TW200423945A - Nucleoside derivatives for treating hepatitis c virus infection - Google Patents

Abstract

Disclosed are compounds, compositions and methods for treating hepatitis C virus infections.

Description

200423945 Description of the invention: [Technical field to which the invention belongs] The present invention relates to the field of medicinal chemistry, especially compounds, compositions and methods for treating hepatitis C virus infection. [Prior art] The following papers and patents with references are listed in this application: 1. Chen, et al, Med. Assoc., 95 (1): 6-12 (1996) 2. Comberg, et al , " Hepatitis C: therapeutic perspectives.n Forum (Genova), 11 (2): 154-62 (2001) 3. Dymock, et aly Antivir. Chem. Chemother. 11 (2): 79-96 (2000) 4 Devos, et alf International Patent Application Publication No- WO 02/18404 A2, published 7 March 2002 5. Sommadossi, et aly International Patent Application Publication No. WO 01/90121, published 23 May 2001 6. Ducrocq, C ·; β a /., La: 773 (1976), 7. Rizkalla, BH; Broom, AD, J. Org. Chem., 37 (25): 3980 (1972). 8. Anderson, GL; Broom, AD, J. Org, Chem., 42 (6): 997 (1977). 9. Rizkalla, BH; Broom, AD, 1 Org. Chem., 37 (25): 3975 (1972). 10. Furukawa, Y .; Honjo, M., Chem. Pharm. Bull, 16 (6): 1076 (1968). 11. Ektova, LV; et al} Bioorg. Khim., 5: 1369 (1979). 12. De Clercq, E .; et al J. Med. Chem., 26 (5): 661 (1983).

O: \ 88 \ 88427 DOC 200423945 13. Robins, MJ; Barr, PJ, /. Org. 48 (11): 1854 (1983). 14. Griengl, KJMed CW, 28 (11): 1679 (1985). 15. Lichtenhaler, FW; Cuny, E., Chem. Ber., 114: 1610 (1981). 16. Hamilton, HW; Bristol, JA, 1 Med, Chem., 26 (11): 1601 (1983) 17. Seela, F .; Steker, Yi., Liebigs Ann. Chem., P. 1576 (1983). 18. Winkley, MW; et αί, J. Heterocycl Chem., 8: 237 (1971). 19. Barascut, JL; et αί, J. Carbohydr. Nucleosides Nucleotides, 3 (5 & 6): 281 (1976). * 20. Kiriasis, L .; Pfleiderer, W., Nucleosides Nucleotides, 8 (7): 1345 (1989). 21. Schneider, H.-J .; Pfleiderer, W., Chem. Berich., 107: 3377 (1974). 22. Angew, Chem. Int. Ed. Engl., 35: 1968 (1996 ) 23. Hildbrand, S ·; βα / ·, say / v. C7iz > w · Ata, 22: 702 (1996). 24. De Las Heras, F .; et al. 7 J. Heterocycl Chem., 13: 175 (1976). 25. Tam, S. YK .; et aL, J. Heterocycl Chem., 13: 1305 (1976). 26. Chu, CK; aL, /. Heterocycl Chem., 17: 1435 (1980) 27. De Bernardo, S .; Weigele, M., J. Org. Chem., 42 (1): 109 (1977). 28. Saureamid-Reaktionen, L .; Orthoamide, L, Chem. Ber., 101: 41 (1968). 29. Lim, M.-L; Klein, RS; Fox, J. I, Tet. Lett, 21: 1013 (1981). 30. Yamazaki, A .; et aL, J, Org. Chem., 32: 1825 (1967). 31. Yamazaki, A .; Okutsu, M. , J. Heterocycl Chem., 1978, 15: 353 (1978) 32. Lim, M.-L; Klein, RS, Tet. Lett., 22:25 (1981). 33. Bhattacharya, BK; etal, Tet. Lett., 27 (7): 815 (1986). 34. Grisis, NS; ^ aL, J. Med. Chem., 33: 2750 (1990). 35. Li, N-.S .; Tang, X. -Q .; Piccirilli, JA, Organic Letters, 3 (7): 1025 (2001).

O: \ 88 \ 88427.DOC 200423945 36. Cristalli, G .; etai.l Med. 30 (9): 1686 (1987). 37. Seela, F .; et al., Nucleosides Nucleotides, 17 (4): 729 (1998). 38. Sagi, G .; et aL, J. Med. Chem. 35 (24): 4549 (1992). 39. Hawkins, M. E .; et al., Nucleic Acids Research, 23 ( 15): 2872 (1995).-40. Mandal, SB, et al, Synth. Commun., 9: 1239 (1993). 41. Witty, DR, et al., Tet. Lett, 31: 4787 (1990) 42. Ning, J. et al, Carbohydr. Res., 330: 165 (2001).

43. Yokoyama, M., et al, J. Chem. Soc. Perkin Trans./, 2145 (1996). 44. CaiToll, SS, et aL,., International Patent Application Publication No. WO 02057287, published 25 July 2002 45. Carroll, SS, et al.,., International Patent Application Publication No. WO 02057425, published 25 July 2002. All papers, patents, and patent applications listed above are specific or specific to individual papers, patents, and patent applications. To the same extent as a reference to the text as a whole, to the same extent. Hepatitis C virus (HCV) causes a devastating infection of the liver, which can lead to liver | cirrhosis, liver failure or liver cancer, and ultimately death. HCV is a U-coated virus that contains a single-stranded single-stranded RNA genome of approximately 9.4 kb and has a prion particle size of 30-60 nm. 1 HCV is the main initiator of non-A and non-B hepatitis after blood transfusion. People with a high percentage of chronically infected (and infectious) carriers of HCV infection may have no clinical signs for many years. HCV is difficult to treat and it is estimated that 500 million people worldwide are infected with it. There are currently no effective immunizations and hepatitis C can only be controlled by other preventative measures

O: \ 88 \ 88427.DOC 200423945, for example: improving hygiene and cleanliness and cutting off transmission. Currently, the only acceptable treatment for chronic hepatitis C is interferon (IFN-α), which requires at least six months of treatment and / or ribavadn, which inhibits virus replication in infected cells It can also improve liver function in some people. IFN-α belongs to a family of naturally occurring small proteins with specific biological effects such as antiviral, immunomodulatory and antitumor activities. It is the response of nucleated cells of most animals to several diseases, especially viral infections. While producing or secreting. IFN-a is an important growth and differentiation regulator, which affects cell transmission and immune regulation. However, the treatment of HCV with interferons only has a limited long-term efficacy with a response rate of about 25%. In addition, interferon treatment of Hcv occasionally has adverse side effects such as: fatigue, fever, chills, headache, myalgia, arthralgia, relieving baldness, mental effects and related disorders, autoimmune symptoms and related disorders, and sacral gland Malfunction. Ribavirin (;! ♦; □ _Nufur D Nanosyl-Triazolyl Smfe) is an inhibitor of carnitine 5'_monophosphate dehydrogenase, which can strengthen IFN-α In the treatment of HCV. Although the introduction of ribavirin ▲ patients with more than 50 / 〇 can not eliminate the virus by the current standard of interferon α (ΐ) ρΝ and ribavirin. So far, the standard treatment for chronic hepatitis C has been combined with PEG_IFN and ribavirin. However, some patients still have .1 Zhu Tian_ (Zuo Xiao # is mainly due to ribavirin. Ribavirin will cause significant hemolysis in 10% -20% of patients treated at the current recommended dose, and the The drug is also malformed and embryotoxic. Other methods are being used to combat the virus including, for example, the use of antisense oligos

O: \ 88 \ 88427 DOC 200423945 nucleotides or ribozymes to inhibit HCV replication. Furthermore, low molecular weight compounds that directly inhibit HCV proteins and interfere with viral replication are considered as compelling strategies for controlling HCV infection. NS3 / 4A serpin, ribonucleic acid (RNA) helicase, and RNA-dependent RNA polymerase are considered as potential new drug targets. 2,3

Devos et al. 4 illustrate purine and pyrimidine nucleoside derivatives and their use as inhibitors of RNA replication. Sominadossi et al. 5 illustrate dagger 2, or 3, _ modified nucleosides and their use for treating HCV infected hosts.

