclopropyl)oxy]methyl}- 3,7-dioxo-2,4,6_triazin-3; l5_phosphonium-l-pentopyrate (compound 32); [(1-{[2-amino-6-(4) - ))-9Η-嘌呤-9-yl]methyl}cyclopropyl)oxy]methylphosphonic acid (compound 3 7); 3_{[(1-{[2-amino-6-(4-morpholine) ))-9^-嘌呤-9_yl]methyl μ propyl)oxy]methyl}-8,8-dimethyl-3,7-dioxo-2,4,6-triterpene _3; 1, phosphonium-1-yl pivalate (compound 38); hydrazine (2,2,2-trifluoroethyl) ({1-[(2-amino-6-hydroxy-9/) /-嘌呤_9·yl)methyl]cyclopropyl}oxy)methylphosphonate (Compound 45); 贰(2,2,2-trifluoroethyl)({1-[(2-amine) Base-6-gas-9//·嘌呤-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (Compound 46); ruthenium (2,2,2·trifluoroethyl) {1-[(2,6-Diamino-9F-fluoren-9-yl)) This paper scale applies to Chinese national standards (CNS>A4 specifications (2)〇χ 297 public love> 92012 丨丨丨丨·丨丨丨;_丨丨丨丨--.丨丨丨丨丨丨丨- (Please read the note on the back? Please fill out this page again) 1323263 A7 ------ V. Description of invention (29) Base] Cyclopropyl}oxy)methylphosphonate (Compound 47); (Please read the notes on the back and fill out this page) 贰(2,2,2·Trifluoroethyl)({1-[(6 -Amino-9 ugly -呤-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (Compound 48); 贰(2,2,2-trifluoroethyl)({1-[(2-amino)- 9//-嘌呤-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (Compound 49); 贰(2,2,2-Trifluoroethylamino -6-dimethyl Amino group <9//_嘌呤-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (compound 52); hydrazine (2,2,2-trifluoroethyl; amine-6 -isopropylamino-9//-fluoren-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (Compound 53); hydrazine (2,2,2-trifluoroethylamine) _6_methoxy·9/ί_嘌呤_9_yl)methyl]cyclopropyl}oxy)methylphosphonate (Compound 54); 贰(2,2,2-Trifluoroethyl) [(ι_{[2-Amino-6-(4-morpholinyl)-9//-fluoren-9-yl]methyl}cyclopropyl)oxy]methylphosphonate (Compound 58); Department ι(2,2,2-dioxaethyl)[(1_"[2_Amino-6-(phenylthio)-9嗓呤-9-yl]methyl}cyclopropyl)oxy ]methylphosphonate (Compound 61); Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed base (2,2,2-diethylethyl) {[1-((2-amino-6-[(4) -methylphenyl)thio]-9//·嗓吟-9-yl}A ))cyclopropyl]oxy}methylphosphonic acid vinegar (Compound 62); 贰(2,2,2-trifluoroethyl){[1-({2-Amino-6-[(4-A) Oxyphenyl)thio]-9孖-嘌呤-9-yl}methyl)cyclopropyl]oxy}methylphosphonate (Compound 63); 贰(2,2,2-Trifluoroethyl ){[1-({2-Amino-6-[(4-nitrophenyl)thio]-9//-嘌呤-9-yl}methyl)cyclopropyl]oxy}methylphosphine Acid ester (Compound 64); This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 29 92012 1323263 Α7 Β7 V. Invention description (30) [(1-{[2-Amino-6 -(phenylthio)-9//-嘌呤-9-yl]methyl}cyclopropyl)oxy]methylphosphonic acid (compound 6 5); {[1-({2-amino-6) -[(4-methylphenyl)thio]-9//-嘌呤-9-yl}methyl)cyclopropyl]oxy}methylphosphonic acid (Compound 66): 3-({[1- ({2-Amino-6-[(4-mercaptophenyl)thio]-9/f-嘌呤-9-yl}methyl)cyclopropyl]oxy}methyl)-8,8- Dimethyl-3,7-dioxo-2,4,6-tris-3-λ 5-phosphonium-1-yl pivalate (compound 68); 贰{[(t-butoxycarbonyl) )oxy]methyl}({1-[(2-amino-9//-嘌呤-9-yl)methyl]) ring })oxy)methylphosphonate (compound 69); 贰{[(isopropoxycarbonyl)oxy]methyl}({1-[(2-amino-9//-嘌呤-9-) Methyl]cyclopropyl}oxy)methylphosphonate (Compound 70); 贰{[(ethoxycarbonyl)oxy]]}} ({1-[(2-Amino-9) /-嘌呤-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (Compound 71); 贰{[(isobutoxycarbonyl)oxy]methyl}({1-[( 2-Amino-9 ft-oxime-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (Compound 72); 3-[({1-[(2-Amino-9-) /-嘌呤-9-yl) fluorenyl]cyclopropyl}oxy)methyl]-9-methyl-3,7-dioxo-2,4,6-tris-3 λ 5·phosphonium 1-yl 3-methylbutyrate (compound 74); 3-[({1-[(2-amino-9-open-9-yl)methyl]cyclopropyl}oxy)) ]--8-methyl-3,7-dioxo-2,4,6-tris--3 λ 5-phosphonium-buyl 2-methylpropionate (compound 78); 3-({[ 1-({2-Amino-6-[(4-methoxyphenyl)thio]-9-)-yl-9-yl}methyl)cyclopropyl]oxy}methyl)-8, 8-Dimethyl-3,7-dioxo-2,4,6-trisyl-3 λ 5-phosphonium-1-yl pivalate (Compound 79); (Please read the notes on the back first) Then fill out this page) - Aw

Na^i II n · a^i 1 ϋ n 1_· n I Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 30 92012 1323263 A7 B7 V. INSTRUCTION DESCRIPTION (31) 3-[({1-[(2-Amino-9//-嘌呤-9-yl)methyl]cyclopropyl}oxy)methyl]-3,7-di Oxo-7-(1-pyrrolidinyl)-2,4,6-triazin-3 λ 5-phosphheptan-1-yl 1-pyrrolidinecarboxylate (Compound 80); 3-[({1 -[(2-Amino-9//-嘌呤-9-yl)methyl]cyclopropyl}oxy)methyl]-3,7-dioxo-7-(1-piperidinyl)- 2,4,6-tris-3 and 5-phosphonheptan-1-yl 1-piperidinecarboxylate (Compound 81); 3-[({1-[(2-Amino-9-open-嘌呤-) 9-yl)methyl]cyclopropyl}oxy)methyl]-7-(4-morpholinyl)-3,7-dioxo-2,4,6-trian-3 λ 5-phosphorus Hept-1-yl 4-morpholinecarboxylate (Compound 82); 贰{[(Tertibutoxycarbonyl)oxy]methyl}[(1-{[2-Amino-6-hydroxy-9]嘌呤{嘌呤-9-yl]methyl}cyclopropyl)oxy]methylphosphonic acid vinegar (Compound 83); 贰{[(isopropoxycarbonyl)oxy]methyl}[(1-{[ 2-Amino-6-hydroxy-9/ί-嘌呤-9-yl]methyl}cyclopropyl)oxy]methylphosphonic acid Ester (Compound 84); 贰{[(Isopropoxycarbonyl)oxy]methyl}{[1-({2-Amino-[6-(4-carbamidophenyl)thio]9/ F-嘌呤-9-yl}methyl)cyclopropyl]oxy}methylphosphonate (Compound 85); 3-[({1-[(2-Amino-6-hydroxy-9//-)嘌呤-9-yl)methyl]cyclopropyl}oxy)methyl]-7-cyclopentyl-3,7-dioxo-2,4,6-tris-3λ 5-phosphon-1 -cyclopentanecarboxylate (compound 86); 3-({[1-({2-amino]-[6-(4-nitro'ylphenyl)thio]-9open-嘌呤-9- Methyl)cyclopropyl]oxy}methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trisyl·3 λ 5-phosphonium-1- Kit valerate (Compound 87); (Please read the notes on the back and fill out this page) Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative. #--------tr------ ---f—----------------------- This paper scale applies to Chinese national standards (CNS> A4 specification (210 X 297 mm) 31 92012 1323263 A7 B7 V. INSTRUCTION DESCRIPTION (32) 贰{[(isopropoxycarbonyl)oxy]methyl}{[1-({2-amino-[6-(4-nitrophenyl)thio]] -9//-嘌呤-9-yl}methyl)cyclopropyl]oxy}methylphosphonate (Compound 88); {[(isopropoxycarbonyl)oxy]methyl}({1-[(6-amino-9/ί-嘌呤-9-yl)f-yl]cyclopropyl}oxy)methylphosphonic acid Ester (Compound 89); 3-[({1-[(6-Amino-9//-嘌呤-9-yl)methyl]cyclopropyl}oxy)methyl]-9-methyl-3 ,7-dioxo-2,4,6-tris--3 λ 5-phosphon-1-yl 3-methylbutyrate (compound 90); 3-[({1-[(6-amine) -9-9//-嘌呤-9-yl)methyl]cyclopropyl}oxy)methyl]-7·cyclopentyl-3,7-dioxo-2,4,6-triterpene·3 λ 5-Phenylheptyl-1-ylcyclopentanecarboxylate C compound 91); 贰{[(Tertibutoxycarbonyl)oxy]methyl}{[1-({2-Amino-[6 -(4·methoxyphenyl)thio]_9 ft-fluoren-9-yl}methyl)cyclopropyl]oxyindole methylphosphonate (Compound 92); 贰{[(T3O3) Alkylcarbonyl)oxy]methyl}{[1-({2-amino-[6-(4-nitrophenyl)thio]-9/ί-嘌呤-9-yl}methyl)cyclopropyl ]]oxy}methylphosphonate (Compound 93); {[1-({2-Amino-[6-(4-nitrophenyl)thio]-9//-嘌呤_9-yl) }methyl)cyclopropyl]oxy}methylphosphonic acid (Compound 95); {[1-({2-Amino-[6-(4-methoxyphenyl)thio]- 9// -嗓吟_9-yl}methyl)cyclopropyl] Oxy}methylphosphonic acid (compound 96); ({1-[(2-amino-6-hydroxy-9//-fluoren-9-yl)methyl]-2-methylcyclopropyl}oxy) Methylphosphonic acid (compound 97); ({1-[(2.amino-9)-/indol-9-yl)fyl]-2-methylcyclopropyl decyloxy) Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 92012 &lt;Please read the notes on the back and fill out this page)

------------------------------------------------ -amino-[6-(4-methoxyphenyl)thio]-9//-fluoren-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonic acid ( Compound 99); {[1-({2-Amino-[6-(4-nitrophenyl)thio]-9//-嘌呤-9-yl}methyl)-2-methylcyclopropane Alkyloxymethylphosphonic acid (compound 1); amino-[6-(4-methylphenyl)thio]-9//--9-yl}methyl)-2- Methylcyclopropyl]oxy}methylphosphonic acid (Compound 1〇1); ({1-[(2,6-Diamino-9i/-嘌呤-9-yl)methyl]-2-) Cyclopropyl}oxy)methylphosphonic acid (Compound 102); ({1-[(6-Amino-9//-嘌呤-9-yl)methyl]-2-methylcyclopropyl} Oxy)methylphosphonic acid (compound 103); 3-[(U-[(2-amino-6-hydroxy-9//-fluoren-9-yl)methyl]-2-methylcyclopropyl }oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-tris--3 λ 5-phosphonium-1-yl pivalate (compound 105 3-[({1-[(2-Amino-9//-嘌呤-9-yl)methyl]-2-methylcyclopropyl}oxy)methyl]-8,8-di Base-3,7-dioxo-2,4,6-tris-315-phosphonium-1-yl pivalate (Compound 106); Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative print (please read first) Precautions on the back side of this page) 3-[( {1-[(6-Amino-9//-嘌呤-9-yl)methyl]-2-methylcyclopropyl}oxy)methyl ]-8,8-Dimethyl-3,7-dioxo-2,4,6-trisyl·3λ 5-phosphonium-bucotate (compound 107); 3-({[1 -({2-Amino-6-[(4-methoxyphenyl)thio]_9//-嘌呤-9·yl}methyl)-2-methylcyclopropyl]oxy}methyl )-8,8-Dimethyl-3,7-dioxo-2,4,6-tris-3-λ 5-phosphonium-1-yl pivalate (Compound 108); 贰{[( Isopropoxycarbonyl)oxy]indolyl}[(1-{[2·Amino-6-hydroxy-- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 544 33 92012 1323263 A7 B7 V. INSTRUCTIONS (34) 9/ί-嘌呤-9-yl]methyl}-2-methylcyclopropyl)oxy]methylphosphonate (Compound 109); 贰{[(isopropyl Oxycarbonyl)oxy]methyl}({1-[(2-amino-9i/-嘌呤-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonate (compound 110); 贰{[(different Oxycarbonyl)oxy]methyl}{[1-({2-amino-[6-(4-methoxyphenyl)thio]-9//--9-yl}methyl) -2-methylcyclopropyl]oxy}methylphosphonate (Compound 112); 贰{[(Tertibutoxycarbonyl)oxy]methyl}{[1-({2-Amino- [6-(4-foxyphenyl)thio]-9//-嘌呤-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate (Compound 113)贰(2,2,2-trifluoroethyl){[1-({2-amino]6-[(4-methoxyphenyl)thio]-9//-嘌呤-9-yl }Methyl)-2-methylcyclopropyl]oxy}methylphosphonate (Compound 114); ·(2,2,2-Trifluoroethyl){[1-({2-Amino) -6-[(4-nitrophenyl)thio]-9 ft-fluoren-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate (Compound 115);贰{[(Tertibutoxycarbonyl)oxy]methylamino-[6-(4-nitrophenyl)thio]-9//·嘌呤-9-yl}methyl)-2- Methylcyclopropyl]oxy}methylphosphonate (Compound 116); 贰{[(isopropoxycarbonyl)oxy]methyl} {[1-({2-Amino-[6-( 4-nonylphenyl)thio]-9F-fluoren-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate (Compound 117); -({[1-({2-Amino-6-[(4-nitrophenyl)thio]]]9----9-yl} (Please read the note on the back and fill out this page) Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