Carroll et al. 44'45, both of which are disclosed after the application of the present invention, illustrate the use of nucleosides as inhibitors of RNA-dependent RNA virus polymerase. This application is not intended to cover all compounds specifically disclosed in these applications. Due to the fact of the global HCV epidemic, there is a strong need for new and effective drugs to treat hcv. The present invention provides nuclear derivatives for treating HCV infection. '[Summary of the Invention] This U is a novel compound which can be used for mammalian treatment of HCv. The compound of the present invention can be represented by the following formulae la, lb and Ic:

O: \ 88 \ 88427.DOC -10- 200423945 wherein R and R1 are independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, dilute, substituted alkenyl, alkynyl, And substituted alkynyl but R and R1 are not both hydrogen; R2 is selected from the group consisting of: alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, dilute , Substituted alkenyl, alkynyl, substituted acylamino, guanidiniumthiothioamido, hydroxyalkyloxy, O: \ 88 \ 88427.DOC -11- 200423945 substituted Alkoxy, halo, nitro, thioalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, NR3R4, wherein R3 and R4 are independently selected from hydrogen, Alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, A group of substituted heterocyclic rings and R3 and R4 together with the nitrogen atom bonded thereto form a heterocyclic ring, substituted heterocyclic ring, heteroaryl, substituted Aryl, -Nr ^ NRSR4 'wherein R3 and R4 are as defined above and are selected from the group consisting of hydrogen and alkyl, and W is selected from the group consisting of: hydrogen, phosphate (including monophosphate Salt, bisphosphate, triphosphate or stabilized phosphonate prodrug), phosphonate, fluorenyl, 'sulfonate' which is selected from the group consisting of alkyl esters, substituted alkyl alcohols, alkenyl esters, Substituted alkenyl ester, aryl ester, substituted aromatic O: \ 88 \ 88427 D0C 12 200423945 based ester, heteroaryl ester, substituted heteroaryl ester, heterocyclic ester A group consisting of a fat, an amino acid, a hydrocarbon, a peptide, and cholesterol; X is selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, And -NR3R4, where R3 and R4 are as defined above; Y is selected from the group consisting of: hydrogen, halo ', sulfanyl, -NR3R4, where R3 and R4 are as defined above; Z is Selected from the group consisting of: argon, halo 'vial, alkyl, O: \ 88 \ 88427 DOC -13-200423 945 azide, and -NR3R4, wherein Han 3 and R4 are as defined above; -NR: > Nr3r4, wherein R3, R4 and R5 are as defined above; and wherein T is selected from the group consisting of: a) 1- and% deazopurine of the formula:

20) n

/ N N

: 20) 〇 b) Purine nuclear bitter of the formula:

Y c) benzimidazole

(R 'pyrimidine: d) 5-α-pyrrolyl group of the following formula

R2〇) n

Or 〇 4-pyrimidinylpyridine of the following formula. N (R20) n sangivamycin analog 〇 〇 R2〇 R2

NT y

O: \ 88 \ 88427 DOC -14- 200423945 f) 2- ° dense lake ° ratio σ sangivamycin analogue

(Ri I 〇 ^ N person N person Y; g) 4- ° dense σ fixed basis ° ratio σ fixed _ 53 叩 丨 ¥ 3111} ^ 11 analogue 〇 Q (R21) c

㈣p N

h) The following formula. Pseudo-base σ ratio analog: Q

Yang 0) ρ, N, or / i) pyrimidinyl-tetrahydropyridine of the formula:

Q

4 j) Furan pyrimidine (& tetrahydrofuran pyrimidine) of the formula: R12

-R10 R12 N / person Μ k) σ ratio 嗤 α dense in the following formula or

Μ, R10 Ν Ρ20

Ν 一 Ν O: \ 88 \ 88427.DOC -15-200423945 1) The ° ratio σ of each of the following equations is determined: R20

m) Three salivas of the following formula. Secret:

〇) pyridine C nucleoside of the formula:

P) pyrazole triazine C nucleoside of the formula:

q) an indole nucleoside of the formula:

O: \ 88 \ 88427.DOC -16- 200423945 r) The basis of the following formula:

s) The basis of the following formula:

Q

IT, R10 N ’\ ^ r2〇 t) the base of the formula

U) Bases of the formula: R20 r

V) The basis of the formula: R20

W) The basis of the following formula:

O: \ 88 \ 88427.DOC -17 200423945

x) The basis of the following formula

y) the base of the formula:

η * and one of the two bonds in which one of the two carbon rings ^ is a double bond, the bond 'then ρ is 1; the double bond is the other single bond, but if P is 0 and if Q and a ring The two in the carbon are double each P is individually 0 or 1; each η is individually 0 or an integer of 1 to 4; each η * is individually 0 or an integer of 1 to 2; L is selected from hydrogen, _ Group, alkyl group, substituted alkyl group, amine group, substituted amine group, azide group and nitro group; Q is selected from the group consisting of hydrogen, halo, = 〇, -OR11, = N -RU, NHR11, -SR11, aryl 'substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic ring and substituted heterocyclic ring; M is selected from the group consisting of = 0, = N-Rn and = S; Y is as defined above; O: \ 88 \ 88427 D0C -18- 200423945 R10 is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, and Group consisting of substituted cycloalkyl, heteroframe, substituted heterocycle, alkyl sulfide, substituted alkylthio scale, aryl, substituted aryl, heteroaryl, substituted heteroaryl , But if T is b), s), v), w) or χ), then Ri. Is hydrogen; each R1 and R is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, amine, substituted amino , Alkyl sulfide, substituted alkyl sulfide, aryl, substituted aryl, heteroaryl, substituted heteroaryl; each r2G is independently selected from the group consisting of: 〇; \ 88 \ 88427 DOC hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, bulk, Substituted alkynyl, _ alkynyl, substituted alkynyl heteroaryl, -19- 200423945 substituted heteroaryl, acylamino guanidinomethylthiothioamidoalkoxy A substituted alkoxy group, a thiothio group, a nitro group, a halogen group, a thio group, -NR3R4, wherein R3 and R4 are as defined above, and -NR ^ NRSr4, wherein R3, R4 and R5 are as defined above; each R21 and R22 are independently selected from the group consisting of: -NR3R4, where; ^ and R4 are as defined above, -NR5NR3R4, where R3, R4 and K Are as defined above; -C (0) NR / R4, where R3 and R4 are as defined above, -c (o) nr5nr3r4, where R3, R4 and R5 are as defined above; and their pharmaceutically acceptable salts However: 〇 For compounds of formula la, when z is hydrogen, halo, hydroxy, azide or R4 'where R3 and R4 are each fluorene or alkyl; Y is hydrogen or _NR3R4, where R3 and R4 are Each is hydrogen or alkyl; then R2 is not alkyl, alkoxy, molybdenum, CF3 or -NW, where R3 and r4 are each hydrogen or alkyl;

O: \ 88 \ 88427.DOC -20-200423945 2) For compounds of formula la, when Z is hydrogen, halo, meridian, azido or -NR3R4, where R3 and R4 are each η or alkyl; Y is hydrogen, dentyl, mesityl, or alkylthio; then R2 is not alkyl, ν, a substituted alkyl, wherein the substituted alkyl is hydroxyl, amine, amine, aryl, Substituted by alkoxy, aryloxy, schottyl, cyano, sulfuric acid, acid salt, phosphoric acid, phosphate or phosphonate, with or without protection, halo, alkoxy, alkoxy, sulfanyl, or -NR R 'Wherein R and r4 are each hydrogen, alkynyl or meridian, amine, amine, arylamine, alkoxy, aryloxy, nitro, cyanide, sulfuric acid, dish salt, phosphoric acid, phosphoric acid Salt or phosphonate substitution, with or without protected alkyl; 3) For compounds of formula lb, when X is hydrogen,! | Group, alkyl, ο] or -NR3R4, where R3 is hydrogen and H 4 is alkyl, then R2 is not alkyl, alkoxy, -yl, hydroxy, CL, or -NR3R4 'where R3 and R4 are Each is hydrogen or alkyl; and 4) for compounds of formula lb, R2 is not halo, alkoxy, hydroxy, sulfanyl, or -NR3R4 (wherein R3 and R4 are each hydrogen, alkyl, or hydroxy, Amine, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyanide, sulfuric acid, sulfate, phosphoric acid, phosphate, or phosphonate substitution, with or without protected alkyl group) sigh and Further, the compound of formula la, lb or Ic is not O: \ 88 \ 83427.DOC • 21- 200423945 a) Luogong methyl-5- (6-phenyl_purσσ-9-yl) · tetrahydro Fusanediol, or b) 2 ^ methyl-5_ (6-thiophenyl-3-yl-purin-9-yl) · tetrahydro_furan_3,4-diol. In a specific embodiment of the vehicle, R1 is selected from the group consisting of _CH3, -CF3, -CH = CH2, and < CH, and more preferably _〇3. In another specific example of Chevroja, if τ is a base of formula a), τ is 3-deazapurine. The present invention is further directed to compounds of formula II: C (H) b Y2

Where R and R1 are independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, · 0 \ 88 \ 88427 DOC -22- 200423945 halogen, azidoamino, and substituted amine; but R and R1 are not both hydrogen; Y2 is CH2, N, s, SO or s02; N and -C ( H) bW together forms a heterocyclic ring, substituted heterocyclic ring, heteroaryl or substituted "group, each of which is a heterocyclic ring, a substituted heterocyclic ring, a heteroaryl group or a substituted heteroaryl group If necessary, it is related to one or more cyclic structures selected from the group consisting of cycloalkenyl, ring county, heterocyclic, aryl and heteroaryl groups (each cyclic structure needs to be Selected from the group consisting of hydroxyl, alkoxy, substituted alkoxy, sulfanyl, substituted sulfanyl, aryl, heteroaryl, heterocyclic, nitro, cyano, carboxyl, carboxylate , Alkyl,, 'disubstituted alkyl, fluorenyl, substituted alkenyl, fastyl, substituted block, amine and substituted amine groups) Form double Or multiple fusion ring systems (preferably no more than 5 fusion rings); b is an integer equal to 0 or 1; A, B 'D and E are independently selected from > n, > CH, > C-CN , ≫ CN〇2,> c-alkyl, > c-substituted alkyl, > C-NHC0NH2, > CC〇NR15R16, > CC〇〇R15, > c-base, > C -Alkoxy, > c, Amine, > C-Amine, > C-Diamine, > C-halogen, > O (1,3-Chrysyl-2-yl), > The group F consisting of c- (l, 3-thiazol-2-yl) and > 0 (imidazol-2-yl) is selected from the group consisting of> N, > CH, > C-CN, > CN〇2 , ≫ 〇 alkyl, > C-O: \ 88 \ 88427.DOC -23-200423945 substituted alkyl, > C-NHC〇NH2, > CC〇NR15r16, > CC〇〇R, gas Group,> C- (l, 3-aoxaσ-2-yl),> C- (l, 3-poxazol-2-yl),> C- (imidazol-2-yl), and > A group consisting of CY, wherein γ is selected from the group consisting of hydrogen, halo, hydroxy, alkyl sulfide, and _NR3R4, wherein R3 and R4 are independently selected from hydrogen, hydroxy, alkyl, substituted Alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl , Alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle and if R3 and R4 A heterocyclic group is formed together with a nitrogen atom bonded thereto, and only ^ of R3 and R4 is a hydroxyl group, an alkoxy group or a substituted alkoxy group; 111: > and R10 are independently selected from the following Groups consisting of: hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and R15 and R16 forms a cycloalkyl group, a cycloalkyl group, a heterocycloalkyl group, a substituted heterocycloalkyl group, a heteroaryl group, and a substituted heteroaryl group together with its connected atom; W is selected from the group consisting of Group: · O: \ 88 \ 88427.DOC -24- 200423945 hydrogen, phosphate (including monophosphate, bisphosphate, triphosphate or stabilized phosphate prodrugs), phosphonate, fluorenyl Sulfonate, sulfonate 'which is selected from the group consisting of alkynyl ester, substituted alkynyl ester, dilute ester, substituted alkenyl ester, aryl ester, substituted aryl group A group of esters, heteroaryl esters, substituted heteroaryl esters, heterocyclic esters, substituted heterocyclic rings, a fat, an amino acid, a hydrocarbon, a peptide, and cholesterol ; And its pharmaceutically acceptable salts. In a preferred embodiment, the compound of formula π is represented by formula IIA:

A group consisting of: wherein R and R1 are independently selected from hydrogen,

O: \ S8 \ 88427.DOC -25-200423945 alkyl, substituted alkyl, alkyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, $ nitro, amino acid, and Substituted amino acids; but R and R1 are not both hydrogen; Y2 is CH2, N, s, SO or S02; N and -C⑻ ^ form a heterocyclic ring, substituted heterocyclic ring, heteroaryl group or A substituted heteroaryl group, wherein each of the heterocyclic ring, substituted heterocyclic ring, heteroaryl group or substituted heteroaryl group is optionally selected from one or more selected from the group consisting of cycloalkyl, cycloalkenyl, % -Like structure of the group consisting of heterocyclic, aryl, and heteroaryl groups (each cyclic structure needs to be selected from the group consisting of hydroxy, halo, alkoxy, and substituted alkoxy Radical, sulfanyl, substituted sulfanyl, aryl, heteroaryl, heterocyclic, nitro, cyano, carboxyl, carboxylate, alkyl, substituted alkyl, alkenyl, substituted Alkenyl, alkynyl, substituted alkynyl, amine, and substituted amine groups are substituted to form a double or multiple fusion ring system (preferably no more than 5 fusion rings) ; B is an integer of 0 or 1; W is selected from the group consisting of lines consisting of the following:

O: \ 88 \ 88427.DOC -26- 200423945 hydrogen, phosphates (including monophosphates, bisphosphates, triphosphates, or stabilizing salt-filling prodrugs), phosphonates, amidino, alkyl, Sulfonate, selected from alkyl esters, substituted alkyl esters, alkenyl esters, substituted alkenyl esters, aryl esters, substituted aryl esters, heteroaryl esters, substituted heteroaryls A group consisting of a base ester, a heterocyclic ester, and a substituted heterocyclic ester, a fat, an amino acid, a hydrocarbon, a peptide, and cholesterol; Y is selected from the group consisting of: Hydrogen, halo, hydroxy, alkyl sulfide, -NR3R4, where R3 and R4 are independently selected from hydrogen, hydroxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted A group of alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle and R3 O : \ 88 \ 88427.DOC -27- 200423945 and R4 form a heterocyclic group with the nitrogen atom bonded to it, but "only one of R and R is hydroxy Group, alkoxy group or substituted alkoxy group; Z is selected from the group consisting of hydrogen, hydroxyl, alkyl, azido, and -NR R, wherein R and R4 are independently selected from hydrogen , Hydroxyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, Heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic group and R3 and R together with the nitrogen atom bound to form a heterocyclic group, but only between R3 and R4 One is hydroxy, alkoxy or substituted alkoxy; and pharmaceutically acceptable salts thereof. Compounds encompassed within the scope of the present invention include, for example, the following (including their pharmaceutically acceptable Salt):

〇: \ 88 \ 88427 DOC -28-200423945 3 Η〇Ί〇 彳 N HO OH 9- (2 ^ C-methylsucralose)-6- (pyrrole-3-yl) -purine 4 ηοΊ ο ^ ν ^ νη2 Η〇〇Η 9- (2'-C-methyl-β-D-ribofuranosyl) -6-phenyl-2-aminopurine 5 CrCN HO ΟΗ 9- (2f-C-fluorenyl-β -D-ribofuranosyl) -6- (3-cyanophenyl) -thyrene 6 Ο < / NXj Η〇 ^ Ν Ν HO ΟΗ 9- (2 ^ C-fluorenyl-0-〇-bital ribose ) 6- (9 than stilbyl-3-yl) -purine 7 〇3% gray Η 〇 〇 Η 9- (2f-0 methyl-β-D-ribofuranosyl) -6- (benzo [b] Thiophenyl-3-yl) -2-aminopurine 8 ΗΟ ΟΗ 9- (2'cardiacyl-β-D-ribofuranosyl)-6- (1 fluorenyl-% indol-5-yl) -threonine O: \ 88 \ 88427 DOC -29- 200423945 9 ΗΟη. Hachiba HO OH 9- (2LC-methyl-β-D-ribofuranosyl) -6- (naphthyl-2-yl) -threonine 10% 0 to H2 HO OH 9- (2'-C-form -Β-D-ribofuranosyl) -6- (dibenzofuran-4-yl) -2-aminopurine 11 OOp HO OH 9- (2'-C-methyl-β-D-furan Ribosyl) -6- (thienthracene small) -purine 13 HO OH 9- (2'-C-methyl-β-D-ribofuranosyl) -6-cyclopropyl-2-aminopurine 14 II HO OH 9- (2'-C-methyl-β-D-ribofuranosyl) -6- (ethoxy) -thyrin 15 15〇η 〇 HO OH 7- (2'-C-methyl ribose Yl) -4-thiobenzyl-3-yl 16 ηοΊ ο ^ n ^ nh2 HO OH 7- (2'-C-methyl-β-D-ribofuranosyl) -4-phenyl-7H-pyrrole [2 , 3-d] pyrimidin-2-ylamine O: \ 88 \ 88427.DOC -30- 200423945 17 Η〇Π HO OH Γ-C-methyl-β-D-sweet ribosyl) -4-sulfan -3-yl-111- £ 7 ^^^-2- 嗣 18 HO—i 0 N ^ 〇% HO OH l- (2 ^ C-methyl-β-D-bite 0 ^ ribosyl) -4 -Benzyl-1H-pyrimidin-2-one 19? LX ΗΟ-η n N " ^ ° Ή .HO OH l- (2'-C-methyl-β-D-ribofuranosyl) -4- (benzene Benzo [b] thiophenyl-2-yl) -1H-pyrimidin-2-one 21 HON ^ N ^ ° HO OH 1-(2'-C-methyl-β-D-sucrose ribosyl)- 4-cyclophenyl-1H-pyrimidin-2-one 22 / N ^ n ^ N, HO OH 9- (2'-C-methyl-β-D-ribofuranosyl) -Νό- (2-dimethylaminoethyl) -adenine 23 hn ~ nh2 H〇-1 1 NN〆% HO OH 9- (2'-C-methyl-β-D-ribofuranosyl) -N6- (2-aminoethyl) adenine — O: \ 88 \ 88427.DOC -31-200423945

24 HN (A HO-1 ~ 〆HO OH 9 W-methyl-β-D-ribofuranosyl) -Νό- [2- (3Η-indolyl) ethyl] adenine 25 HO-1 N eight N% HO OH 9- (2 ·-(:-fluorenyl-β-D-ribofuranosyl) -6- [2-aminocarbonyldecapyridin-1-yl)]-purine 26 .NH. 2 Hon & HO OH l- (2'-C-fluorenyl-β-D-bita ribose) -N4- (aminocarbonylmethyl) -cytosine 27 0 H ”t. Ύ] / 1- ( 2 < -fluorenyl-β-D-ribofuranosyl) -N4-[(pyridyl) -methyl] cytosine γλ HO OH 30 nh2 HO-IN ^ N 9- (2'-C-fluorenyl- β-D-ribofuranosyl) -N6-[(Adenine-8-yl) -aminoethyl] adenine Hi HO OH 31 A: NH 1 9- (2 ^ (3-fluorenyl-β-D -11 Fuco ribosyl) -NM (benzene-3,4,5-triol) -fluorenyl] Adenine M HO OH O: \ 88 \ 88427.DOC -32- 200423945

O: \ 88 \ 88427.DOC -33-200423945

O: \ 88 \ 88427 DOC -34- 200423945 56 HO-1 N Eight N% HO OH 9- (2LC-methyl-β-D-ribofuranosyl) -N6- (2,2,3,3,3 , -Pentafluoropropyl) purine 57 0 HON HO OH 9- (2'-C-methyl-β-D-ribofuranosyl) -6- (piperidinyl) purine 60 00 HO-I HO OH l- (2'-C-methyl-β-D-ribofuranosyl) -1H-benzimidazole 61 nh2 1 f6 HO OH 3- (2 ^ C-fluorenyl-β-D-ribofuranosyl) -3H-imidazole [4,5-b] pyridine-7-ylamine 62 HN ~ NH2 〈/ NxV_ HO— | N eight N > · HO OH 9- (2'-C-trifluoromethyl-β- D-ribofuranosyl) -N6- (2-aminoethyl) adenine 63 3 H〇 ^ c; HO OH 9- (2'-C-trifluoromethyl-β-D-ribofuranosyl)- Ν6- [2- (3Η ^ 朵朵 -3-yl) -ethyl] adenophylline 64 rUNHj H ". HO HO 9- (2'-C-trifluoromethyl-β-D-ribofuranosyl ) -6- [2-Aminocarbonyl- (pyrrolidinyl)]-purine 0 \ 88 \ 88427.DOC -35-200423945