II - nn n-*Te- n - - nn II nnnn ϋ ii n —if I —i — I nn II This paper scale applies to the Chinese National Standard (CNS) A4 specification &lt;210 X 297 mm. ) 34 92012 Economy Ministry of Intellectual Property Bureau employee consumption cooperative printed 1332263 A7 B7 V. Description of invention (35) Methyl)-2-methylcyclopropyl]oxy}methyl)-8,8-dimethyl-3,7- Dioxo-2,4,6-tris-3λ 5-phosphonium-1-yl pivalate (compound Π8); ({1-[(2-amino-6-hydroxy-9//-)嘌呤-9-yl)methyl]cyclopropyl}amino)methylphosphonic acid (compound 119); ({1·[(2·amino-9//-嘌呤-9-yl)methyl)) ring Propyl}amino)methylphosphonic acid (compound 120); ({1-[(6-amino-9- -9-yl)methyl]cyclopropyl}amino)methylphosphonic acid ( Compound 121); [U-[(2-Amino-6-hydroxy-9/f-fluoren-9-yl)methyl]cyclopropyl}(methyl)amino]methylphosphonic acid (Compound 122) ; [{1-[(6-Amino-9//-嘌呤-9-yl)methyl]cyclopropyl}(ethyl)amino]methylphosphonic acid (Compound 125); 3·{[{ (1-[(6-Amino-9β-fluoren-9-yl)methyl]cyclopropyl)(methyl)amino}methyl)-8,8-dimethyl-3,7-dioxo Generation-2,4,6 -trim-3;15-phosphonium-1-yl pivalate (compound 126); 贰{[(isopropoxycarbonyl)oxy]methyl}[{1-[(6-amino)- 9/f-嘌呤-9-yl)methyl]cyclopropyl}(methyl)amino]methylphosphonic acid (Compound 127); 3-{[{1-[(2-Amino]9// -嘌呤-9-yl)methyl]cyclopropyl}(ethyl)amino]methyl}-8,8-dimethyl-3,7-dioxo-2,4,6-triazine- 3;15-phosphonium-1-yl pivalate (compound 129); (£&gt;2-{1-[(2-amino-6)hydroxy-9//-嘌呤-9-yl) A (cyclo)vinylpropylphosphonic acid C compound 130); (v)-2-{1-[(2-amino-9/f-fluoren-9-yl)methyl]cyclopropyl}vinylphosphine Acid (Compound 131); &lt;Please read the notes on the back and fill out this page) 0 ϋ n· II nnnnn I Line-雠-------------------- -- This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm); ?ΗΟ 35 92012 1323263 A7 __ . B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (36) (£ &gt;2-{1-[(6-Amino-9/ί-嘌呤-9-yl)methyl]cyclopropyl}vinylphosphonic acid (Compound 132); 3-((£·)-2- { 1-[(2-Amino-6-carbyl-9//-嗓)呤-9-yl)methyl]cyclopropyl}vinyl-8,8-dimethyl-3,7-dioxo-2,4,6-tris--3λ5·phosphonium _ 1-kitt Valerate (Compound 133); (£&gt;2-{1-[(6-Amino-9-indolyl)indenyl]cyclopropyl}vinyl)-8,8-dimethyl-3 , 7-dioxo-2,4,6-tris--3 λ 5-phosphonium-1· pentate valerate (compound 134); (v)-2-{1-[(6-amino group) -9//-嘌呤-9-yl)methyl]cyclopropyl}·ι·propenylphosphonic acid (formula 137); 2-{1-[(2-amino-6-hydroxy-9) /ί-嘌呤-9-yl)methyl]cyclopropyl}ethylphosphonic acid (Compound 138); 2-{ 1-[(2-Amino-9//-嘌呤-9-yl)methyl] Cyclopropyl}ethylphosphonic acid (compound 139); 2-{1-[(6-amino-9/ί-嘌呤-9.yl)methyl]cyclopropyl}ethylphosphonic acid (compound 140) ; 2-[1-({2-Amino-6-[(4-methylphenyl)thio]-9//-嗓吟_9-yl}methyl)cyclopropyl]ethylphosphonic acid (Compound 141); 2-{1-[(2-Amino-6-hydroxy-9//-fluoren-9-yl)methyl]cyclopropyl}propylphosphonic acid (Compound 142); 2_{1 -[(6-Amino-9孖-嘌呤_9_yl)methyl]cyclopropyl}propylphosphonic acid (Compound 143); 2-{1-[(2-Amino-9//·嘌呤-9-yl)methyl]cyclopropyl}propyl Acid (Compound 144); {Please read the notes on the back and fill out this page) - Words This paper scale applies to China National Standard (CNS) A4 specification (210 297 297 mm) 36 92012 1323263 A7 B7 Ministry of Economics Intellectual Property Bureau employee consumption cooperative printing 5, invention description (37) 3-(2-{1-[(6-amino-9//-嘌呤-9-yl)methyl]cyclopropyl}propyl)_ 8 ,8-Dimethyl-3,7-dioxo-2,4,6-tris-3 and 5-phosphonium-1-yl pivalate (Compound 145); ({1-[(2) -amino-6-hydroxy-9F-fluoren-9-yl)indolyl]-2,2-dimercaptocyclopropyl}oxy)methylphosphonic acid (compound 146); ({1-[(2) -amino-9//-嘌呤-9-yl)methyl]-2,2-dimethylcyclopropyl}decyl)methylphosphonic acid (Compound 147); (U-[(6-Amino) -9幵-嘌呤-9-yl)methyl]-2,2-dimethylcyclopropyl}oxy)methylphosphonic acid (compound 148); 3-[({1-[(2-amino)) -6-hydroxy-9//-嘌呤-9-yl)methyl]-2,2-dimethylcyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-di Oxo-2,4,6-trisff_3 λ5-phosphonium-1-yl pivalate (compound 149); 3_[({[2-amino-9-9-yl-9-yl)) Methyl]-2,2-dimethylcyclopropyl}oxy Methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-triazin-3 λ 5-phosphonium-1-yl pivalate (compound 150); -[({1-[(6-Amino-9//-嘌呤-9-yl)methyl]-2,2-dimethylcyclopropyl}oxy)methyl]-8,8-di Methyl-3,7-dioxo-2,4,6-tris-3-λ 5-phosphonium-1-yl pivalate (compound 151); 贰{[(isopropoxycarbonyl)oxy Methyl}({1-[(6.amino-9)/嘌呤-9-yl)methyl]-2,2-dimethylcyclopropyl}oxy)methylphosphonate ( Compound 152); and 贰{[(isopropoxycarbonyl)oxy]methyl}[(1-{[2-amino-6-hydroxy-9 Η-9-yl]methyl}-2, 2-Dimethylcyclopropyl)oxy]methylphosphonate (Compound 153). This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) (please read the notes on the back and fill out this page) #

Tr---------Line J 37 92012

1323263 A7 _B7 V. INSTRUCTION DESCRIPTION (π: The compound of the formula (1) of the present invention can be produced by the following procedure, and therefore, another object of the invention is to provide such a preparation method. However, the conditions of the preparation method, for example, the reactant, The solvent, the base 1 and the amount of the reactant used are: and are prepared within the range explained below. The compound of the present invention can also be conveniently obtained by combining various synthetic methods described in the specification or known (4). Prepared in such a manner that it can be easily carried out by a person skilled in the art. The method for preparing the compound of the formula (1) of the present invention has the following characteristics: (4) a compound represented by the following formula (7) and the following formula (3) The compound shown is reacted to produce a compound of formula (1), a compound of formula (2): (2) wherein wusmn is defined as defined above and L represents a leaving group which is preferably a methoxyl group or a toluene group. Or halogen, a compound of the formula (3): QH (3) wherein Q is as defined above, (b) reacting a compound represented by the following formula (9) with a compound of the formula (3) to give a formula (10) Compound, compound of formula (9): paper The scale applies to the China National Standard (CNS) A4 specification (2) G * 297 public) ----- f 38 92012 I--------^-11111 (please read the notes on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing line _!·----------------------- 1323263 A7 B7

Wherein R, R, R, R, R8, Y and L are as defined above, and trans 9 and R1G independently of each other represent an optionally substituted alkyl group, a compound of formula (10):

Wherein R1, R2, R3, R7, R8, Y, Q, R9 and rio are as defined in the preceding block, and the resulting compound of formula (10) is hydrolyzed in the presence of Lewis acid to produce the formula Compounds shown in (la):

Rn:Q (la) (Jing Xian read the back 夂 note and fill out this page) - set - Ministry of Economic Affairs Intellectual Property Bureau employees consumer cooperatives printed in which R1, R2, R3, R7, R8, γ and Q are defined as above Or (C) introducing a R4' and R5' group into the (la) compound to produce a compound of the formula (lb) below or further using the compound thus obtained in a conventional manner (see U.S. Patent No. 6,037,33) 5, 5, 93 5,946 and 5,792,756) Conversion:

(lb) wherein R1, R2, R3, R7, r8, Y and Q are as defined above, and L4' and R5' respectively represent R4 and R5 other than hydrogen. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 39 92012 Line 1323263 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 ---------B7___ V. Invention description ( 40) 'In the above preparation of the compound of the formula (1), the different steps (a) to (c) may be carried out in a solvent in which a base is present. One or more of the solvents mentioned are selected from L-methylformamidine. a group consisting of amine, dichloromethane, tetrahydrofuran, gas imitation, methylpyrrolidone and bis-glycidylamine, and one or more of the following: selected from sodium hydride, sodium carbonate, potassium carbonate, sodium hydrogencarbonate a group consisting of potassium hydrogencarbonate, potassium third potassium hydride, hydrazine (trimethyl decyl) amidinohydride, sodium aminated 'carbonate bismuth (trimethyl decyl) potassium amide. In the step (b), a Lewis acid containing a trimethylsulfonyl group can be used. Further, in the step (C), a compound of the formula R4' and R5' can be introduced to the compound of the formula (a), and the compound is The alkyl group is subjected to an ether-forming reaction in the presence of a base or treated with a sulfurous gas, grassy chlorine or phosphorus pentachloride. Generating dichloro-phosphonate derivative of the desired compound is then obtained again appropriate reaction with alcohols or amines. The phosphonate compound of the formula (2) which is a starting material in the above step is itself a novel compound. Therefore, another object of the present invention is to provide a compound of the formula (2). When the compound of the formula (2) wherein γ is hydrazine, ri is hydrogen, and each of r2, R3, R7 and R8 is hydrogen or an alkyl group, that is, a compound of the following formula (8), the preparation characteristics are as follows: (i) glycolic acid B The ester's alcohol group is protected, and the following formula (4) represents: 〇~(4) wherein P1 represents an alcohol-protecting group, preferably a benzyl group (Bn), a tetrahydroindoleyl group (THP), a third group. Butyl diphenyl decyl (TBDPS), or tert-butyl dimethyl decyl (TBDMS), with formula (4) and ethylmagnesium bromide [C2H5MgBr] or corresponding alkyl magnesium bromide or Gasified alkyl magnesium is applied to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) on the paper scale of tetraisopropoxide. 40 92012 (Please read the note on the back and fill out this page) # tSJ· -Line - ^4 1323263 A7

Wherein p1 is defined as described above and each of r2, R3, R7' and the base, and (5) is reacted in the presence of the following formula with the following formula: _ _ _ _ _ _ _ _ _鲢-form pR4 (6) wherein L'R4 and R5 are as defined above, and vice versa. Phosphonate compound: The result should be as follows: f Jingxian read the back note and fill in this page) 0 OR* (7) where P1, R2', R3·, R7·, R8·, R4 and R5 are defined as described above

(iii) removing the alcohol-protecting group of the compound of the formula (7) and introducing the derivative to produce a compound represented by the following formula (8): A ’ and (L) Printed by the Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative

OR5 (8) wherein L, R2', R3., R7, R8, and 4 are defined as described above. The steps for preparing the simplest compound of formula (8) (ie, all R2, R3, and R8' are hydrogen) are outlined in the following reaction. Figure 1: Reaction Figure 1 This paper scale applies to the Chinese National Standard (CNS). A4 specification (210 X 297 public 92012 n I n «^1 a n ϋ nn III n I n ϋ nn 1 ϋ inm ϋ nn &lt; 1323263 A7 B7 V. Description of invention (42

+ ^'MgBr Ti(OiPr)4U pi^C pi. /〇, (4) (5) OR4 卜OR5 (6) OR4 (7) 0 4 (8) For the specific reaction conditions of the above steps, refer to the following. Preparation and implementation of 'when the compound of formula (2) wherein γ is _CH2_, and each of r, R2, R3, R7 and R8 is hydrogen, that is, the compound of the following formula (11): (Please read the back of the note first) Please fill out this page again)

(11) wherein L, R4 and R5 are as defined above, and the steps for preparing the compound of the formula (11) are briefly described in the following reaction scheme 2: Reaction Scheme 2

, ΟΗ yAW4‘ HO, In, Βγ —►

This paper scale applies to the Chinese National Standard (CMS) Α 4 specification (210 297 297 mm) 42 92012 1323263 A7 Β 7 V. Description of the invention (43) The reaction diagram 2 is briefly explained below. (i) reacting a dialkyl malonate with bidentane by a known method (see: JOC, 1975, Vol. 40, 2969-2970) to obtain malonic acid, wherein a cyclopropyl group is introduced to it 2- position. (ii) Reduction of malonic acid to give a diol compound, and then protecting one of the hydroxyl groups with a suitable protecting group (P1 is as defined above). Oxidation of another hydroxy group to an aldehyde group (Hi) reacts the resulting aldehyde compound with a tetraalkylmethylene diphosphonate to give the desired phosate compound. (iv) Reduction of the obtained phosphonate compound to give a compound having no unsaturated bond. The alcohol/protecting group (ρι) is removed, and the leaving group (L) is introduced to give a compound of the formula (11). Further, when the compound of the formula (2)', and each of Ri, R2, R3, R7 and R8 is hydrogen, the compound of the following formula (12):

Wherein L, R4 and R5 are as defined above, and the steps for preparing the compound of formula (12) are briefly described in the following reaction scheme: Figure 3: Reaction sheet (please read the notes on the back and fill out this page) — ------ --Book --------- Line 'Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperation Du printing This paper scale applies Chinese national standards (CNS > A4 specifications (210 X 297 mm) 43 92012 1323263 Ministry of Economics wisdom The property bureau employee consumption cooperative printed five 'invention instructions (44 W, Ο r5o, ^^n- I. I OR4 CH3 Α7 Β7 H0. 一Ρ^Χ^ΟΡ1 -— ch3 Ρ^Ν^〇Ρ, R^- ϋ ' OR4 Cl· (12)

X The reaction diagram 3 is briefly explained below. (丨) 1,1_Diethylcyclopropyldicarboxylate is selectively hydrolyzed to obtain a monocarboxylic acid. (ii) The amine group is introduced into the monocarboxylic acid by the known Curtious reaction (see S. Linke, .G. T.. Tisue and W. Lowowski, J. y4w. CAe/w Soc. 1967, 89, 63 08). (iH) The amine group is protected with a suitable protecting group [p2 may be a carbamate or various benzyl protecting groups, or an alkyl group (methyl 'ethyl group, etc.)]. (iv) Reducing the opposite ester group to a hydroxyl group and then protecting it (P1 is as defined above). The protecting group protected compound is reacted with methyl iodide in the presence of sodium hydride to introduce a methyl group into the amine group. (vi) Removal of the amine-protecting group The resulting compound is reacted with a dialkyl desert methylphosphonate to give the desired phosphonate compound. (vii) removing the alcohol-protecting group (pi) from the obtained phosphonate compound and then introducing the leaving group (L) to give a compound of the formula (12) (please read the back note before filling in this page) - -------Settings--------" The specific reaction conditions of the above steps can be referred to the following preparation examples and implementation of the 'paper and scale applicable China Guohong Yanhuai 4 πΐη V 9Q7 Α4Ϊ - ί V Λ 4 \ τ«· τ rt / 0 NV - 44 92012 1323263 A7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (45 After the reaction is completed, the product can be further divided into general, for example, chromatographic analysis And recrystallization or the like to be isolated or purified. Purification step The compound of the formula (1) of the present invention can be effectively used as an antiviral agent. Therefore, it is a purpose of providing a composition for treating a viral disease, and 1 comprises a compound of the formula (1) as an active ingredient, and a pharmaceutical composition. Acceptable salts, hydrate solvates or isomers and pharmaceutically acceptable carriers. When using the active compounds of the invention for clinical use, generally preferred dosages range from (M to 10,000 mg, preferably per ounce) Clever to ι(10) mg / Kg body weight. The total daily dose can be administered once or in multiple doses. However, the specific dose of a patient can be excreted depending on the specific compound weight, sex or patient's health, diet, time of administration or method. The rate, the ratio of the mixture of the drugs, the severity of the disease to be treated, etc. The compound of the present invention can be administered by injection or an oral preparation. The injection preparation, for example, a sterile aqueous solution or an oily suspension for injection, can be moistened with a suitable dispersing agent. The agent or suspension is prepared by a known method. The solvent used for preparing the injection comprises water, a fluid solution of Lin Jiashi and an isotonic NaCl solution, and a sterile solidified oil can also be conveniently used as a solvent or suspension medium. Any non-irritating agent. The solidified oil comprises both mono- and di-glycerides as a solvent or a suspending medium. Fatty acids such as oleic acid can also be used for injection. Oral formulations such as capsules, lozenges, tablets, powders and granules are administered orally. Jiawei capsules and lozenges. Tablets and tablets can also be prepared into enteric coating preparations as needed. Solid preparations can be mixed by the formula (j) a compound and at least one selected from the group consisting of an inactive diluent (eg, sucrose, lactose, cedar--------1----1----&lt;&gt; Fill in this page) .0 This paper size applies to China National Standard (CNS) A4 specification (210 X 297 public; g)

45 92012 1323263 A7 B7 Printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs. 5. Inventives (46), etc., based on carriers, lubricants (such as magnesium stearate), disintegrants and binders. When the compound of the present invention is applied to clinical treatment to obtain a desired antiviral effect, the active compound of the formula (1) can be administered in combination with one or more selected from the known anticancer or antiviral agents. Anti-cancer or anti-viral agents (such as 5-fluorouracil, Cisplatin, Doxorubicin, Taxol, Gemcitabine, Lamivudine, etc. ) can be administered in this manner together with the compounds of the invention. However, the preparation comprising the compound of the present invention is not limited to the above-exemplified, but may include any substance for treating or preventing cancer or viral diseases. The invention will be more clearly explained in the following examples and test examples. However, it is to be understood that the examples and test examples are intended to illustrate the invention and not to limit the scope of the invention. Preparation Example 1 Synthesis of 1-({[t-butyl(diphenyl)fluorenyl)oxy}methyl)cyclopropanol as reference material (see: Office w. Zeii. 07, 1053-1054, 1999) The preparation of the 'title compound is as follows. 12 g (3 5 mmol) of ethyl 2-·{[··=* butyl(monophenyl)a]oxy}acetic acid vinegar was dissolved in 2 mM of tetrahydrofuran (THF) And then adding 2.2 ml of tetraisopropoxide. 29.2 ml of ethylmagnesium bromide (3. 〇μ in THF) was slowly added to the mixture, and the reaction solution was stirred at room temperature for 12 hours. Add (please read the notes on the back and fill out this page) ·· III l· III ·11111111 I-n 1 ϋ nnnn ϋ ϋ ί li I _ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public)

Ss? 46 92012 1323263 A7 B7 V. INSTRUCTIONS (47) (Please read the back of the page and then fill out this page) 20 ml of saturated ammonium sulfate to stop the reaction. About 150 ml of tetrahydrofuran (THF) as a solvent was removed by distillation under reduced pressure, and the mixture was extracted twice with ethyl acetate (200 ml). The ethyl acetate extract was evaporated under reduced pressure to give the title compound. NMR (CDC13) δ 0.44 (q, 2H), 0.78 (q, 2H), 1.09 (s, 9H), 3.67 (S&gt; 2H), 7.41 (m, 6H), 7.70 (m, 4H) ESI: 344 (M+NH4)+, C20H26O2Si Preparation Example 2 Synthesis of diisopropyl {[1_({[t-butyl(diphenyl)decyl)oxy}f)cyclopropyl]oxy}methylphosphine The ester was prepared by dissolving the compound prepared in Example 1 (65 g) in 1 ml of di-f-carbamamine (DMF), and then adding 32 ml of lithium tributoxide (1.0 M in THF). The resulting mixture was stirred for 1 minute. 7 gram of diisopropylbromomethylphosphonate was added to the mixture, 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, and 40 ml of saturated ammonium chloride was added to the residue and then ethyl acetate. The ethyl acetate extract was evaporated under reduced pressure and the residue was purified eluting eluting elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut (CDC13) δ 0.53 (m, 2H), 0.88 (m, 2H), 1.07 (s, 9H), 1.29 (t, 12H), 3.78 (s, 2H), 3.98 (d, 6H), 4.75 (m, 2H), 7.40(m, 6H), 7.67(m, 4H)

Hfi-h 47 92012 A7 __B7 V. Invention description (you---------^------- (please read the notes on the back and fill out this page) Alcohol, then add 3.1 The mixture was heated under reflux for 2 hours. After completion of the reaction, the methanol was removed by a distillation apparatus under reduced pressure and the residue was chromatographed on a silica gel column (eluent: dichloromethane / The title compound NMR (CDC13) δ 0.60 (t, 2 Η), 0.87 (t, 2H), 1.28 (d, 12H), was obtained by purification of methanol (30/1, v/v). 2.5 (br s, 1H), 3.65 (s, 2H), 3.83 (d, 2 H), 4.82 (m, 2H) '

ESI: 267 (M+l)+, Cl 1H2304P Preparation Example 4 Synthesis of {1-[(diisopropoxyphosphonyl)methoxy]cyclopropyl}methylmethane_ citric acid vine; line. Preparation Example 3 The compound (1 - 5 g) was dissolved in 5 ml of methane, and 0.85 ml of triethylamine and 84 g of methanesulfonium chloride were added thereto, and the resulting mixture was stirred at room temperature for 3 minutes. Saturated ammonium hydride is added to stop the reaction. The product was extracted with dichloromethane and the chloroformate extract was concentrated by evaporation of the crane under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed 'H NMR (CDC13) δ 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 ({1-[(6.Amino-9/f-嘌呤_9_yl)methyl]cyclopropane Base oxy)f-phosphonate This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 48 92012 1323263 A7 V. Description of invention (49 Preparation of compound prepared in Preparation 4 (43 mg Dissolved in 18 ml of dimethylformamide, and then added 576 mg (purity of 6%) of sodium hydride and 162 mg of adenine'. The resulting mixture was heated under reflux for more than 4 hours. The ammonium was vaporized to stop the reaction. The product was extracted with ethyl acetate and then the ethyl acetate extract was distilled under reduced pressure. The residue was purified by chromatography on a gel column (eluent: methylene chloride/methanol = 20/). /v) Purified to give the title compound (yield: 44%). NMR (CDC13) δ 0.86 (t, 2H), 1.01 (t, 2H), 1.24 (d, 6H), 1.34 (d, 6H ), 3.86 (d, 2H), 4.34 (s, 2H), 4.71 (ra, 2H), 5.9 7 (br s, 2H), 8.32 (s, 1H), 8.58 (s, 1H)

ESI: 384 (M+l)+, C16H25N504P Preparation Example 6 Synthesis of diisopropyl ({l-[(2-amino-6-chloro-9/i-indol-9-yl)methyl] cyclopropyl) }oxy)methylphosphonate The compound prepared in Preparation 4 (1.64 g) was dissolved in 70 ml of dimethylformamide, and 219 mg (60% purity) of sodium hydride and 773 mg were added thereto. 2-Amino-6-chloro-9仏嘌呤, the resulting mixture was stirred for 4 hours while heating at 80 °C. Saturated chloride was added to stop the reaction. The product was extracted with ethyl acetate and then the ethyl acetate extract was evaporated under reduced pressure. The private paper scale applies to the Chinese National Standard (CNS) A4 specification (210x297 mm) 92012 (please read the note on the back and fill out this page) Printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs-m 49 ------ --tr----------^丨^------------------------ 1323263 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative Preparation of A7 B7 V. Description of the invention (5 〇 The residue was purified by column chromatography (eluent · methylene chloride / methanol = 2 〇 / 1, v / v) to give 765 mg (yield 40) %) of the title compound Ή NMR (CDC13) 6 0.80 (t, 2H), 1.02 (t, 2H), 1.27 (d, 6H), 1.28 (d, 6H), 3.82 (d, 2H), 4.21 (s , 2H), 4.68 (m, 2H), 5.13 (br s, 2H), 8.15 (s, 1H)

ESI: 418 (M+l)+, C16H25C1N504P Preparation Example 7 Synthesis of diisopropyl [(1 {[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidine) Methyl}cyclopropyl)oxy]methylphosphonate

The compound (11. 8 mg) and thymidine prepared in Preparation 4 were reacted in the same manner as in Preparation 6 to give 26 mg (yield: 21%) of the title compound. HNMR(CDC13) δ 0.82 (t, 2H), 0.95 (t, 2H), 1.31 (m, 12H), 1.92 (s, 3H), 3.74 (d, 2H), 3.89 (s, 2H), 4.71 ( m, 2H), 7.62 (s, 1H), 9.15 (s, 1H)

ESI: 375 (M+l)+, C16H27N206P Preparation Example 8 Synthesis of 1-({[T-butyl(diphenyl)decyl)oxymethylmethylcyclopropanol

For example, refer to the information (see: "L State.07, 1053-1054, 1999" (please read the notes on the back and fill out this page) ------- order ------- -line"

The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 ng jg) rifA 50 92012 ^20263 A7 B7 5. Inventive Note (51) The title compound is prepared as follows. 5 g (146 mmol) of ethyl 2-{[t-butyl(diphenyl)decyl]oxy}acetate was dissolved in 7 ml of tetrahydroanthracene (THF) and Further, 3 ml of tetraisopropoxide was added thereto. 29 ml of propylmagnesium chloride (2 〇M in THF) was slowly added to the mixture at -10 C, and the reaction solution was stirred at room temperature for 12 hours. 200 ml of saturated ammonium sulfate was added to stop the reaction. Tetrahydrofuran (TIiF) as a solvent was removed by distillation under reduced pressure, and the mixture was extracted twice with 2000 ml of n-hexane. The n-hexane extract was distilled under reduced pressure and purified using a silica gel column to afford 42 g of the title compound. NMR NMR (CDC13) δ 0.06 (t, 1Η), 0.88 (dd, 2H), 0.97 (d, 3H), 1.09 (s, 9H) 1.1 (m, 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 Example 9 Synthesis of diisopropyl [t-butyl (di) Phenyl)decyloxy]oxy)methyl)-2-methylcyclopropyl]oxy}methylphosphonate

The compound prepared in Preparation Example 8 (4.2 g) was obtainedyyyyyyyyyyyyyyyyyyyyy 'H NMR(CDC13) 8 0.04 (t, 1H), 0.96 (dd, 1H), 0.97 (d, 3H), 1.05 (m, 1H), 1.06 (s, 9H), 1.23 (t, 12H), 3.72 (d, 1H), 3.95 (d, 2H), 3.98 (d, 1H), 4.75 (m, 2H), 7.40 (m, 6H), 7.68 (m, 4H) Preparation Example 10 (Please read the back of the note first) Please fill in this page again&gt; Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives--------tr-----^-----A 丨^---------- -------------- This paper scale applies to China National Standard (CNS) A4 specifications (2) 0 X 29/ public hair) « 51 92012 1323263 52 A7 V. Description of invention (52 ) Synthesis Diisopropyl {1-[(methyl))-2-methylcyclopropyl]oxy}decylphosphonate Α The compound prepared in Preparation Example 9 (33 g) was subjected to the same procedure as in Preparation 3. 1.7 g of the title compound were obtained. (br s, 1H), 3.80 (d, 2H), 3.96 (d, 1H), 4.80 (m, 2Ή) ESI: 303 (M+Na)+, C12H22504 M Preparation 11 Synthesis of diisopropyl ({1 ·[(6_Amino~9孖_嘌呤_9yl)methyl]_2methylcyclopropyl}oxy)methylphosphonate ^ Preparation of Preparation Example 10 The compound (15 g) was dissolved in 5 ml of methane, then 0.85 ml of triethylamine and 84 g of methanesulfonate were added thereto, and the resulting mixture was stirred at room temperature for 3 minutes. Ammonium chloride was used to stop the reaction. The product was extracted with dichloromethane and then the residue was purified by evaporation in vacuo. The residue used for the next reaction did not require purification. NMR (CDC13) δ 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 (χπ, 2H), 4.31 (d , 1H), 4.71 (d, 1H), 4.76 (m, 2H) The methanesulfonate (43 mg) thus obtained was dissolved in 18 ml of di-f-carbamide, and 57.6 mg (purity) was added thereto. 6〇%) Hydrogenation This paper scale applies to China National Standard (CNS) A4 specification (2) 0 χ 297 mm) 92012 Order --------- Line! (Please read the notes on the back and fill out this page) -n I- n I* ·1 1323263 A7 V. Description of invention (53) Sodium and 162 mg of adenine, the resulting mixture is heated under reflux for more than 4 hours . Saturated ammonium hydride is added to stop the reaction. The product was extracted with ethyl acetate and then the ethyl acetate extract was concentrated by distillation under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc 'HNMRiCDCU 6 0.53 (t, 1H), 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 (M+l)+, C17H28N504P Preparation Example 12 Synthesis of diisopropyl ({l-[(2-amino-6-chloro-9//-in-9-yl)methyl]-2-) Methylcyclopropyl}oxy)methylphosphonate

The compound prepared in Preparation 10 was reacted in the same manner as in Preparation 11 except that adenine was replaced by 6-chloroguanine (2-amino-6-a-9-/--) to give the title compound. NMR (CDC13) δ 0.47 (t, J = 6.4 Hz, 1H), 1.12 (m, 4H), 1.24 (dd, J = 2.8 Hz, 6.4 Hz, 6H), 1.28 (t, J = 6.0 Hz, 6H) , 1.38 (m, 1H), 3.80 (m, 2H), 4.28 (m, 2H), 4.68 (m, 2H), 5.13 (brs, 2H), 8.15 (s, lH)

ESI: 432 (M+l)+, C17H27C1N504P Preparation Example 1 3 Synthesis of diisopropyl [(1 {[5-methyl·2,4-dioxo-3,4-dihydro-1(2Η)-) Pyrimidinyl]methyl}-2-methylcyclopropyl)oxy]methylphosphonate This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 92012 丨! Hey! _爹 (Please read the note on the back and fill in the page on this page) Printed by the Intellectual Property Office of the Ministry of Economic Affairs

^ ^ I ^1 .1· ϋ ϋ ϋ I n n I 1_1 I ·1 _1 n n n n 1 1 a__i I 53 1323263 A7 _ B7 V. Description of invention (54)

The compound prepared in Preparation 10 was reacted in the same manner as in Preparation 11 to give the title compound. lH NMR (CDC13) δ 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 (M+1) + C17H29N206P Preparation 14 Synthesis of 1-(ethoxycarbonyl)cyclopropanecarboxylic acid (Please read the back note first and then fill out this page)

Diethyl 1,1-cyclopropanedicarboxylate (20 g) was hydrolyzed in IN NaOH (107 ml) and ethanol (220 ml) for 16 hr. The remaining starting material was removed via use of ethyl acetate and the aqueous layer was acidified with 1N HCl. The reaction mixture was extracted with ethyl acetate and evaporated under reduced pressure. The residue was purified on a silica gel column to give the title compound. *H NMR(CDC13) δ 1.06 (t, 3H), 1.53 (m, 2H), 1.62 (m, 2H), 4.21. (q, 2H) ESI: 159 (M+l) + C7H10O4 Preparation 15 L-{[()oxy)carbonyl]amino}cyclopropanecarboxylate line. Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative

This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm). 54 92012 1323263 A7 B7 ------ V. Description of Invention (55) The carboxylic acid prepared in Preparation Example 14 (16 g) was dissolved. In the second gas, methane, 10.8 ml of oxalic acid was added dropwise and 2 drops of dimethylformamide were added. The reaction mixture was stirred at room temperature for 3 hours and distilled under reduced pressure to give an ethoxy group of 1,1-cyclopropenyl chloride. This compound was dissolved in 3 ml of dimethylformamide without purification and the resulting solution was cooled with water-ice. 36 g of NaN3 was added and the reaction was carried out for 3 hours at room temperature. The reaction solution was extracted with 1 ml of water and 2 ml of diethyl ether. The diethyl ether extract was concentrated to give a crude product, and the crude product was purified on a silica gel column to give an azide compound. • HNMRiCDClj) 6 1.28 (t, 3H), 1.54 (m, 4H), 4.19 (q, 2H) The thus obtained azide compound (13 g) was added dropwise 11 ml of T alcohol and the reaction mixture was heated to loot The reactants react strongly with each other and generate a gas. The reaction mixture was purified by EtOAc (EtOAc EtOAc). (m, 5Η), 1.54 (m, 2H), 4.11 (m, 2H), 5.15 (br.s, 2H), 7.32 (m, 5H) Preparation Example 1 6 Synthesis of benzyl 1-{[t-butyl (diphenyldecylalkyl)oxy]methylcyclopropyl}(methyl)carbamate

The carboxylic acid ester (13.2 g) prepared in Preparation Example 15 was dissolved in diethyl ether, and diethyl ether containing 1.3 g of LiBH4 was slowly added dropwise thereto. At room temperature + take m / c degrees 中国 use China National Standard (CNS) A4 specifications (210x297 public) 92012 (please read the back of the note and then fill out this page &gt; order --------- Line· Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Printing Agriculture n H · 55 1323263 A7 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printing ______B7_________ 1 &quot; —^ V. Invention Description (56) Stir the reaction mixture for 16 hours, then 50 ml 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 celestial column to obtain a benzyl-(methyl)cyclopropylcarbamic acid vinegar. This compound (9.3 g) was dissolved in dichloromethane, and 42 g of imidazole and 13.5 ml were added sequentially. Tributyldiphenylphosphonium chloride. 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 hydrazine gel to give benzyl 1-({[Third (diphenyl) aryl]oxy}methyl)cyclopropyl carbamate. *H NMR(CDC13) δ 0.71-1.19 (m, 4H), 1.04 (s, 9H), 3.68 (br.s, 2H), 5.04 (s, 2H), 7.25-7.45 (m, 11H), 7.62 ( d, 4H) ' The carbamate thus obtained (5.5 g) was dissolved in THF, 3 - 5 ml of methyl iodide (Mel) was added dropwise and then 1 g of NaH was added. The reaction mixture was stirred at room temperature for 4 hours and The title compound was obtained by EtOAc (EtOAc) (EtOAc). -0.84 (m, 4H), 1.03 (Sj 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 Example 17 Synthesis of diisopropyl [1-({[T-butyl(diphenyl)decyl)oxy}f-yl)cyclopropyl)(methyl)amino]methylphosphonate The paper size _ China National Secret 4 (CNS) A4 specifications (210 X 297 public) 56 92012 (please read the back of the note before you fill out this page) # -------Book----- ----line" A7