O: \ 88 \ 88427.DOC -36- 200423945 75 3 HO— ~ IN ^ N &gt; HO OH i 9- (2'-C-ethynyl-β-D-ribofuranosyl) -N6_ [2- ( 3H-indolyl) -ethyl] adenine 76 HO-I HO OH 9- (2'-C-ethynyl-β-D-ribofuranosyl) -6- [2-amine Rockbiter)] _ Horline 79 „n (¾ HO OH l- (2'-C · ethynyl-β-D-ribofuranosyl) -1H-benzimidazole 80 (HO C ^ nh2) H 5 -(2'-C-methyl-β-D-ribofuranosyl) -5H-pyrrole [3,2-c] pyridine <4-ylamine 81 0 0 nh2 Η0Π 0 i N π HO OH 4-amino group Each (2, -C-methyl-β-D-ribofuranosyl) -5-oxy-5,8-dihydroj specific bit [2,3-d] «f bit-6-carboxylic acid amidine 82 〇〇nh2 Ύ human NH2 HO OH 2,4-diamino-8- (2 * -C-methyl-β-D-ribofuranosyl) -5-oxy-5,8-dihydro "ratio 〇 ^ [2,3-d] pyrimidin-6-carboxylic acid amide 83 H2N X 〇 human r HO-1 HO C 〆〇nh2 into J) H 4-amino-8- (2'-C-form -Β-D-ribofuranosyl) -7-oxy-7,8-diargon-at (^ [2,3-d] ° S ° ^ -5-carboxamide-37-

O: \ 88 \ 88427.DOC 200423945

0: V88 \ 88427.D0C -38- 200423945

O: \ 88 \ 88427 DOC -39- 200423945 98 nh2, n, N human N H0_ ^ V HO OH 8- (2 * -C-methyl-β-D-11 Fusyl ribosyl) _. Bidazole [l, 5-a] [l, 3,5] triazin-4-ylamine 99 〇 Human NH HO OH 8- (2'-C-fluorenyl-β-D-ribofuranosyl) -3H -Nizol [1,54] [1,3,5] triazin-4-one 100 〇 N, N human NH human NH 2 HO OH 2-amino-8- (2'-C-methyl-β -D-, ribofuranosyl) -3H-pyrazole [l, 5-a] [1,3,5] triazinone 104 NO- 〇0 Η〇 ^ / ^ HO OH 1-(2 ^ 0 甲-Β-D-ribofuranosyl) -4-nitroindole 105 nh2 HO OH l- (2f-C-methyl-β-D-ribofuranosyl) -4-aminoindole 106 HA HN AH 〇l〇j N HO 〇H 9- (2'-C-methyl-β-D-ribofuranosyl) -6- [2- (1H-imidazol-4-yl) -ethyl] purine 107 &lt; r &gt; H〇UN HO 0H 9- (2'-C-methyl-β-D-11 Fusylribosyl) -6- (acridinyl) purine O: \ 88 \ 88427 DOC -40-200423945

〇: \ 88 \ 88427 DOC -41-200423945 151 9 Para palm isomers &amp; 〇 〇 2f-C-fluorenyl-β-D-ribofuranosyl-Knee 0 ^ 152 pairs of zero isomer '-C-methyl-β-D-ribofuranosyl-thymus 08 bite 155 pair palm isomers V 0 (iN 0 0 2 · -0 fluorenyl-β-D · ribofuranosyl-6-phenyl gland Purine 156 Para palmar isomer rN \ y O '&quot; 0-9- (2 * -C-methyl-β-D-crete ribose) -6- (2- (1Η-imidazole-1-4 -Yl) -ethylamino) thyrin 157 〇N ^ para-isomer 009- (TC-methyl-β-D-ribofuranosyl) -6- (2-trabino-1-yl -Ethylamino) Sore-42-

O: \ 88 \ 88427.DOC 200423945 158 Paraisomeric family N 〇 wide 〇 〇 〇09- (2'-C-methyl-β-D-ribofuranosyl) -6- (cyclopropane Aminoamino) purine 159 palmar isomer ^ \ 〇〇9- (2 ^ C-methyl ribosyl) -6- (cyclopentylamino) purine 160 palmar isomer 009 9- (2 '-C-methyl-β-D-biting ribosyl) »6- (cyclohexylamino) purine 161 〇〇〇ό 6 8- (3,4-dienyl-5-pentyl-3 -Fluorenyl-tetraaza-pyran-2-yl) -4,5-dioxy-3,4,5,8-tetrahydropyridine · [2,3-d] pyrimidine-6-carboxylic acid Amine 162 CI 0〇 ° ~ W Ν ', ..... ° b 2- (4-Gas-pyrrole [2,3-d] pyrimidin-7-yl) -5-hydroxymethyl-3- Methyl-tetramurine-alpha-fusicum-3,4-diol O: \ 88 \ 88427.DOC .43-200423945 163 3 N Μ 〇〇- (2'-C-methyl-β-D-furan Ribosyl) -6- (6-fluoro-1,3,4,9-tetrahydro + carborin-2-yl) purine 164 0 Μ〇〇- (2'-C-methyl-β-D -Ribofuranosyl) -6- (3,6-dihydro-211-hey-1-yl) snoring 165 S Ν Ν Ν '0 ο 4-amino-8- (3,4-two meridian Methyl-5- via fluorenyl-3-methyl ~ tetraphosphino) -2-methylthio-811-0 specific bite [2,3-d] pyrimidin-7-one 166 Γ, ~ N ο ^ &lt; 〇 &gt; 〇 5-hydroxymethyl- 3-methyl-2- (l, 3a, 5,6-®aza-asshen-6-yl) -tetraargon-sigmafo-3,4-diol 168 Γ2 i 5-hydroxyfluorenyl- 3-fluorenyl-2- (7-nitro-amidazole [4,5-b]-. Specific bite-3-yl) -tetrahydro-bite-3,4-diol O: \ 88 \ 88427 .DOC -44-200423945

O: \ 88 \ 88427.DOC -45- 200423945

5-amino-2- (3,4-dihydroxy-5-hydroxymethyl: methyl-tetrahydro-furan-2-yl K5-dihydro-2H- [1,2,4] triol-3 -Keto 5-hydroxyfluorenyl-3-methyl-2- (4-nitro-benzimidazole small group) -tetramurine-sigma-3,4-diol: 2- (4-amino- Benzimidazol-1-yl) -5-hydroxyfluorenyl-3-methyl-tetramurine- ° Fufen-3,4-diol 1- (3,4-dienyl-5-mercapto- 3-methyl-tetramus-sigma 9- (2'-C-methyl-β-D-ribofuranosyl) -6- (4-methylphosphoryl) purine 2- (4-amino-la P1,3-b] pyrimidin-1-yl))-5-hydroxyfluorenyl-3-fluorenyl-tetramus-bite-3,4-monool

O: \ 88 \ 88427.DOC -46- 200423945

O: \ 88 \ 88427.DOC -47-200423945

2- (4-Amino-2- [l, 2,4] tria-s--1-yl- ° -tetra-5-yl) -5- via methyl-tetra-argon-furan-3,4- Diol 2-hydroxymethyl-5- (4-methylamino-2- [1,2,4] triazol * 1-yl-bite-5 ** yl) -quadrat-bite-3 , 4-diol 2-hydroxymethyl 5- [4-fluorenylamino-2- (N'-methyl-hydrazinyl)-° ¾--5-yl) -tetracycline-α-flavour- 3,4-diol 2- (4-amino-5H-pyrrole [3,2-d] pyrimidin-7-yl) -5- via fyl-3-methyl-tetram- ° f °°- 3,4-diol 7- (3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl) -4-oxy-4,7-dihydro-3H -Pyrrole [2,3-d] pyrimidin-5-carboxamidine 2- (4-amino group-; 5-sigmathio-2-yl-17-bihar [2,3-d] bite-7-yl ) -5-hydroxyfluorenyl-tetrahydro-furan-3,4-diol-48-

〇: '.88 \ 88427 DOC 200423945

O: \ 88 \ 88427.DOC -49-200423945 212 nh2 &lt; 〇rS H〇]. % OHOH 2- (4-amino-pyrrole [3,2-c] pyridinyl) -5-hydroxyfluorenyl-3-fyl-tetrahydro-octane-3,4-diol 213 &lt; / ΝΛ H〇- ^ NT OHOH 4-chloro-7-fluoro small (2'-C-fluorenyl-β-D-ribofuranosyl) imidazole [4,5-c] anidine 214 nh2 &lt; / NxS OHOH 4 -Amino-7-fluoro small (2'-C-methyl-β-D-ribofuranosyl) imidazole [4,5-c] pyridine 1 215 NH-OHOH, 2- (4-amino-5H- Pyrrole [3,2-d] pyrimidin-7-yl) -5-hydroxyfluorenyl-3-fluorenyl-tetraargon-furan-3,4-diol 216 nh2 &lt; / NyS HO] mono-OHOH 4-amine -1- (PD-ribofuranosyl) imidazole [4,5-c] pyridine 217 ΗΟη ^ Ν y OHOH 'Ga-7-fluoro-1-(β-D-ribofuranosyl) imidazole [4, 5-c] ° ratio pyridine 218 nh2 &lt; &quot; xS H0 ^ N ^ T OHOH 4-amino-7-fluoro small (β-D-ribofuranosyl) imidazole- [4,5-c] ° ratio Pyridine

O: \ 88 \ 88427.DOC -50- 200423945

O: \ 88 \ 88427.DOC -51-200423945

O: \ 88 \ 88427.DOC -52- 200423945 The present invention is also directed to a pharmaceutical diluent and an effective amount of a compound of formula la, lb, ic, II, IIA, III or IV or a mixture of one or more of these compounds Pharmaceutical composition. The present invention is further directed to a method for treating mammalian HCV, which method comprises administering to a mammal diagnosed with HCV or at risk of HCV development a pharmaceutical diluent and an effective amount of formulae Ia, Ib, Ic, n, IU , M or IV or a pharmaceutical combination of a mixture of one or more of these compounds in another method aspect, the present invention is directed to a method for preparing a compound of formula m:

Where R, R contains:

, R3, R4, W, X, Y and Z are as defined above, and the method (a) oxidizes a compound of formula IV

〇h〇h

O: \ 88 \ 88427 DOC -53-200423945 where R6 is selected from the group consisting of alkyl and aryl groups, (b) oxidizes the thio group to sulfoxide or lanthanide; and The prepared oxidized compound is connected to the leg 3r4 of at least stoichiometric equivalent under the condition that the formula π can be combined to form, wherein R3 and "are independently selected from hydrogen 1 group, substituted alkyl group, alkenyl group, substituted group County, alkynyl, substituted alkynyl, aryl, substituted aryl heteroaryl, substituted heteroaryl, heterocyclic ring, substituted heterocyclic ring and R and R with nitrogen bonded to it The atoms are linked together to form a heterocyclic group. The present invention is directed to compounds, compositions, and methods for treating hepatitis C virus infection. However, before describing the present invention in detail, the following terms are defined: Defined as used herein, "Alkyl" means an alkyl group having from 1 to 3 carbon atoms, preferably to 5 slave atoms, and more preferably from 1 to 3 carbon atoms. Exemplary groups for this term are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl and the like. "Substituted alkyl" means an alkyl group having one to three, and preferably one to two, selected from the group consisting of alkoxy, substituted alkoxy, fluorenyl, halogenated amine, Alkoxy, amine, substituted amine, amidino, aryl, substituted aryl, square oxo, substituted aryloxy, cyano, molybdenum, warpyl, schottyl, carboxyl, Carboxyl esters, cycloalkyls, substituted cycloalkyls, heteroaryls, substituted heteroaryls, heterocycles, and substituted heterocycles are a group of substituents. Refers to a "alkyl" group, which includes, for example: fluorenyl, ethoxy O: \ 88 \ 88427.DOC • 54- 200423945, n-propoxy, isopropoxy, n-butoxy, second butoxy Base, n-pentyloxy and the like. "π substituted alkoxy" refers to &quot; substituted alkyl. &quot; Fluorenyl &quot; refers to the group HC (〇)-, alkyl-C (O)-, substituted alkyl-c ( 〇)-, alkenyl-c (o)-, substituted alkenyl-c (o)-, alkynyl-c (〇)-, substituted alkynyl-c (o)-, cycloalkyl- c (o)-, substituted cycloalkyl-c (〇)-, aryl-c (〇)-, substituted aryl-c (〇)-, heteroaryl-c (〇)-, Substituted heteroaryl-c (o)-, heterocyclic-c (o)-, and substituted heterocyclic-c (o)-, among which alkyl, substituted alkyl, alkenyl, substituted Alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted Heterocyclic systems are as defined herein. `` Amidinylamino '' refers to the group -C (0) NRR, where each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, Substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle And each R is connected to a nitrogen atom to form a heterocyclic ring or a substituted heterocyclic ring, wherein the alkyl group, substituted alkyl group, alkenyl group, substituted alkenyl group, alkynyl group, substituted alkynyl group, and cycloalkane Radical, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocyclic system are as defined herein. `` Bis''oxyπ refers to the group alkyl-C (〇) 〇-, substituted alkyl-C (〇) 0-, alkenyl-C (0) 〇-, substituted alkenyl- c (o) o-, alkynyl-C (〇) 〇-, substituted alkynyl-C (〇) 〇-, aryl-C (〇) 〇-, substituted O: \ 88 \ 88427. DOC -55- 200423945 aryl-C (〇) 〇-, cycloalkyl · 〇 (〇) 〇_, substituted cycloalkyl-C (〇) 〇 ... heteroaryl-C (〇) 〇-, Substituted heteroaryl_c (〇) 〇-, heterocycle-C (〇) 〇- and substituted heterocycle -c (o) o-, among which alkyl, substituted alkyl, alkenyl , Substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, A substituted heterocyclic ring is as defined herein. "πalkenyl" means preferably having 2 to 6 carbon atoms and more preferably 2 to 4 carbons