1323263 The carbamate (1 gram) prepared in Preparation Example 16 was dissolved in ethanol, 100 mg of 10% Pd/C was added, and the reaction mixture was hydrogenated under a hydrogen atmosphere. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified to give 1-({[t-butyl(diphenyl)decenyl)oxy}methyl)-N. -methylcyclopropaneamine. JH NMR (CDC13) δ 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 thus obtained methylcyclopropanamine (1 gram) was dissolved in dichloromethane', and 1.03 ml of diisopropylethylamine and 13 ml (diisopropyl oxime) were added dropwise. Methyl trifluoromethane acid ester. The reaction mixture was scrambled at room temperature for 4 hours' and then extracted with 1 mL of diethyl ether and hydr. The solvent in the diethyl ether extract was removed by distillation under reduced pressure, and the residue was purified to purified crystals. I lH NMR (CDC13) δ 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, 6H), 7.65 (d, 4H) Preparation 18 Synthesis of diisopropyl (l-{[(6-amine) Base-9//-嗓吟-9_yl)methyl]cyclopropyl}(methyl)amino)methylphosphonate (please read the notes on the back and fill out this page) ----- --Book --------- Line" Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperatives printed? clothes

The paper grade is halogenated by Yin Guo National Standard (CNS) A4 specification (2〗 〇χ 297 male dragon) 57 92012 1323263 A7 B7 V. Inventive Note (58) The compound prepared in Preparation Example 17 (0 32 g) was dissolved in methanol. And add 1_5 grams of fluorinated money dropwise. The reaction mixture was stirred at 6 ° C for 24 hours and then the solvent was removed by distillation under reduced pressure. The residue was purified by a silica gel column to give methylamine diisopropylmethylphosphonic acid 1} 1-cyclopropaneethanol. *H NMR(CDC13) δ 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 continuously reacted in the same manner as in Preparations 4 and 5 to give the title compound. lH NMR (CDC13) δ 0.78 (m, 2H), 0.86 (m, 2H), 1.25 (m, 12H), 2.35 (s, 3H), 4.10 (s, 2H), 4.68 (m, 2H), 5.13 ( m, 2H), 8.32 (s, 1H), 8.58 (s, 1H)

ESI: 397 (M+l)+, C17H29N603P Preparation Example 19 Synthesis of diisopropyl (1-{[(2-amino-6-a-9-y-yl)-yl)methyl]cyclopropyl} Base) Amino) methylphosphonate (please read the notes on the back and fill out this page) 0

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Employees' Consumption Cooperatives 58 The compound prepared in Preparation Example 17 (0.32 g) was dissolved in methanol and 1.5 g of fluorinated was added dropwise. The reaction mixture was stirred at 601: for 24 hours and then the solvent was removed by evaporation under reduced pressure. The residue was purified by a dream gum column to give methylamine diisopropylmethylphosphonic acid 1,1-cyclopropaneethanol. *H NMRiCDClj) δ 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 compounds thus obtained are in accordance with the same procedures as in Preparations 4 and 6. The paper scale applies to the Chinese National Standard (CNS) A4 specification &lt;210 x 297 mm) 92012 Printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs 59 1323263 V. INSTRUCTION DESCRIPTION (59) The title compound is obtained by continuous reaction. NMR (400MH2, CD3OD): δ 0.79 (m, 2H), 0.89 (to, 2H), 1.26 (m, 120), 2.38 (s, 3H), 2.76 (d, 2H, ^=7Hz), 4.11 (s , 2H), 4.65 (m, 2H), 5.13 (m, 2H), 8.02 (s, 1H)

ESI: 431(M+1)+, C17H28CIN603P Preparation Example 20 Synthesis of diisopropyl [(l-{[5-methyl-2,4-dioxo-3,4-dihydro-1 (2 Η) -03⁄4 bite base] methyl}cyclopropyl)(methyl)amino]methylphosphonium vinegar The compound prepared in Preparation Example 17 (0.32 g) was dissolved in a yeast fermentation _ and a gas chromatography recorded at 1.5 g was added dropwise. . The reaction mixture was stirred at 6 Torr for 24 hours and then the solvent was removed by evaporation under reduced pressure. The residue was purified on a phantom column to give methylamine diisopropylmethylphosphonic acid. lH NMR (CDC13) δ 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 thus-obtained compound was reacted in the same manner as in Preparations 4 and 7 to give the title compound. H NMR(CDC13) δ 0.79 (4) 2H), 0.90 (m» 2H), 1.31 (4) 12H), 1.92 (s, 3H), 2.38 (s, 3Η), 3.75 (d, 2H), 4.10 (s, 2H) , 4.65 (m, 2H), 7.62 (s, 1H), 9.15 (s, 1H) Preparation 2 1 Synthesis of 1,1-cyclopropanedicarboxylic acid hoAoh ο 50 50% 187 ml of NaOH towel dissolved at room temperature 15 grams of two. Ethyl paper size applies to the Central Standards (CNS) A4 specifications (210 X 297 public) 92012 -------- order --------- line! (Please read the back of the note first and then fill out this page) » 1323263 A7

V. Description of the invention (6〇) Malonate. Benzyltriethylammonium hydride (21.3 g) was added and the resulting mixture was stirred for 10 minutes. 1,2-Dibromoethane (12.3 g) was added to the reaction solution, and the resulting mixture was stirred at room temperature for 18 hours or more. The concentrated sulfuric acid was added dropwise to neutralize the reaction mixture and then extracted with ethyl acetate. The extract was evaporated under reduced pressure to give the title compound, m. 'HNMRCCDClj) 6 1.88 (s, 4H) Preparation 22 Synthesis of hydrazine-({[t-butyl(diphenyl)decyl)oxy}methyl)cyclopropyl]methanol (Please read the back note first) Fill in this page again).

Order i line A hydrogenated Mingzhong (L AH) 1 5.3 g was dissolved in 39 g of tetrahydroanthraquinone, and 11.7 g of the carboxylic acid prepared in Preparation Example 21 was slowly added dropwise at 〇 °C. The reaction solution was refluxed for 17 hours. 1 〇% HCl was added at room temperature to stop the reaction and the mixture was extracted with ethyl acetate. The extract was evaporated under reduced pressure and the residue was purified to give y. NMR (CDCl3) δ 0.56 (s, 4H), 2.22 (s, 2H), 3.63 (s, 4H) The compound thus obtained (400 mg) was dissolved in 12 ml of the product. THF' was added with 184 mg of NaH and 1.16 g of t-butyldiphenylsulfonyl chloride (TBDPSC1), and the resulting mixture was refluxed for 6 hours. The reaction was stopped by adding 10 ml of water and the mixture was extracted with ethyl acetate. The extract was distilled under reduced pressure and the residue was purified using a silica gel column to give 11 g of the title compound. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm). 60 92012 1323263 A7 _______B7___ V. Description of invention (61 ) 'H NMR(CDC13) δ 0.33 (t, 2Η), 0.48 (t, 2H ), 1.23 (s, 9H), 3.59 (d, 4H), 7.42 (m, 6H), 7.68 (m, 4H) Preparation 23 Synthesis of diethyl (Ε)-2-[1·({[third Butyl (diphenyl)nonanyl]oxy}indenyl)cyclopropyl]vinylphosphonate

The compound prepared in Preparation 22 (2 g) was dissolved in 50 ml of dichloromethane. Then, at room temperature, 1.03 g of hydrazine-methyl phenanthrene-oxide and 103 mg of tetrapropylammonium perrhenate were added. (ΤΡΑΡ). The reaction mixture was stirred at room temperature for 1 hour, and 20 ml of water was added to stop the reaction. The reaction solution was extracted with dioxane and the extract was concentrated under reduced pressure to give 2.0 g of aldehyde compound. *HNMR(CDCl3) δ 1.03 (s, 9H), 1.04 (t, 2H), 1.05 (t, 2H), 3.94 (s, 2H), 7.37 (m, 6H), 7.64 (m, 4H), 9.10 ( s, 1H) Tetraethylmethanediphosphonate (1.7 g) was dissolved in 60 ml of four gas-purpur (THF). 264 mg of NaH was added at -78 ° C, and the resulting mixture was stirred for 20 minutes' then 1.9 g of the above-obtained compound was added. Stir at room temperature: The reaction solution was mixed for 1 hour, and 20 ml of water was added to stop the reaction. The reaction solution was extracted with ethyl acetate and the extract was concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAc. 'H NMR(CDC1,) δ 0.76 (t, 2H), 0.81 (t, 2H), 1.04 (s, 9H), 1.31 (1, 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 This paper size applies to the Chinese National Standard (CNS) A4 specification. (210x297 public) 92012 (Please read the notes on the back and fill out this page) I I-----Book·! 11---Line — _ Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 61 1323263 A7

V. INSTRUCTIONS (62) Preparation Example 24 Synthesis of diethyl 2-[1-(hydroxyf-)cyclopropyl]vinylphosphonic acid vinegar

The compound prepared in Preparation 23 was reacted in the same manner as in Preparation 3 to give the title compound. 'H NMRiCDCl3) δ 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) + C28H41〇4PSi f Preparation 25 Synthesis of diethyl 2-{l-[ (6-Amino-9//-嘌呤-9-yl)methyl]cyclopropyl}vinylphosphonate

(Please read the unintentional matters on the back and then fill out this page) — II.-------" Department of Economics, Intellectual Property Office, Staff Consumer Cooperative, Printed the compound prepared in Preparation Example 24 in the same manner as Preparation Examples 4 and 5. The step is carried out to give the title compound. NMR (CDC13) δ 1.07 (t, 2Η), 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 (M+1) + C15H22N503P 备备例26 Synthesis of diethyl 2-{1-[(2 -Amino-6-gas-9//-嘌呤-9-yl)methyl]cyclopropyl}vinylphosphonate This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 62 92012 1323263 A7 V. INSTRUCTIONS (63) The title compound was obtained by the same procedure as the preparation of the preparation of Example 4 and 6. lH NMR (CDC13) δ 1.06 (t, 2 Η), 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 (M+1) + C15H21C1N503P Preparation Example 27 Synthesis of diethyl 2-(1-{[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidine Base] methyl}cyclopropyl)vinylphosphonate Ο 0 (Please read the note on the back and fill out this page) 4· Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, print the compound prepared in Preparation Example 24 The same steps as in Preparations 4 and 7 were obtained. lHNMR(CDCl3) δ 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, 1H), 5.87 (m, 1H), 7.62 (s, 1H). 9.15 (s, 1H) ESI: 343 (M+l) + C15H23N205P He prepared Example 28 Synthesis l-({[Third (diphenyl)nonanyl]oxy}methyl)_2,2-dimethylcyclopropanol

Table paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) 63 92012 — —— — — —— ------ Line — i

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V. INSTRUCTIONS (64) STATEMENT = (Material: 1.). The title compound was prepared as follows. 1 g (29 mmol) of ethyl {[butyl(diphenyl)saltyloxy)acetic acid vinegar was dissolved in 100 ml of tetrahydroanthracene (THF) and 6 was added thereto. 〇ml of four titanium isopropoxide. 37 ml of desertified isobutylidene (2 times) was slowly added to the mixture in the order of -, and the reaction solution was stirred at room temperature for η hours. A 5 G mL saturated gasification recording was added to stop the reaction. The tetrahydroanthracene (THF) as a solvent was removed by distillation under reduced pressure, and the reaction mixture was extracted twice with 500 ml of n-hexane. The n-hexane extract was distilled under reduced pressure and purified on a silica gel column to give the title compound. NMR NMR (CDC13) 6 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)+, C22H30〇2Si Preparation 29 Synthesis of diisopropyl[t-butyl(diphenyl)decane (yloxy)methyl)-2,2-dimethylcyclopropyl]oxy)methylphosphonate-----.-.-----,#- (Please read the back Note: Please fill out this page again) ίσ· -- Line. Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

The compound prepared in Preparation 28 was reacted in the same manner as in Preparation 2 to give the title compound. NMR NMR (CDC13) δ 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 (M+l)' C28H4305PSi This paper size applies to Chinese national standards (CNS) A4 size (210x297 mm) 64 92012 1323263 A7 B7 V. INSTRUCTION DESCRIPTION (65) Preparation Example 30 Synthesis of diisopropyl {1-[(hydroxymethyl)_22_dimethylcyclopropyl]oxy } Methyl phosphonate The compound prepared in Preparation 29 was reacted in the same manner as in Preparation 3 to give the title compound. JH NMR (CDC13) δ 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 ({1-[(6-Amino-9//-嘌呤-9-yl) )methyl]-2,2-dimethylcyclopropyl}oxy)methylphosphonate (please read the notes on the back and fill out this page). IIII _ II Order -- ------ -I. Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed The compound prepared in Preparation Example 30 was reacted in the same manner as in Preparation 11 to give the title compound. NMR^OOMHz^ CDC13): δ 0.62 (formula ================== Hz, 1H), 3.85 (dd, J=15.1, 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 &lt;s, 1H), 8.32 (s, 1H) ESI: 412 (M+l)+, C18H30N5O4P Preparation 32 This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) S?f&gt; 65 92012 1323263 A7 ---B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed V. Inventions (66) Synthesis of Diisopropyl ({1-[(2-Amino-6) -Iodo-9//-嘌呤-9-yl)methyl]. 2,2-dimethylcyclopropyl}oxy)methylphosphonate The compound prepared in Preparation Example 30 was obtained in the same manner as in Preparation 12. The reaction was carried out but the 6-valvequinone was substituted with 6-ostavidin to give the title compound. It NMROOOMHz^ CDC13): δ 0.58 (d, 1=6.43⁄4 1H), 0.80 饨J=6.4Hz, 1H), 1.10 (s, 3H), 1.24 (m, 8H), 3.72 (dd, J=13.0, 11.0 Hz, 1H), 3.88 (dd, J = 13.0, 9.3 Hz, 1H) 4.08 (d, J = 15.1 Hz, 1H), 4.47 (d, J = 15.1 Hz, 1H), 4.67 (m, 2H), 5.05 (bs, 1H), 8.10 (s, 1H) ESI: 538 (M+l)+, C18H29IN504P Preparation 33 Synthesis of diisopropyl [(1{[5-methyl-2,4-dioxo- 3,4-Dihydro-1(2H)-pyrimidinyl]methyl}-2,2-dimethylcyclopropyl)oxy]methylphosphonate) - Preparation and Preparation of the Compound Prepared in Preparation Example 30 The same procedure as in Example 13 was carried to give the title compound. NMR NMR (CDC13) δ 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 (M+1) + C18H31N206P </ RTI> </ RTI> </ RTI> </ RTI> Synthesis of l-[l-({[T-butyl(diphenyl)decyl)oxy}methyl)cyclopropyl]- 1-Methanol This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 66 92012 (Please read the note on the back and fill out this page again) - nnnn I · nn tv 1 I n ·1 T_i nn ^^1 n ϋ 1323263 V. Description of invention (π)

6 g of the compound prepared in Preparation 22 was dissolved in 150 ml of methylene chloride. Further, 3 g of N• oxide and 3 mg of tetrapropylammonium perrhenate (TPAp) were added thereto at room temperature. The reaction mixture was stirred at room temperature for about 1 hour, and added to 20 ml of water to quench the reaction. The reaction solution was extracted with dioxane and the extract was concentrated under reduced pressure to give 6 gram of aldehyde compound which was used in the next step without further purification. A solution of 5.23 grams of the compound was dissolved in 350 ml of THF. Solution