An alkenyl group having at least one and preferably 1-2 unsaturated alkenyl groups. `` Substituted alkenyl '' means an alkenyl group having 1 to 3 substituents, and preferably 1 to 2 substituents, the substituent being selected from the group consisting of alkoxy, substituted alkoxy, fluorene Group, halogenated amino group, methyloxy group, amino group, substituted amino group, amino group, aryl group, substituted aryl group, aryloxy group, substituted aryloxy group, cyano halide, ^ group , Nitro, weyl, retarder, cycloalkyl, substituted

A group consisting of cycloalkyl, heteroaryl, substituted heteroaryl &apos;, heterocycles and substituted heterorings. Bulk group refers to an alkynyl group preferably having 2 to 6 carbon atoms and more preferably 2 to 3 carbon atoms and having at least one and preferably two unsaturated alkynyl groups. "Substituted alkynyl" means an alkynyl group having 1 to 3 substituents, and preferably 1 to 2 substituents, the substituent being selected from the group consisting of alkoxy, substituted Fluorenyl, halogenated amine, fluorenyloxy, amine, substituted amine, amino acid, aryl, substituted aryl, aryloxy, substituted aryloxy, murine, halogen , Building group, nitro, carboxyl, fluorene, cycloalkyl, substituted

O: \ 88 \ 88427.DOC -56- 200423945 A group consisting of cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic ring and substituted heterocyclic ring. "πamino" refers to the -nh2 group. 'Substituted amine "refers to the -NRR group, where R * R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted Alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted hetero A group of rings in which R and R are connected to a nitrogen atom bonded thereto to form a heterocyclic ring or a substituted heterocyclic ring, but R and R are not both hydrogen. If R is chloro and R is alkyl, then a substituted amine group is sometimes referred to herein as an alkylamino group. If R and R are alkyl groups, the substituted amine group is sometimes referred to herein as a monoamine group. '' Methenyl '' refers to a group having the formula / (, ^ ,, ^, where ^, ^, and RfM are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, and substituted olefin Group, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic ring, substituted heterocyclic ring A group consisting of R, and R, connected to a nitrogen atom bonded thereto to form a heterocyclic ring, a substituted heterocyclic ring, a heteroaryl group, or a substituted heteroaryl group. The term also refers to the inverse fluorene base structure of the formula: R · ”1

NR 'NR &quot; wherein R is an alkyl or substituted alkyl as defined above and R ... and R are as defined above. O: \ 88 \ 88427.DOC '57-200423945 "Guanidine" refers to a group having the formula -NHC (= NR ...) NRV, wherein R 'and RlnR⑴ are as defined above. `` Amine group '' refers to the group -NRC (0) alkyl, -NRC (0) substituted alkyl, -NRC (O) cycloalkyl, -NRC (O) substituted cycloalkyl, -NRC (〇) alkenyl, -NRC (O) substituted alkenyl, -NRC (O) alkynyl, -NRC (〇) substituted alkynyl, -NRC (〇) aryl, -NRC ( 〇) substituted aryl, -NRC (〇) heteroaryl, -NRC (〇) substituted heteroaryl, -NRC (〇) heterocycle, -NRC (〇) substituted heterocycle, where R is Is hydrogen or alkyl and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted fastyl, cycloalkyl, substituted cycloalkyl, aryl, Substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic ring, and substituted heterocyclic ring are as defined herein. "Aryl" or "Ar ·" means having a single ring (eg, phenyl) Or multiple condensed rings (for example: a monovalent aromatic ring of 6 to 14 carbon atoms of naphthyl or anthracenyl), the condensed ring may be aromatic or non-aromatic (for example: 2-benzoxazolinone, 2H-1,4-benzoxazine-3 (4H) -one-7-yl, and the like). Preferred aryl groups include benzene And naphthyl. "Substituted aryl" refers to an aryl group substituted with 1 to 3 substituents, and preferably 1 to 2 substituents, the substituent being selected from the group consisting of hydroxy, fluorenyl , Tritiated amine, alkoxy, alkyl, substituted alkyl, alkoxy, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl 'amino, Substituted amine, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, carboxyl, carboxylate, cyano , Thio, thioalkyl, substituted thioalkyl, sulfur O: \ 88 \ 88427.DOC -58-200423945 aryl, substituted thioaryl, thioheteroaryl, substituted thiohetero Aryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocycle, substituted thioheterocycle, cycloalkyl, substituted cycloalkyl, i-based, nitro, heteroaryl Group consisting of amino, substituted heteroaryl, heterocyclic, substituted heterocyclic, heteroaryloxy, substituted heteroaryloxy, heterocyclooxy, and substituted heterocyclooxy. " "Aryloxy" means aromatic -O-, which includes, for example, phenoxy, naphthyloxy and the like. "Substituted aryloxy" means a substituted aryl-0- group. F'aryloxyaryl " Refers to -aryl-0-aryl hydrazone. "Substituted aryloxyaryl" refers to one or two aryl rings that have 1 to 3 aryl groups as defined above. An aryloxyaryl group substituted with a substituent in the above. "Carboxylπ refers to -COOH or a salt thereof. Picarboxylate" refers to the group -C (0) 0alkyl-, via- C (〇) 〇-substituted alkyl, -C (〇) 0aryl-, -C (〇) 〇-substituted aryl, wherein alkyl, substituted alkyl, aryl and substituted Alkyl is as defined herein. π-Cycloalkylπ means a cycloalkyl group having 3 to 10 carbon atoms which is mono- or polycyclic, and includes, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and Like. π-Cycloalkenyl '' means a cycloalkenyl group having 4 to 10 carbon atoms having mono or polycyclic ring and further having at least 1 and preferably 1 to 2 internally unsaturated ethylene (C = C). • 'substituted alkyl' and π substituted alkenyl ff refer to a cycloalkyl or O: \ 88 \ 88427.DOC -59- 200423945 cycloalkenyl group having 1 to 5 members selected from oxygen (20), thio (= 0), alkoxy, substituted alkoxy, fluorenyl, halogenated amine, fluorenyl, amine substituted amine, amine, aryl , Substituted aryl, aryloxy, substituted oxo, cyano, hydrogen, triphenyl, schottyl, carboxyl, Weiyi, cycloalkyl, substituted cycloalkyl, heteroaryl, triphenyl A group consisting of a substituted heteroaryl group, a heterocyclic group, and a substituted heterocyclic group. "Π cycloalkyloxy" refers to a cycloalkyl group. π substituted cycloalkyl &quot; refers to a substituted cycloalkyl group. "πhaloπ or πhalogen" means fluorine, chlorine, bromine and iodine and is preferably fluorine or chlorine. Πheteroaryl "means 1 to 15 carbon atoms, preferably 1 to 10 carbons Atomic and aromatic compounds containing 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. These heteroaryl groups may have a single ring (eg, pyridyl or furyl) Or multiple condensed rings (eg, indolyl or benzothienyl). Preferred heteroaryl groups include pyridyl, pyrrolyl, indolyl, thiophenyl, and furyl. Substituted heteroaryl "means 1 to 3 substituents selected from the same group as the substituents defined by the substituted aryl group. Also, "aryloxy" refers to a -0-heteroaryl group, and, substituted hetero, aryloxy "refers to a -0- substituted heteroaryl group. Hetero '' refers to A saturated or unsaturated group with a single ring or multiple condensed rings with 5 to 10 carbon atoms and 4 to 4 heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen in a fusion ring In the system, one or more rings thereof may be an aryl group or a heteroaryl group. A "t-substituted heterocyclic ring" means one to three substituted cycloalkyl groups as defined above.