Cool to -78 C and slowly add 1 〇 3 ml of methylmagnesium bromide (3.0 M solution)' and then stir at room temperature for 1 hour. The reaction was quenched with 5 ml of water and 5 ml of methanol and the mixture was concentrated under reduced pressure. The residue was purified to silica gel elut elut elut elut elut elut elut • HNMRCCDCl,) δ 0.22 (m, 1H), 0.39 (m, 2H), 0.61 (m, 1H), 1.06 (s, 9H), 124 (d, 3H), 3.3 (d, 1H), 3.47 (s , 2H), 3.9 (d, 1H), 7.43 (m, 6H), 7.64 (m, 6H) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Preparations 35 Synthesis of diethyl (5)-2-l- [l-({[T-butyl(diphenyl)decyl]oxy}methyl)cyclopropyl]-1-propenylphosphonate

4 g of the compound prepared in Preparation 34 was dissolved in 10 ml of hexane. The paper scale was applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) &gt; 67 92012

UZSZ0J A7

V. INSTRUCTIONS (68). Further, 2" gram of n morpholine N oxide and 209 mg of tetrapropylammonium perrhenate (TpAp) were added thereto at room temperature. The reaction mixture was stirred at room temperature for 1 hour and added to 2 mL of water to quench the reaction. The reaction mixture was extracted with methylene chloride and EtOAc was evaporated. Tetraethylmethanediphosphonate (27 g) was dissolved in 3 mL of THF at -78 ° C, and 4 ml of n-butyllithium was added. The resulting mixture was stirred for 20 minutes, and then 1. gram of the ketone compound obtained above was added. The reaction mixture was stirred at room temperature for 1 hour and 2 ml of water was added to stop the reaction. The reaction mixture was extracted with EtOAc. The residue was purified to give 654 mg of the title compound.屯NMR (CDC13) δ 0.58 (% 1H), 0.69 (4) 2H), 1.02 (s, 9H), 1_20 α 6H), 2.09 (d, 3H), 3.59 (s, 2H), 4.05 (m, 4H), 5.61 (d, 1H), 7.38 (m, 6H), 7.63 (d, 4H) Example 1 Synthesis ({1-[(6-Amino-9//-嘌呤-9-yl)methyl]cyclopropane Methylphosphonic acid (Compound 1) Printed by the Ministry of Economic Affairs, Intellectual Property Office, Consumer Cooperatives (please read the notes on the back and fill out this page). Dissolve the compound prepared in Preparation 5 (159 mg). 15 ml of dioxane methane was added thereto to add 1.27 g of trif-decylalkyl bromide, and the resulting mixture was heated under reflux for 18 hours. After the reaction was completed, the reaction mixture was extracted with water and the aqueous extract was distilled under reduced pressure. The residue was purified by high-performance liquid chromatography (HPLC) to give the title compound (yield: 'H NMR (MeOH-d4) δ 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 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 68 92012 1323263

V. Description of invention (71)

The compound prepared in Preparation Example 6 (1 50 mg) was dissolved in 15 ml of tetrahydrofuran, and 15 mg of 5% palladium on carbon was added thereto, and the reaction mixture was reduced under a hydrogen atmosphere of 1 atm for 8 hours. After the reaction is completed, the particles/carbon are removed by suction filtration and the steam is discharged under the dust reduction. The residue was purified by column chromatography (eluent: methylene chloride/methanol = 20/1, v/v) to give 130 mg of diisopropyl compound (ESI: 384(]V[+i)+ , C16H26N 504P). This compound was treated with trimethylsulfonyl bromide in the same manner as in Example 1 to give 91 mg (yield: 90%) of the title compound. !H NMR (MeOH-d4) δ 0.94 (m, 2H), 1.03 (m, 2H), 3.93 (d, 2H), 4.40 (s, 2H), 8.66 (s, 1H), 8.74 (s, 1H) ' ' ' ESI: 300 (M+l)+, C10H14N5O4P --I I.---------I . (Please read the notes on the back and write this page again &gt; Ministry of Economic Affairs Intellectual Property Office Employees' Consumption Cooperative Printed Example 6 Synthesis of 3-[({l-[(2-amino-9//-嘌呤-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8 -Dimethyl-3,7-dioxo-2,4,6-triazin-3 and 5-indole-1_ ketalic acid vinegar (Compound 10) The compound prepared in Example 5 was used in accordance with the examples. 2 The same procedure was carried out to give the title compound: NMR (CDCl3-d4) δ 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 ({1-[(2-Amino-) 6-Cyclopropylamino-9/f-fluoren-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid (Compound 11) The compound prepared in Preparation 6 (200 mg) was dissolved in 20 The paper size of the milliliter is over the Chinese National Standard (CNS) A4 specification (2〗 〇χ 297 mm) 71 92012 Order line 13 23263 A7 B7 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 5, Inventions (72) Ethanol 'Addition of 53 ml of triethylamine and 82 mg of cyclopropylamine' and heat the mixture under reflux. Hour. 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 chromatographic column chromatography (eluent: two gas / methanol = 20 / 1, v/v) The residue was purified to give 178 mg (yield: 85%) of isopropyl compound. NMR (CDC13) δ 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 (bra, 2H ), 5.71 (s, 1H), 7.68 (s, 1H). The thus-obtained compound was treated in the same manner as in Example 1 with trimethyl ethoxylate-based desertification to give 128 mg (yield: 90%). The title compound 0 'H NMR (MeOH-d4) δ 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 ({l- [(2-Amino-6-ethylamino-9-/-fluoren-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid (Compound 13) The compound prepared in Preparation 6 ( 115 mg) was dissolved in .20 ml of ethanol, and 31 ml of triethylamine and 7 ml of ethylamine were added thereto, and 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 eluting with EtOAc EtOAc EtOAc EtOAc %) bis isopropyl compound. (Please read the notes on the back and fill out this page) % - Line. This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 72 92012 1323263 A7 __ . B7 V. Invention description (73) (Please read the notes on the back and fill out this page) Ή NMR(CDC13) δ 0.82 (m, 2H), 1.00 (m, 2H), 1.24 (d, 6H), 1.27 (t, 3H), 1.29 (d , 6H), 3.60 (brs, 2H)S 3.81 (d, 2H), 4.15 (s, 2H), 4.65 (m, 4H), 5.50 (br s, 1H), 7.78 (s, 1H) The compound was reacted in the same manner as in Example 1 to give the title compound (yield: 90%). NMR (MeOH-d4) δ 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 [(1-{[2-amino-6-(dimethylamino)-9/f-嘌呤-9-yl]methyl} ring Propyl)oxy]decylphosphonic acid (Compound 15) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed The compound prepared in Preparation Example 6 (115 mg) was dissolved in 20 ml of ethanol, followed by 38.6 ml of triethyl Amine and 1.74 ml of hydrazine, hydrazine-dimethylamine, 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 EtOAc EtOAc EtOAc EtOAc %) bis isopropyl compound. NMR NMR (CDC13) δ 0.75 (t, 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 in the same procedure as in Example 1 to give 86 mg (yield: 90%) Title compound. ΉΝΜΚ(ΜβΟΗ·ά4) δ 0.89(^211), 1.05(1^211), 3.300^611), 3.90 (423⁄4) This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 73 92012 1323263 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printing V. Inventions (74) 4.37 (s, 2H), 7.92 (br s, 1H) ESI: 343 (M+l)+, C12H19N604P Example 10 Synthesis [( 1·{[2-Amino-6-(isopropylamino)-9/f-fluoren-9-yl]fluorenyl}cyclopropyl)oxy]methylphosphonic acid (Compound 17) Preparation Example 6 The compound (133 mg) was dissolved in 20 ml of ethanol, then 0.049 ml of triethylamine and 0.082 ml of isopropylamine were added, 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 purified by column chromatography (eluent: dioxymethane / methanol = 20/1, v / v) 95 mg (yield 68%) of the diisopropyl compound. NMR (CDC13) δ 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, 2 H), 4.70 (m, 2H), 5.40 (br s, 1H), 7.77 (s, 1H) The compound thus obtained was reacted in the same procedure as in Example 1 to give the title of 72 mg (yield 91%). 'H NMR (MeOH-d4) δ 0.89 (m, 2H), 1.05 (m, 2H), 1.34 (d, 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 (U-[(2,6-diamino-9/i-嘌呤-9-yl)) The compound prepared in Preparation Example 4 (246 mg) and 2,6-diaminoguanidine were reacted in the same manner as in Preparation 5 to obtain 7 8 . · 5 mg (yield 2 9%) (Please read the notes on the back and fill out this page) 鳓*5. -Line paper size applies to China National Standard (CNS) A4 specification (210x 297 mm) 74 92012 1323263 A7 B7 V. The isopropyl compound of the invention (75). 'H NMR(CDC13) δ 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)

ESI: 399 (M+l) +, C16H27N. NMR NMR (DMSO-d6 + CF3COOH) δ 0.70 (m, 2 Η), 0.82 (m, 2H), 3.58 (d, 2H), 4.21 (s, 2H), 8.16 (brs, 1H)

ESI: 315 (M+l)+, C10H15N6O4P Example 12 Synthesis ({l-[(2-amino-6-ethoxy-9//-purin-9-yl)methyl]cyclopropyl}oxy Methylphosphonic acid (Compound 23) The 6-chloroguanine derivative (100 mg) prepared in Preparation Example 6 was dissolved in 10 ml of ethanol, and 32 ml of triethylamine and 53 mg of sodium methoxide were added, and The resulting mixture was refluxed for 4 hours. The reaction was stopped by adding 10 ml of water, and the reaction solution was extracted with dioxane and distilled under reduced pressure. The residue was purified by hydrazine column chromatography to give a compound in which the 6-position of guanine was substituted with ethoxy. 'HNMRiCDCla) δ 0.83 (t, 2H), 1.00 (t, 2H), 1.24-1.28 (m, 12H), 1.45 (t, 3H), 3.82 (d, 2H), 4.21 (s, 2H), 4.53 ( M, 2H), 4.67 (m, 1H), 5.76 (s, 2H), 7.90 (s, 1H) The compound thus obtained was reacted in the same procedure as in Example 1 to give the title compound. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 92012 rmti (please read the note on the back and fill out this page) -SJ.· - Line _ Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative t 75 1323263

V. INSTRUCTIONS INSTRUCTIONS (77) f Shi 丨1 4 Synthesis [(1 {[5-Mercapto-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl] fluorenyl} Cyclopropyl)oxy)methylphosphonic acid (Compound 31) The title compound (m.p.

ESI: 291 (M+l)+, C10H11N2O6P lK NMR (MeOH^14) δ 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 1 5 Synthesis [(l-{[2-Amino-6-(4-morpholinyl)-9//-嘌呤-9-yl]methyl} Cyclopropyl Ethyloxy]methylphosphonic acid (Compound 37) The compound prepared in Preparation Example 6 (134 mg) was dissolved in 20 ml of ethanol, and then 0.049 ml of triethylamine and hydrazine 85 ml of morpholine were added thereto. 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: methylene chloride / hexane = 20/1, v/v) 44%) of the diisopropyl compound. , lH NMR (CDC13) δ 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 trimethyldecyl bromide according to the same procedure as in Example 1 to give 49 mg (yield: 91%) of title compound. Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 92012 (Please read the note on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau employee cooperation cooperation printing -I * nnn 1^1 n Ej&gt; n Bn fn I nn I ^1« nnn 77 1323263 • A7 B7 V. Inventive Note (78 ) *Η NMR (MeOH-d4) δ 0.89 (m, 2H), 1.07 (m, 2H), 3.81 (m , 4H), 3.92 (d, 2H), 4.40 (br s, 6KQ, 7.87 (s, 1H)

ESI: 384 (M+l)+, C14H21N605P Example 1 6 Synthesis [(1-{[2-amino-6-(1-piperidinyl)-9//--9-yl]methyl} Cyclopropyl)oxy]methylphosphonic acid (Compound 39) The compound prepared in Preparation Example 6 (154 mg) was dissolved in 20 ml of ethanol, and then 0.049 ml of triethylamine and 0.11 ml of piperidine were added thereto. 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 eluting with EtOAc EtOAc EtOAc EtOAc %) bis isopropyl compound. HNMR(CDa3) δ 0.80 (4) 2H), 0.99 (吼2H), 1.22 (4 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)+, C21.sub. NMR (MeOH-d4) δ 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 (M+l)+, C15H23N604P Example 17 Synthesis of [(1-{[2-amino-6-(4-methyl-1-pipedyl)-9//--9-yl) ] Methyl}cyclopropyl)oxy]methylphosphonic acid (Compound 41) (Please read the note on the back and fill out this page) Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Standard (CNS) A4 specification (210 X 297 mm) :\ Ο 71 78 92012 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 79 1323263 Α7 Β7 V. Inventive Note (79) The compound prepared in Preparation Example 6 (128 mg It was dissolved in 20 ml of ethanol, and 0.10 ml of 4-methyl-piperidin 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 EtOAc EtOAc EtOAc EtOAc 83%) of the diisopropyl compound. lU NMRiCDCU) δ 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 (s, 2H), 4.22 (br s, 4H), 4.57 (s, 2H), 4.66 (m, 2H), 7.73 (s, 1H)

ESI: 482 (M+l) +, C.sub.2H.sup.ss.ssssssssssssssssssssss *H NMR(MeOH-d4) δ 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 1 8 Synthesis [(1-{[2-amino-6-(1-pyrrolidinyl)-9//--9-yl]methyl} Cyclopropyl)oxy]methylphosphonic acid (Compound 43) The compound prepared in Preparation 6 (122 mg) was dissolved in 20 ml of ethanol, and then 0.07 ml of pyrrolidine was added thereto, and the resulting mixture was refluxed. Heat for 1 hour. 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: methylene chloride/methanol = 20/1, v/v) to yield 110 mg. %) bis isopropyl compound. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 92012 words (please read the notes on the back and fill out this page)

1323263 A7 B7 V. INSTRUCTIONS (80) 'H NMR(CDC13) δ 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.sup.1), C.sub.2H.sub.3. *H NMR(MeOH-d4) δ 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, 2H), 8.42 (s, 1H)

ESI: 369 (M+l)+, C14H21N604P Example 19 Synthesis of 3-[({l-[(2-amino-9仏嘌呤-9-yl)methyl]cyclopropyl}oxy)methyl] -9-Methyl-3,7-dioxo-2,4,6-triazin-3λ5-phosphonium-l-yl 3-methylbutyrate (Compound 74) The compound prepared in Example 5 ( 100 mg) was dissolved in dimethylformamide (2 ml) and then reacted with gas methyl 3-methylbutyrate at room temperature for 24 hours in the presence of triethylamine (3 equivalents). The obtained product was purified by silica gel column chromatography to yield 41% of title compound. NMR NMR (CDC13) δ 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//-嘌呤-9-yl)methyl]cyclopropyl}oxy) oxime ]],7,7-dioxo-2,4,6-tris-3-λ 5-phosphonium-1-butyrate·(Compound 75) The compound prepared in Example 5 was reacted at room temperature with Chloromethylbutyrate (Please read the note on the back and fill out this page) 士-ο Γ Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed on this paper scale Applicable to China National Standard (CNS) A4 specification (210 X 297 PCT) 80 92012 1323263 A7 B7 V. Inventive Description (81) The reaction was carried out for 24 hours in the same manner as in Example 19. The obtained product was purified by silica gel column chromatography to give the title compound. 'H NMR(CDC13) δ 0_88 (t,2H), 0.92 (d,6H), 1.60 (4) 4H), 2.32 4H), 3.96 (4 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 2 1 Synthesis of 3-[({l-K2-amino-9//-嘌呤-9-yl)methyl]cyclopropyl}oxy)methyl ]-8-Methyl-3,7-dioxo-2,4,6-tris-3-λ 5-phosphon-1-yl 2-methylpropionate (Compound 78) will be at room temperature The compound prepared in Example 5 was reacted with gas methyl isobutyrate in the same manner as in Example 19 for 24 hours. The obtained product was purified by chromatography on a silica gel column to yield the title compound. Ή m4R(CDCl3) δ 0.84 (t, 2H), 0.97 (t, 2H), 1.11 (d, 12H), 2.52 (m, 2H), 3.91 (d, 2H), 4.16 (s, 2H), 5.21 ( s, 2H), 5.58 (m, 4H), 7.96 (s, 1H), 8.61 (s, 1H)

ESI: 499 (M+l)+, C21H31N408P Example 22 Synthesis of 3-[({l-[(2-amino-9//-嘌呤-9-yl)methyl]cyclopropyl}oxy) A -3,7-dioxo-7-(1-pyrrolidinyl)-2,4,6-triazin-3 λ 5-phosphan-1-ylpyrrolidinecarboxylate (Compound 80) The compound prepared in Example 5 and chloromethyl 1-pyrrolidinecarboxylate were reacted for 24 hours in the same manner as in Example 19 at room temperature. The obtained product was purified by EtOAc EtOAc (EtOAc) 'H NMR(CDC1,) δ 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 This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 92012 (please read the notes on the back and fill out this page) -6· • Line. Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 81 1323263 A7 B7 V. Description of Invention (82) Example 23 Synthesis of 3-[({1-[(2-Amino-9//-嘌呤-9-yl)) ]]cyclopropyl}oxy)methyl]-3,7-dioxo-7-(1-piperidinyl)-2,4,6-triazin-3 λ 5-phosphonium-1-yl 1-pulse tartary vinegar (Compound 81) The compound prepared in Example 5 was reacted with oxymethylpiperidone at room temperature for 24 hours in the same manner as in Example 19. The obtained product was purified by column chromatography to affordyyyyyy 'Η NMR(CDC13) 6 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)+, C25H37N608P Example 24 Synthesis of 3-[({l_[(2-amino-9/7-嘌呤-9-yl)methyl]cyclopropyl}oxy) fluorenyl ]-7-(4-morpholinyl)-3,7-dioxo-2,4,6-tris-3 and 5-phosphonium-1-yl-4-morpholine tartrate (compound 82) The compound prepared in Example 5 and the gas methyl 4- morpholino acid ester were reacted in the same manner as in Example 19 at room temperature for 24 hours. The obtained product was purified by chromatography to give 40% of title compound. !H NMR(CDC13) δ 0.89 (t, 2H), 1.03 (t, 2H), 3.47 (bnn, 8H), 3.65 (bnn, 8H), 4.00 (d, 2H), 4.24 (s, 2H), 5 .CM (s, 2H), 5.70 (m, 4H), 8.07 (s, 1H), 8.69 (s, 1H)

ESI: 586 (M+l) &quot;, C23H33N6O10P Example 25 Synthesis {[1-({2-Amino-6-[(4-methylphenyl)thio]-9//-嘌呤-9- (Methyl)cyclopropyl]oxy}methylphosphonic acid (Compound 66) The 6-gas guanidine derivative (4.86 g) prepared in Preparation Example 6 was dissolved (please read the back note first and then fill in the form) Page) #

Order·-------Line 丨J Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed This paper scale applies China National Standard (CNS) A4 specification (210 X 297 public Chu) 82 92012 Ministry of Economic Affairs Intellectual Property Bureau employees Consumer Cooperatives Printed 83 1323263 A7 __ B7 V. Description of the Invention (83) 85 ml of methanol 'Addition of 14 g of triethylamine and 2 9 g of 4-methyl toluene. The reaction mixture was reacted under reflux for 24 hours. 20 ml of water was added to stop the reaction, and methanol was distilled off under reduced pressure. The reaction mixture was extracted with dichloromethane and purified on a silica gel column to give a compound in which the 6-position of guanine was substituted with 4-methylphenylthio. 'H NMR(CDClj) δ 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&gt; 1H) The compound thus obtained is reacted in the same manner as in Example 然后 and then from methanol-two-story ( The 1/20, v/v) mixture was recrystallized to give the title compound. Ή MMR(MeOH-d4) δ 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 (M+l)+, C18H21N404PS Example 26 Synthesis of 3-({[l-({2-amino-6-[(4-methylphenyl)thio]-9H-嘌呤-9_ }]methyl)cyclopropyl]oxy}methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-tris-3 and 5-lin-1 The methic acid ester (Compound 68) The methylphosphonic acid prepared in Example 25 was reacted in the same manner as in Example 2 to give the title compound. &gt; NMR (CDC13) δ 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 {[l-({2-Amino-6-[(4-methoxyphenyl)thio]-9//-嘌呤- Zhang scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 92012 — — — — — — — — — I — — --- — I--订··-----— I (Please Read the precautions on the back and fill out this page. 1323263 A7 B7 V. INSTRUCTIONS (84) 9-Methyl}methyl)cyclopropyl]oxyindole methylphosphonic acid (Compound 96) Preparation of Preparation 6 The chloroguanine derivative (4.86 g) was dissolved in 85 ml of methanol' and 14 g of triethylamine and 29 g of 4 methoxytoluenethiophenol were added. The reaction mixture was reacted under reflux for 24 hours. 20 ml of water was added to stop the reaction, and methanol was distilled off under reduced pressure. The reaction mixture was extracted with dioxane methane and purified by a silica gel column to give a compound in which the 6-position of the bird was substituted with 4-methoxyphenylthio. The compound thus obtained was reacted in the same manner as in Example i and then recrystallized from methanol diethyl ether (1/20, v/v) to give the title compound. NMR (MeOH-d4) δ 0.77 (吼2H), 1.05 (called 2H), 3.87 (s, 3H), 3.92 (2H), 4.45 (s, 2Η), 7.10 (d, 2H), 7.59 (d, 2H), 8.09 (s, 1H) '

ESI: 438 (M+l)+, C17H20N5O5PS Example 28 Synthesis {[l-({2-Amino-6-[(4-mercaptophenyl)thio]-9//·-嗓吟_9 · methyl}cyclopropyl]oxy}methylphosphonic acid (Compound 95) The compound prepared in Preparation Example 6 was reacted in the same manner as in Example 27 except that 4-nitrotoluenephenol was used instead of 4-A. The title compound is obtained from oxytoluene phenol. NMR NMR (MeOH-d4) δ 0.86 (m, 2H), 0.95 (m, 2H), 3.82 (d, 2H), 4.35 (s, 2H) 7.81 (d, 2H), 8.22 (d, 2H), 8.72 (s, 1H) '

ESI: 453 (M+l)+, C16H17N606PS Example 29 Synthesis ({1-[(2-amino-6-hydroxy-9//-嘌呤-9-yl)methyl) 2-methylcyclopropyl }oxy)methylphosphonic acid (Compound 97) This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mil) 92012 (Please read the back of the note first and then fill out this page) IAW-- ------Book---------Line 'Ministry of Economics Intellectual Property Bureau Staff Consumer Cooperative Printed 84 1323263 Α7 Β7 V. Description of Invention (85) Preparation of 6-chloroguanine prepared in Example 12 The derivative was continuously reacted in the same manner as in Examples 3 and 4 to give the title compound. HNMRC MeOH-d^ δ 0.73 (t, 1H), 1.15 ih), i.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 {Π·({2-Amino-[6-(4-methoxyphenyl)) Thiopurine 9 嘌呤·嘌呤_ 9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonic acid (Compound 99) The 6-aviphenone derivative prepared in Preparation Example 12 was The same procedure as in Example 27 was carried out to give the title compound. NMR (MeOH-d4) δ 0.67 (t, 1H), 1.13 (m, 2H), 1.20 (d, 3H), 1.45 (m, 1H), 3.85 (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 {[1-({2-Amino-[6-(4-methylphenyl)thio]-9//_嘌呤_9-yl} Methyl)-2-methylcyclopropyl]oxy}methylphosphonic acid (Compound 101) The 6-gas guanidine derivative prepared in Preparation Example 12 was reacted in the same manner as in Example 25 to give the title compound. NMR (MeOH-d4) δ 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)thio]-9/^-嘌呤-9-yl) }Methyl)-2-methylcyclopropyl]oxy}methylphosphonic acid (Compound 1〇〇) The 6-aviphenone derivative prepared in Preparation Example 12 was prepared in accordance with the examples (please read the back of the note first) Matters fill out this page again r r Liang Economics Department Intellectual Property Bureau Staff Consumer Cooperatives Printed Paper Size Applicable National Standard (CNS) A4 Specification (210x297 mm) 85 92012 1323263 A7 B7 V. Invention Description (86) The same procedure was followed for the title compound. NMR (MeOH-d4) δ 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 ({1-[(6-Amino-9/f-嘌呤-9-yl)methyl]-2-methylcyclopropyl}oxy Methylphosphonic acid (Compound 103) The adenine derivative prepared in Preparation 11 was reacted in the same manner as in Example 1 to give the title compound. β NMR OVleOH·^) δ 0.64 (t,1H), 1.09 (吼1H), 1_20 to 3H), 1.43 (1^1H), 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 (s, 1H)

ESI: 314 (M+l)+, C11H16N504P Example 34 Synthesis of 贰{[(t-butoxycarbonyl)oxy]methyl}({l-[(2-amino-9//--9) -yl)methyl]cyclopropyl}oxy)methylphosphonic acid vinegar, (Compound 69) The compound prepared in Example 5 (187 mg) was mixed with 6 ml of N-methyl-2-pyrrolidone. Add 300 mg of triethylamine and 150 mg of gas methyl tert-butyl carbonate. The reaction solution was stirred at room temperature for 4 hours. The reaction was stopped by adding 10 ml of water, and the reaction mixture was extracted with ethyl acetate. The extract was distilled under reduced pressure and purified to give the title compound. 'HNMR(CDC13) δ 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)

ESI: 344 (M+l)+, C22H34N5010P Example 3 5 (Please read the notes on the back and fill out this page) I. -Line·Ministry of Commerce, Intellectual Property Bureau, Staff and Consumer Cooperatives Printed Paper Size Applicable to Chinese National Standards (CNS) A4 size (210 x 297 mm) S today 7 86 92012 1323263 A7 ______ B7 V. Description of invention (87) Synthesis of 贰{[(isopropoxycarbonyl)oxy]methylamino _9// _ 嗓呤-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (Compound 7 〇) The compound prepared in Example 5 (1 mg) and 5 ml of N-methyl- 2-3⁄4 of a mixture of 'aldolone' was added with 11 mg of triethylamine and 15 mg of methylene isopropyl carbonate. The reaction solution was stirred at 50 ° C for 4 hours. The reaction was stopped by adding 10 ml of water' and the reaction mixture was extracted with ethyl acetate. The extract was evaporated under reduced pressure and purified to give the title compound. 'HNMR(CDC13) δ 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 (s, 1H), 8.69 (s, 1H)

ESI: 532 (M+l)+, C20H30N5010P Example 3 6 Synthesis (U_[(2-amino-6-hydroxy-9//-嘌呤-9-yl)methyl)-2,2-didecyl Cyclopropyl}oxy)methylphosphonic acid (Compound 146) The title compound was obtained from the title compound. lH NMR (MeOH-d4) δ 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 (M+l)+, C12H18N505P Example 37 Synthesis ({1-[(2-amino-9//-嘌呤-9-yl)fyl]-2,2-dimethylcyclopropyl }oxy)methylphosphonic acid (Compound 147) The compound prepared in Preparation 32 was reacted in the same manner as in the procedure of Example 5 to give a compound in which the 6-position of guanine was reduced by hydrogen. (Please read the notes on the back and fill out this page) ----- -- Order · 11_!-- Line — . Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Print this paper scale applicable to China National Standard (CNS) A4 size (210 X 297 mm) 87 92012 1323263 A7 ------ B7 V. Description of invention (88) ^NMRCCDCls) δ 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, 1H), 9.67 (s, 1H) The title compound (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH d, 1Η), 0.81 (d, 1H), 1.21 (s, 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 (M+l)+, C12H18N504P Example 3 8 Synthesis ({1-[(6-Amino-9//-嘌呤-9-yl)methyl]-2,2-dimethylcyclopropane The compound of Preparation 31 was reacted in the same manner as in Example 1 to give the title compound: NMR (MeOH-d4) δ 0.77 (d, 1 Η) , 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 (5)-2-{l-[(2-amino-6-hydroxy-9/f-purin-9-yl)methyl]cyclopropane The vinyl phosphonic acid (Compound 130) The compound prepared in Preparation 26 was reacted in the same manner as in Example 1 to give a phosphine acid derivative. NMR NMR (MeOH-d4) δ 1.07 (t, 2H), 1.33 (t, 1H), 4.41 (s, 2H), S.76 (dd, 1H), 6.45 (dd, 1H), 9.18 (s, 1H) The compound thus obtained was subjected to the same reaction as in Example 4, and the paper was passed through the National Standard for Insects (CNS) A4 (210 X 297 public). 92012 ίPlease read the notes on the back and fill in the instructions. This page&gt; Face I! I — I order _ ----- ! Line” Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 88

1323263 V. Inventive Note (89) The title compound was obtained. NMR NMR (MeOH-d4) δ 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+1V, C11H14N504P, Example 40 Synthesis of 2-{l-[(2-Amino-9孖·嘌呤-9-yl)methyl]cyclopropyl}ethylphosphonic acid (Compound 139) The title compound was obtained from the title compound m. , 1.95 (m, 2H), 4.11 (s, 2H), 5.78 (dd, 1H), 8.55 (s, 1H), 8.75(s, 1H)

ESI: 298 (M+l)+, C11H16N503P Example 41 Synthesis (£&gt;2·{1-[(6-Amino-9//-嘌呤-9-yl)methyl]cyclopropyl}vinyl Phosphonic acid (Compound 132) The title compound was obtained from the title compound (m.m.). 4.36 (s, 2H), 5.63 (dd, 1H), 6.37 (dd, 1H), 8.30 (s, 1H), 8.31 (s, 1H)

ESI: 296 (M+l)+, C11H14N503P Example 4: Synthesis of 2·{1-[(6-Amino-9/7-fluoren-9-yl)indolyl]cyclopropyl}ethylphosphonic acid ( Compound 14 〇) The compound prepared in Preparation Example 25 was subjected to the same procedure as in Example 5 (please read the precautions on the back side and then fill out this page) !------ II--Line--Improvement of the Ministry of Economic Affairs Property Bureau staff consumption cooperation Du printing This paper scale applies China National Standard (CNS) A4 specification (210 x 297 public) 89 92012 Worker 323263 A7

5. Description of the invention (9〇) The title compound a Ή NMR (MeOH-d4) δ 0.58 (t, 2 Η), 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)+, C11H16N503P Example 43 Synthesis 2·{1·[(2-Amino-6-carbyl-9//-purin-9-yl)methyl]cyclopropyl}B The phosphinic acid (Compound 138) The compound prepared in Preparation 26 was reacted in the same manner as in Example 12 to give a compound in which the position of the guanine was substituted with an ethoxy group. 'H NMR(CDC13) 6 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 (80 mg) was dissolved in methanol at 2 mg 10% Pd/C The reaction is carried out in the presence of a hydrogen atmosphere to obtain a compound in which a double bond is reduced. *H NMR(CDC13) δ 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 title compound was obtained by reacting the compound thus obtained in the same procedure as in Example i. NMR (MeOH-d4) 6 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 (M+l)+, C11H16N504P Example 44 Synthesis of 2-{l-[(2-amino-9//-purin-9-yl)methyl]cyclopropyl}propylphosphonic acid (compound) 144) (Please read the notes on the back and fill out this page) 0 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 90 92012 1323263 A7 B7

NMR (MeOH-d4) δ 0.62-0.77 (m, 4 Η), 1.04 (d, 3H), 1.52 (m, 2H), 1.90 (m, 1H), 4.24 (m, 2H), 8.58 (s, 1H) ), 8.74 (&amp;, 1H)

ESI: 312 (M+l)+, C12H18N503P Example 4 5 Synthesis (5)-2-{ l-[(6-Aminopurine-9-yl)methyl]cyclopropyldipropenylphosphine Acid (Compound 137) The title compound was obtained by successively reacting the compound obtained in the procedure of Example 3, in the same procedure as in the preparation of *HNMR(MeOH-d4) δ 0.86 (t, 2H), 1.10 (t, 2H), 2.19 (d, 3H), 4.38 (s, 2H), 5.23 (d, 1H), 8.34 (s, 1H), 8.37(s, 1H)

ESI: 310 (M+l)+, C12H16N503P Example 46 Synthesis of 2-{l-[(6-Amino-9/7-嘌呤_9_yl)methyl]cyclopropyl}propylphosphonic acid (Compound) 143) The compound obtained in Preparation 35 was successively reacted in the same procedure as in Preparations 24, 25 and Example 5 to give the title compound. 'H 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, 1H), 8.45 (s, 1H)

ESI: 312 (M+l)+, C12H18N503P Example 47 Synthesis of hydrazine (2,2,2-trifluoroethyl) ({l-[(6-Amino-9/f-嘌呤-9-yl)) (cyclopropyl)oxy)methylphosphonate (Compound 48)

91 92012 4ή9 (Please read the note on the back and fill out this page) Lin -------Book---------Line" Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1323263

V. INSTRUCTIONS (92) Methylphosphonic acid (15 mg) prepared in Example 1 was added dropwise, and 0.73 liters of NN•diethyltrimethyldecylamine was added dropwise thereto. The resulting mixture was stirred at room temperature for 2 hours. Grass 醯 gas (0.15 ml) and 2 drops of dimethyl decylamine were added to the reaction vessel. The mixture was further stirred for 2 hours and the solvent was removed by distillation under reduced pressure. 1 ml of pyridine and 2 ml of difluoroethanol were added to the residue, and the reaction was stirred for 16 hours. The solvent was removed by distillation under reduced pressure and the residue was purified eluted eluted NMR NMR (CD3OD) δ 1.02 (m, 4Η), 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 oxime (2,2,2-trifluoroethyl) ({i_[(2_amino~9//_嘌呤_9_yl) methyl) [cyclopropyl}oxy)methylphosphonate (Compound 49) The compound obtained in Example 5 was reacted in the same procedure as in Example 47 to give the title compound. NMR NMRCCDC13) δ 0.88 (m, 2Η), 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 [Μ+ΗΓ, C14H16F6N504P Example 49 奋成贰(2,2,2-trifluoroethyl)[1-({2-amino-[6-(4-methylphenyl)thio) ]-9F·嘌呤-9-yl}methyl)cyclopropyl]oxy}methylphosphonate (Compound 62) The compound prepared in Example 25 was subjected to the same procedure as in Example 47. Note: Please fill out this page) ------- Order--------- Line - · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed on this paper scale applicable to China National Standard (CNS) A4 Specification &lt;210x297 mm) 92 92012 1323263 A7 B7 V. Inventive Note (93) The title compound was obtained by a reaction. (Please read the notes on the back and fill out this page) Ή NMR(CDC13) δ 0.88 (m, 2Η), 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 hydrazine (2,2,2-trifluoroethyl) [(1 _{[2-amino-6-hydroxy-9//--9 -Methyl}cyclopropyl)oxy]methylphosphonate (Compound 45) The compound obtained in Example 4 was reacted in the same manner as in Example 47 to give the title compound. NMR NMR (CDC13) 6 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 5 1 Synthesis of hydrazine (2,2,2-trifluoroethyl) (1-{[2-amino-6-cyclopropylamino-9//嗓呤-9-yl]methyl}cyclopropyl)oxy]methylphosphonate (Compound 5 〇) The title compound was obtained by the same procedure as in Example 47. . NMR (CDC1,) δ 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 ({l-[(2-amino-9//---9-yl)methyl)-2-methylcyclopropyl} Oxy Methylphosphonic acid (Compound 98) The 6-chlorourethane derivative prepared in Preparation Example 12 was applied in accordance with Example 5 of this paper scale in accordance with the Chinese National Standard (CNS) A4 specification (210x 297 public) 93 92012 1323263 A7 B7 V. Inventive Note (94) The same procedure was carried out to obtain the title compound. &gt;H NMR(MeOH-d4) δ 0.68 (t, 1H), U3 (m, 1H), 1.21 (d, 3H), 1.42 (t, 1H), 3.84 (t, 1H), 3.97 (t, 1H ), 4.40 (d, 1H), 4.66 (d, 1H), 8.63 (s, 1H), 8.73 (s, 1H)

ESI: 314 (M+l)+, C11H16N504P The compound of the present invention exhibits a medicinal effect on a hepatitis B cell line (HepG2.2.15). When administered intravenously or orally, a transgenic mouse is generally used to develop an anti-B. Hepatitis therapeutic agent. The test procedures and results are described below. Test Example 1 Measurement and analysis of anti-hepatitis B virus (HBV) inhibitory effect (1) Cell culture and drug treatment in HexG2.2.15 cells (MA Shells, etc.) in an incubator at 5% C02 atmosphere and 37 °C Human, P, NAS 84, 1005 (1987)) (for liver cancer cell line producing hepatitis B virus) cultured in DEME medium (GIBCO BRL, #430-2200) containing 10% FBS (fetal calf serum, GIBCO BRL, #1600-044), 1% ABAM (antibiotic-antimycin, GIBCO BRL, #1600-028) and 400 μg/ml of geneticin (Sigma, #G-9516) In the T-75 flask, the cell division ratio was 1:3 during the 3-day period. The cells were dispensed into 96-well plates in an amount of about 4 x 104/well and then 200 microliters of DEME medium (containing 2% FBS, 1% ABAM and 400 μg/ml Kina) when the cell density reached 80 to 90%.摂; 素) Replace the old medium. The drug solution was serially diluted five times each time and was obtained from a concentration of 100 M to 0.16 M. In order to minimize the test error, the treatment for each drug was repeated 2 to 3 times. Change every 2 days (please read the notes on the back and fill out this page) .---Booking! I----. Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives, Printed Paper Scale Applicable to Chinese National Standards (CNS) A4 size (210 χ 297 mm) 94 92012 4ttr&gt; 丄__ B7 V. Description of the invention (95) Medium. One day after the drug treatment, the microliter medium was collected and the degree of inhibition of viral replication by the drug was determined by the amount of PCR (polymerase chain reaction). (2) Determination of cytotoxicity After the culture medium (10) microliters on the 10th day after the drug treatment, 75 mg/ml of mtt (male (tetra)-based blue tetra-iron" Amresco, #0793_5G was added in an amount of 30 μl per well. The solution was applied to each well and each cell was cultured in an incubator at 5 / 〇 C02 and 37 C for 2 hours. The solution was discarded, and an isopropanol solution containing 1% Trit〇nx i〇〇& 〇 4 μl of c-HCl was added to each well in an amount of uo microliters/well. The thus stained cells were transferred to an isopropanol solution by shaking for 2 hours. The absorbance at 540 nm was measured with an Elisa Reader. (3) Evaluation of the effect of inhibiting replication of hepatitis B virus by PCR The degree of inhibition of replication of hepatitis B virus by a drug was determined by using a cell culture solution collected on the 10th day after drug treatment. The cell culture solution was treated with each drug diluted 10 times with distilled water and pretreated by heating at 95 C for 15 minutes to destroy the cells. As for the gene fragment of about 320 bp which is expanded by pCR, the base at position 2001 is retained in all the para- lines of hepatitis B virus and the base line at position 2319. Between the core antigen gene and the polymerase gene, respectively The base at the 2nd position and the 2319th position are used as the primers at the 5th and 3' ends. The genomic DNA of hepatitis B virus is then quantified and the inhibitory effect of the drug on hepatitis B virus replication is determined accordingly. First, the cell culture solution of hepatitis B virus that has not been treated with drugs is applied to the paper size of China National Standard (CNS) A4 specification (2〗 〇χ 297 mm) 95 line 92012 1323263 A7 ___ B7__ V. Invention description \ % ) Continue to dilute and expand via PCR. The expanded DNA was subjected to electrophoresis on a 2% agarose gel and stained with ethyl bromide (EtBr) and analyzed by an IS-1000 (Innotech Scientific Corporation) digital imaging system. Next, the cell culture solution treated with the drug whose dilution factor was maintained in a linear range was analyzed. The DNA obtained from the drug-treated group was expanded by the same PCR method to electrophoresis on a 2% agarose gel to evolve hexyl bite staining and analysis by IS-1000. The extent to which the drug inhibits viral replication is quantified by calculating the ratio of the test group to the control group. Table 8 summarizes the inhibition (medical activity and toxicity) of the representative drugs of the present invention. &lt;Please read the notes on the back and fill out this page.} Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed Moderate Ruler | Zhang Nuclear I, 97 12 X 10 ; 2 /•V Grid A4 S)AN (c Home % 1323263 A7 B7 V. Description of invention (97 ) Table 8 Ministry of Economic Affairs Intellectual Property Bureau Η Consumer Cooperatives Printed Compound No. HBV EC50(u M) HepG2.2_15 CC50(y Μ) PMEA (Comparative Compound) 5.0 &gt; 500 1 &gt; 1.0 &gt; 1000 2 &gt; 0.1 &gt; 1000 3 &gt; 0.5 &gt; 1000 5 &gt; 0.1 &gt; 1000 9 &gt; 0.3 &gt; 1000 10 &gt; 0.08 &gt; 1000 11 &gt; 20 &gt; 13 &gt;1.0 &gt;1000 15 &gt;0.8 &gt;1000 17 &gt;0.5 &gt;1000 19 &gt;0.3 &gt;1000 23 &gt;0.1 &gt;1000 25 &gt;5.0 &gt;1000 31 &gt;50 &gt;1000 37 &gt;5.0 &gt;1000 41 &gt;1.0 &gt;1000 45 &gt;0.5 &gt;1000 46 &gt;1.0 &gt;1000 62 &gt;0.5 &gt;1000 66 &gt;0.1 &gt;1000 69 &gt;1.0 &gt;1000 95 &gt ; 0.5 &gt; 1000 97 &gt; 0.05 &gt; 1000 98 &gt; 1.0 &gt; 1000 99 &gt; 5.0 &gt; 1000 100 &gt; 0.05 &gt; 1000 101 &gt; 0.1 &gt; 1000 From the results of Table 8, the present invention Compound in the third The stage is coming (please read the notes on the back and fill out this page) ------—Book--------- Line — . This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 4 97 92012 1323263 V. Description of the invention (98) The activity of the comparative compound PMEA was 4 to 10 times higher in the bed test. Test Example 2 The medical test of the transgenic mouse (T/G mouse) was carried out in the following animals. The compounds were administered by subcutaneous and oral route. The test compounds were administered to 4 to 5 weeks old HBV transgenic mouses by reference (see Jone D. Morrey, Kevin W. Bailey, Brent E. Korba). , Robert W. Sidwell, "Ultra-hepatitis B virus replicated in a transgenic mouse for Ramen's suspected antiviral assessment"

The method described by Antiviral research, 1999, 42, 97-108) was obtained from a mouse of the FVB species. Compounds were administered subcutaneously for 9 days at a dose of 10 mg/kg/day and orally administered at a dose of 1 〇, 2 and 0.4 mg/kg/day, respectively, once daily (using the same number of male and female rats). day. Five microliters of serum was obtained by collecting blood from the tail. I5 ml of the gene release solution (Genereleaser sol) was added to the serum, followed by pretreatment at different temperatures. The DNA of HBV was obtained from the pretreated solution. DNA was amplified by pCR (polymerase chain reaction) in 4 μl of 1 〇x buffer (perkin Elmer), 0.8 μl of 10 mM concentration dNTp, 5 〇〇 nanogram of HBV primer (for use) This was carried out in the presence of MgCL, DMSO, and Taq polymerase at a concentration of 125 mmol in the same test primers of Examples 1 and 2. To assess the pharmaceutical action of the compounds of the invention, the amount of DNA of HBV was analyzed by electrophoresis. The results are described in Table 9 below. The "showing a medical action mouse" in the following Table 9 indicates that the mouse ash does not contain HBV DNA. 92012 (Please read the note on the back and fill out this page) Lin Zhu----------Line » Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 263 3 2 3 A7 B7 V. Invention Description ( 99) Table 9 Quantity « Route of administration compound number (mg/kg/曰) Result 23 10 4/4 Subcutaneous 66 10 4/4 Subcutaneous 97 10 4/4 Subcutaneous 95 10 3/4 Subcutaneous 98 10 4/4 Subcutaneous PMEA Dai Pifu 2 1/3 Oral PMEA Dai Pifu 0.4 1/6 Oral 10 2 4/4 Oral 10 0.4 5/6 Oral ---------^------ (Please read the back Note: Please fill in this page again. The results table does not show the number of rats with the effect of the drug/the total number of mice. The results of the following Table 9 show that the compound of the present invention shows effective hepatitis B treatment when administered orally or in the test animal. effect. In particular, the clinical test of the line|substance=segment, the compound of the present invention is superior to the primary MbA, and therefore it is considered to be effective. Compounds of the Moon for the Treatment of Hepatitis B: Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Scale (CNS) A4 Regulation, ^^ 297 mm) 99 92012

Claims (1)

Sixth, the scope of application for patents 1 - - the following formula (1) Table I Annex 3 The first cable 18 years 1 January Non-cyclic nucleus. Glycosylphosphonate derivatives: Where = represents a single bond or a double bond, h abbreviated RR and R8 independently of each other represents hydrogen or C丨 to c7-hospital, R and: R5 are independently of each other, or not, or represent C! to C4- The alkyl group is optionally substituted with a substituent selected from the group consisting of dentate and C2 to C5-decyloxy, or represents _(CH2)m_0C(=0)_R6 wherein m is an integer from 1 to 3 and 66本本_ and R represents not Ci to C7-alkyl, Ci to C5-, a radical C3 to C6-cycloalkyl or 5 having 1 or 2 heteroatoms selected from the group consisting of nitrogen and oxygen. Or a 6-membered heterocyclic ring, exemplified by 0 _CH (Z Bu, = c 〇, wherein Z represents hydrogen, or is represented as C1 to c7-alkyl, and Q represents a group having the formula: - ---:--- -------装--- (Please read the notes on the back and fill out this page again) Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed Clothing, where N X1 X3 Or xx, x and χ4 independently of each other represent hydrogen, an amine group, a radical or a functional group ' or a ^ to c7-homogeneous group, ^ to a C5_ alkoxy group, or a phenylthio group which may optionally be subjected to a nitro group. , Amine, hydrazine to C6_alkyl or q to Cr alkoxy substituted, or (^ to c7_alkylamine, two paper scales applicable to China National Standard (CNS) A4 specification (210 x 297 mm) 100 (Revised) 92012 S A8 B8 C8 Patent Application No. 91100541 (November 17, 1998) Read the specific &gt;] to C7-alkyl) amine group, c3 to c6_ cycloalkylamine group or structure is η is an integer of 1 or 2 and γι denotes 〇, cH2 or NR (R is not C丨As for 7_ hospital base), its pharmaceutically acceptable salt, or a stereoisomer thereof. 2. For the application of the compound of claim 1, the pharmaceutically acceptable salt is a salt of sulfuric acid, methanesulfonic acid or hydrohalic acid. 3. The compound of claim i, wherein the compound represents a single bond, and R1, R2, R3, R7 and R8 independently of each other represent hydrogen. R4 and R5 independently of each other represent hydrogen or represent ^ to c4_alkyl Substituting one or more substituents selected from the group consisting of fluorine, or -(CH2)m-〇C(=0)_R6, wherein 31 is an integer from 1 to 3 and R is not q To a (V alkyl, Cl to c" alkoxy group, or a 5 or 6 membered heteroatom having hydrazine or 2 heteroatoms selected from the group consisting of nitrogen and oxygen, Y represents -〇-, Q represents Groups of the following formula: * (Please read the notes on the back and then fill out this page) Pack--------Book. Line· Wherein f, X2, X3 and X4 represent hydrogen, an amine group, a group or a dentate, or an alkyl group, ... to a C5 alkoxy group, or a phenylthio group which is visible. National Standard (CNS) A4 Specification (210 κ 297 public 301 (Revised) 92012 S 1323263 Sixth, the scope of application for patents needs to be replaced by nitro, amine, C! to c6-alkyl or C! to c4-yardoxy or 'C! to &lt;:7-alkylamino, two (c) To a c7-alkyl)amino group, a C3 to C6-ring-based amine group or a structure Where η is 1 or 2, the Intellectual Property Intelligence Bureau member of the Ministry of Economic Affairs and the Consumer Cooperatives print integers and Υ1 denotes 〇, CH2.. or .N-R (R denotes Ci to C7.-burning base). 4. A compound according to claim 1 of the patent application, which is selected from the group consisting of: (U-[(6-amino-9-ugly-indol-9-yl)methyl]cyclopropyl}oxy Methylphosphonic acid (compound 1); , p-valeric acid 3-[({1-[(6-amino- 9//· 啥-9-yl.) fluorenyl]cyclopropyl}oxy ) fluorenyl]-8,8-dimercapto-3,7-dioxo-2,4,6-trisyl--3 λ5-phosphonium-1-ester (compound 2); ({1-[( 2-Amino-6-chloro-9ίΓ-嘌呤-9-yl)methyl]cyclopropyl)oxy)methylphosphonic acid (Compound 3); ({1-[(2-Amino-6-hydroxyl) -9孖-嘌呤_9_yl)methyl]cyclopropyl decyloxy) methylphosphonic acid (compound 5); 'ternic acid 3-[({1-[(2-amino-6- Zhao) Base-noise _9_yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trisophilic _3 λ 5-phosphonium-1-ester (compound 6); ({1-[(2-aminopurin-9-yl)methyl]cyclopropyl}oxy)methyl squaric acid (compound 9); 3-[({1-[(2-Amino-9i7-嘌呤_9-yl)methyl) valerate; |cyclopropyl}oxy)indolyl]-8,8-dimethyl-3,7 -dioxo-2,4,6-tris(pf-3λ5_scalein-1-ester (compound 10); ------------装--- {please read the back first INI entries and then fill in this page) book .. The private paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) S 1323263 A8 B8 C8 Patent Application No. 91100541 Sixth, the scope of application for patents ({1-[(2-amino-6-cyclopropylamino-9-ugly-oxime--9-yl)methyl]cyclopropyl}oxy)decylphosphonic acid ( Compound 11); [(1-{[2-Amino-6-(dimethylamino)-9i/-嗓呤-9-yl]indenyl}cyclopropene (please read the back of the note first) This page) oxy]methylphosphonic acid (compound 15); [(1-{[2-amino-6-(isopropylamino)-9 ugly-fluoren-9-yl]methyl }cyclopropyl)oxy]decylphosphonic acid (Compound 17); ({1-[(2,6-Diamino]-9/Γ-嘌呤-9-yl)indolyl]cyclopropyldecyloxy Methylphosphonic acid (Compound 19); 3-[({1-[(2-Amino-6-methoxy-9 ugly- -9-yl)methyl)] }oxy)indenyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trisole-3 and 5-carbon 壬· 1 - xi (compound 22) U-[(2-Amino-6-ethoxy--9孖-fluoren-9-yl)indolyl]cyclopropyl}oxy)decylphosphonic acid (Compound 23); pivalic acid 3- [({1-[(2-Amino-6-ethoxy-9β-嘌呤_9-yl)indenyl]cyclopropyl}oxy)indolyl]·8,8-dimethyl_3, 7_二氧代_2,4,6_三噚_ I -3 again-filling - ΐ-g (compound 24); Ministry of Economics wisdom Printed by the Bureau of Staff and Consumers of the Production Bureau [(1-{[5-methyl-2,4-oxo-3,4-dihydro-1 (2H),- ing)] a Cyclopropyl) Oxy]methylphosphonic acid (compound 3 1); amine group _6_(4·morpholinyl)_9^^吟吟基基]methyl}cyclopropyl)oxy]methylphosphonic acid (compound 37) (Π-((2-amino-6-hydroxy-9i7-fluoren-9-yl)indolyl]cyclopropyl}oxy) methyl phosphonate bismuth (2,2,2-trifluoroethyl) Ester (Compound 45); (U-[(2-Amino-6-chloro-9-indol-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid C (2,2,2 -trifluoroethyl) hydrazine (compound 46); 1323263 A8B8C8D8 Patent Application No. 91100Μ1 by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs (November 17, 1998; VI. Patent Application Range ({1-[(6-Amino-9仄嘌呤-9-yl)) Hydrazino]cyclopropyl}oxy)methylphosphonic acid (2,2,2-tris-fluoroethyl) oxime (Compound 48); ({1-[(2-Amino-9-ugly-嘌呤) (9-[(2-aminoethyl)-6)] -Methoxy-9 ugly-oxime-9-yl)mercapto]cyclopropyl}oxy)methyl.phosphonic acid €(2,2,2-trifluoroethyl) ester (Compound 54); {[ 1-({2-Amino-6-[(4-methylphenyl)thio]-9 ugly-fluoren-9-yl}methyl)cyclopropyl]oxy}methylphosphonium hydride (2 , 2,2-trifluoroethyl)ester (Compound 62); {[1-({2-Amino-6-[(4-mercaptophenyl)thio]]]-9-yl-9-yl }methyl)cyclopropyl]oxy}methylphosphonic acid (compound 66); tert-acid 3-({[1-({2-amino-6-[(4-methylphenyl))thio) ]-9&quot;-嘌呤-9-yl}fluorenyl)cyclopropyl]oxyindole methyl)-8,8-dimercapto-3,7-dioxo "2,4,6-triazine- 3 λ 5-phosphonium-1-ester (compound 68); "(l-[(2-Amino-9-ugly-indol-9-yl)indolyl]cyclopropyl}oxy)methylphosphonium hydrazide {[(Tertidinoxycarbonyl)oxy]indole Ester (compound 69); ({1-[(2-amino-9 ugly-indol-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid *{[(isopropyl) Oxylyl)oxy]methyl}acetate (Compound 70); 3-methylbutyric acid 3-[({1-[(2-amino]9-------9-yl))棊]cyclopropyl oxy)indolyl]-9-methyl-yl-3,7-dioxo-2,4,6-tris.-3 λ 5 -disc-bu ester (compound 74) ; 2-methylpropionic acid 3-[({1-[(2-amino- 9//·°)-9-yl)methyl]cyclopropyl}oxy).methyl]-8- Methyl-3,7-dioxo-2,4,6-tris-3-λ 5-phosphonium-indol-1-ester (Compound 78); This paper scale applies to Chinese national standards (CNS>A4 specification (210) κ 297 mm) (Please read the notes on the back and fill out this page) 104 (Revised) 92012 1323263 A8 B8 C8 D8 Patent Application No. 91100541 (November 17, 1998) Patent Application. 1-Pyrrolidinecarboxylic acid 3-[({1-[(2-Amino-9) //-嘌吟-9-yl)methyl]cyclopropyl}oxy)methyl]-3,7-dioxo-7-(1-pyrrolidinyl)-2,4,6-triazine -3入5-鳞庚__ _. 酉 ( (compound go) 1-piperidinecarboxylic acid 3-[({卜[(2-amino-9i/-嘌呤-9-yl) fluorenyl] cyclopropane })oxy)indolyl]_3,7-dioxo-7-(1-piperidinyl)-2,.4,6-triazin-3 oxime 5-phosphan-1-one (Compound 81) 4-morpholinecarboxylic acid 3-[({1-[(2-amino-9-ugly-indol-9-yl)indolyl]cyclopropyl}oxy)indolyl]-7-(4-? Lolinyl)-3,7-dioxo-2,4,6-tris-3-λ 5-phosphan-1-one (combination 82); 3-methylbutyric acid 3·[({ 1-[(6-Amino-9-yt-9-yl)indolyl]cyclopropyl}oxy)indolyl]-9-indolyl-3,7-dioxo-2,4,6 -trim-3 λ 5-phosphonium-1-ester (compound 90); cyclopentanecarboxylic acid 3-[({1-[(6-amino-9 ugly-indol-9-yl)methyl]] Cyclopropyl}oxy)indolyl]-7-cyclopentyl-3,7-dioxo-2,4,6-triazin-3 λ 5-phosphan-1-one (Compound 91); Ul -({2-Amino-[6-(4-nitro) Methyl)thio]-9 ugly-嘌呤-9-yl}methyl)cyclopropyl]oxy.}methylphosphonic acid (compound 95); {[1·({2-amino-[6-( 4-methoxyphenyl)thio]:9 ugly-嘌呤_9_yl}methyl)cyclopropyl]oxy}methylphosphonic acid (Compound 96); ({1-[(2-Amino) -6-hydroxy-9 ugly-indol-9-yl)methyl]-2-indolylcyclopropyl}oxy)methylphosphonic acid (Compound 97); (U-[(2-amine tomb-9孖) -嘌呤-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonic acid (compound 98); {[1-({2-amino-[6-(4-f-oxygen) Phenyl phenyl) thio]-9 good-嘌呤_9_ base} Good paper scale applies to China National Standard (CNS) A4 specification (21〇κ 297 mm!:---装-------- -Book---------Line (please read the notes on the back and fill out this page) Economy Zou Intellectual Property Bureau Staff Consumer Cooperative Printed 105 (Revised) 92012 1323263 ΟΛ 8 3 8 ABaD Ministry of Economics Patent Office Staff Consumer Cooperatives Printed Patent Application No. 91100541 (November 170, 1998) VI. Patent Application Range methyl)-2-methylcyclopropyl]oxy}methylphosphonic acid (Compound 99); {[ 1-({2-Amino-[6-(4-nitrophenyl)thio]-9 -嘌呤_9_yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonic acid (Compound 1〇〇); {[1-({2-Amino-[6_(4-A) Phenylphenyl)thio]indole-9-yl}methyl)-2-indolylcyclopropyl]oxy}methylphosphonic acid (Compound 1〇1); ({1-[(6-Amino-) 977-嘌呤-9-yl) fluorenyl]-2-methylcyclopropyl}oxy) decylphosphonic acid (compound 103); p-pentanoic acid 3-[({1-[(2-amino-6) -hydroxy-9孖-嘌呤-9-yl)methyl]-2-methylcyclopropyl}oxy)methyl]_.8,8-dimethyl-3,7-oxaxo-2, 4,6-II. Dyslipid-3 and 5-scale 壬-1-acetic acid (Compound 1〇5); p-valeric acid 3-[({1-[(2-amino)9 ugly-嘌呤-9- Methyl bromide 2_methylcyclopropyl}oxy)methyl]-8,.8-dimethyl-3,7-dioxo-2,4,6-three-drink-3 λ 5- Phosphonium-bupropion (compound 106); 2-{1-[(2-amino-6-hydroxyindol-9-yl)methyl]cyclopropyl}ethylphosphonic acid (compound 138); 2-{ 1-[(2-Amino-9 ugly-indol-9-yl)methyl]cyclopropylphosphonium ethylphosphonic acid (Compound 139); 2-{1-[(6-amine tomb-9if-嘌呤- 9-yl)methyl]cyclopropyl}ethylphosphonic acid (compound 140); 2-{1-[(6-amino-9-yt-9-yl)methyl]cyclopropyl}propyl Phosphonic acid Compound 143); 2-{1-[(2.Amino-97/-in-9-yl)indolyl]cyclopropyl}propylphosphonic acid (Compound 144); ({1-[(2-amine) Base-6-Zhaoji- 9//-嘌呤-9-yl)methyl]_2,2_dimethyl ring paper size applicable to China National Standard (CNS) A4 specification (2)〇X 297 mm) 106 ' (Revision) 92012 (Please read the notes on the back and fill out this page) 丄WOJ 丄WOJ A8 B8 C8 D8 Patent Application No. 91100541 (November 17, 1998) t, patent application range propyl}oxy)methylphosphonic acid (compound 146); (Π·[(2-amine Base. Methyl]·2,2_Dimethylcyclopropyl}oxy)methyl-butyric acid (Compound 147)· Please read the back. Note the refill 'I loading page I ( U-K6-amino n-m-methyl)methyl]_22 dimethylcyclopropyl}, oxy)methyl-butyric acid (compound 148); and pivalic acid 3-[({1-[(2·) Amino-hydroxyl-9-yt-ytyl-9-yl)indenyl]-2,2-disylcyclopropyl}oxy)methyl]_8,.8-dimethyl-3-3,7-dioxo -2,4,6-dioxin-3 and 5-cyclodecanoate (Compound Γ49) 5. A compound according to the scope of claim 2, wherein = represents a single bond, and R1, R3, R7 and R8 are independently represented Hydrogen, R2 represents hydrogen or methyl 'R and R5 independently of each other represent a third butylcarbonyloxymethyl group, an isopropoxycarbonyloxymethyl group or a 2,2,2-trifluoroethyl group, γ represents _ 〇_, Q represents, wherein χΐ represents hydrogen, hydroxy, ethoxy, 4-methoxyphenylthio or 4-nitrophenylthio, and 2 represents an amine group. 6. The compound of claim 1, wherein the dentate which is a substituent of the Ci to C4 alkyl group which is optionally substituted is fluorine. Economic Zou Intellectual Property Officer X Consumers Association. Printed 7. A method for preparing a compound of formula (1) as defined in claim 1 of the patent application, characterized in that (a) a compound represented by the following formula (2) is The compound represented by the following formula (3) is reacted to produce a compound of the formula (1), a compound of the formula (2) · This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (2 〗 0 X 297 mm) 107 (Revision) Ben) 92012 IS 丄WUJ (2) - The definition of R, R2, R3, R4, r5, r7, r8 and γ is as defined in the patent application 笫1, Q, 'and L is the leaving group, and the compound of formula (3): QH (3) The definition of Q in the patent scope is the first item, (b) the compound represented by the following formula (9) and the compound of the formula (3) are represented by the formula (9), the compound of the formula (9): , generated under (please read the notes on the back and fill out this page) OR9 (9) wherein R, R2, R3, R7., r8, γ and L are as defined above, and R and R1Q independently of each other represent Ci to C4_alkyl, compound of formula (10): Employee consumption cooperative printed R* R7 (10) wherein R1, R2, R3', R7, r8, Y, Q, r9 and R10 are as defined above, and the resulting compound of formula (10) is hydrolyzed in the presence of Lewis acid to produce Compounds of the following formula (la): The private paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇x 297 public love 108 (amendment) 92012 Application for patent Fan Gu, Patent Application No. 91100541 (November 17, 1998) (la) where Rl, R2, R3, R7, 8 (ren) will be 1^4' and only 5, | Han, Y And Q is as defined in the above or the compound of the formula: Ua) to produce the following formula (lb) wherein Ri, (lb) R3 R7, R8, Y and Q are as defined above and R4', R5, respectively, I knife is not dangerous 7 k 8. R4 and R5 other than the scope of patent application /. a compound of the phosphonate compound, which is obtained by using the following formula (2): Ministry of Economic Affairs Intellectual Property Bureau member X Consumer Cooperatives printed it. R1, R: Scope Item 1 (2) R, R4, R5, 7 Anti-7, R8 and Y are defined as patent application 'and L main 9 ▲* indicates leaving the base. y· for the treatment of type B liver ^ range of the first formula (n &lt; pharmaceutical composition, including the patent application) acyclic nucleoside phosphonate derivatives, and therapeutically acceptable salts, Glycerin; , again | or its stereoisomers. 10. A compound according to claim i, which is ({1_[(2-amino-6-hydroxy-9H-indol-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid. · I ------------------^ (Please read the note on the back and fill out this page) The private paper scale applies to the national standard (CNS) A4 specification (2) 0 X 297 mm.) 109 (Revised) 92012 1323263 Scope of application for patents u. For the compound of claim 1 of the patent range, the system is ({1_[(2•amino]9H_ -9-9-yl)indolyl]cyclopropyl}oxy)methylphosphine acid. I2. A compound according to claim 1 which is a compound of the formula 3-[({1-[(2-amino-9H-嘌呤-9-yl)indolyl]cyclopropyl}oxy) Base]-8,8-dimercapto-3,7-dioxy-2,4,6-tri-terpene, 3-person 5-filled·;^ ester. 13 _ The compound of claim 1 is used in the manufacture of a medicament for the treatment of hepatitis B. 14. The compound of claim 13 wherein the compound is ({1-[(2-amino-6-hydroxy-9H-indol-9-yl)methyl]cyclopropyl}oxy) Base) methylphosphonic acid. The compound according to claim 13, wherein the compound is ({1-[(2-amino-9H-fluoren-9-yl)methyl]cyclopropyl}oxy)fluorenyl) Phosphonic acid. 1 6 · A compound according to claim 13 wherein the compound is 3-[({1-[(2-amino-9H-indol-9-yl)methyl]cyclopropyl}) Oxy) fluorenyl]-8,8-dimercapto-3,7-dioxy-2,4,6-tris-3 into 5-quinone.-1 - 6 〇. ---- ---------^装--- (Please read the note on the back and fill out this page) Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives. This paper scale applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 110 (Revised) 92012 S