O: \ 88 \ 88427.DOC -60- 200423945 heterocyclic group substituted with a substituent having the same meaning. Examples of heterocyclic and heteroaryl groups include, but are not limited to, acridine, pyrrole, miwa, σ ratio tz, ϋ ratio σ, σ ratio σ, and. Pyridazine, pyridazine, α indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinine Phthaloline, phthalazine, carbazine, carbazine, meat lin, pipidium, σ carbazole, carboline, phenanthridine. Yadian, phenanthroline, heterologous sigma sitting, phenazine, iso ° evil. Sit, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indolin, phthalimide, 1, 2 , 3,4-tetrahydro-isoquinoline, 4,5,6,7-tetrahydro-benzo [b] thiophene, thiazole, thiazolidine, thiophene, benzo [b] thiophene, morpholin Base, morpholinyl (also known as thiamorpholinyl), bridging stilbyl, pyrrolidine, tetrahydrofuranyl and the like. "Heterocyclic oxyπ means a heterocyclic group and" substituted heterocyclic oxy "means -0-substituted heterocyclic group." Phosphate π means -0P (0) (0Η) 2 (monophosphate), -0P (0) (0Η) 〇P (0) (0Η) 2 (bisphosphate g), -0P (0) (0H) 0P (〇) (0H) 〇P (〇 ) (〇H) 2 (triphosphate) or its salts, including some salts thereof. '' Phosphonate π means -0P (0R) (0H) or -〇P (OR) (OR) or Its salts, including some of its salts. Di "thiol π refers to -SH group. Η sulfanyl" or "alkyl thioether" or "thioalkoxy" refers to -S- Alkyl group. π substituted sulfanyl π or "substituted alkane sulfide π or π substituted thio O: \ 88 \ 88427.DOC -61-200423945 Alkoxy f 'means -s-substituted alkane "Sullocycloalkyl" refers to the -S-cycloalkyl group and "substituted thiocycloalkyl" refers to the -s-substituted cycloalkyl group. "Aryl" refers to an aryl group and, "substituted thioaryl" refers to a substituted aryl group. • 'thioheteroaryl' refers to the -s_heteroaryl group and "substituted thioheteroaryl" refers to a substituted heteroaryl group. "Thiothioheterocycle" refers to a heterocyclic ring And a substituted thioheterocycle means a substituted heterocyclic group. The term "amino acid" means an alpha-amino acid of the formula H2NCH (R7) COOH, of which R7 is an alkyl group, a substituted alkyl group, or an aryl group. Preferably, the α-amino acid is one of the twenty naturally occurring L amino acids. The term "π hydrocarbon" means that it contains 2 Sugars to 20 sugar monomers. The specific oligosaccharide monomers used are not critical and include, for example, glucose, galactose, acetylglucosamine, N-acetylgalactosamine, fucose, sialic acid and all natural and synthetic derivatives of the same kind. In addition, in the pyranose type, all sugar monomers described herein are of type 1), except that fucose is ^ type. The word "fat" is a defined term known in the art, such as:

Lehninger, Biochemistry '1970, p. 189, which is incorporated herein by reference in its entirety. The term "bis" peptide refers to a polymer of α-amino acid, which contains about 2 to about 20 ', preferably about 2 to about 10, more preferably about 2 to about 5 amine groups. Acid monomer. "The term" substituted phosphate prodrug "refers to a alkoxy, substituted alkoxy group with one or more hydroxyl groups O: \ 88 \ 88427 D0C -62- 200423945 overhangs. Mono, bis, and triphosphate groups of aryl, aryloxy, or substituted aryloxy groups. The term "accepted salt" refers to a pharmaceutically acceptable salt of a compound, where the salt is derived Various organic and inorganic counter ions that are well known in the art and include, for example, sodium, potassium, calcium, magnesium, ammonium, tetraalkyl, and the like; and if the molecule contains an experimental functional group , Organic or inorganic acid salts, such as ... Hydrochloric acid, Hydroxamic acid, Tartaric acid, Metarite K acid ester, Acetic acid, Maleic acid ester, Oxalic acid salt and the like. In a substituted group, by a defined substituent which is further substituted by itself (for example [a substituted aryl group having a substituted aryl group as a substituent, which itself is substituted by a-substituted aryl group Substituted 'etc.) polymers are not expected to be included herein. In this case The following 'the maximum number of these substituents is three. That is, the above definitions are restricted' For example: substituted aryl is limited to _ substituted aryl-(substituted aryl) · substituted Similarly, the above definition is not intended to include inadmissible types of substituents (for example: methyl or ethyl or five ethyl substituted with 5 fluoro unsaturated ethylenyl groups. Such inadmissible substitutions The basic type is known to those skilled in the art.… The compounds of general synthesis can be prepared by a variety of methods known in the art of general nuclear and nuclear acid ^ 胄 chemistry. For synthesis The starting materials can be obtained from the market or can be prepared by techniques known in the 9 ^^ art. Or general review of the preparation of nuclear bitter and nuclear bitter analogs is included

O: \ 88 \ 88427.DOC -63-200423945 includes the following:

Michelson A.M. &quot; The Chemistry of Nucleosides and Nucleotides'Academic Press, New York, 1963.

Goodman L • 丨 'Basic Principles in Nucleic Acid Chemistry 丨 丨, Academic Press, New York, 1974, vol.l, Ch. 2. &quot; Synthetic Procedures in Necleic Acid Chemistry' Eds · Zorbach W. &amp; Tipson R ·, Wiley, New York, 1973, νο1.1 &amp; 2. The synthesis of cyclic carbonucleosides has been reviewed by Agrofoglio et al. (Tetrahedron, 1994, 50, 10611). The compounds of the present invention can be prepared by the method abstracted in US Provisional Application Serial No. 60 / 378,624, which is incorporated herein by reference in its entirety. Available strategies for synthesizing compounds of the present invention include: General synthesis of A · 2 branched ribonucleosides 2'-C- branched ribonucleosides of the following structure:

Y and z are as defined above, and can be prepared by one of the following methods: R1, r2, W, X, 1 and R1.

O: \ 88 \ 88427.DOC -64- 200423945 1 · Convergence method · Glycosylation of nucleobases with appropriate modified sugars The key starting material for this method is the appropriate substituted sugars, which have 2'- OH and 2'-H have a suitable leaving group (1_ 叩 Yi Qing), for example: a donkey group, m fluorine or molybdenum. The sugar can be purchased commercially or prepared by any known method, including standard deviation isomerization (epimedzation), substitution, oxidation, and reduction techniques. For example, a commercially available U3I tri-o-benzyl ribofuranose (pfanstiei Laboratories, Inc.) can be used. The substituted sugar can be oxidized to 2'-modified sugar in a compatible solvent at a suitable temperature by a suitable oxidant. Possible oxidants are, for example: Dess-Martin periodine reagent, Ac20 + DCC dissolved in DMS〇, Swern oxidant (DMSO, chlorchloramine, triethylamine), Jones reagent (mixture of chromic acid and sulfuric acid) , Commns, s reagent (dipyridine * Cr (VI) oxide), Corey's reagent (pyridine chlorochromate), pyridinium dichromate, acidic monochromate, high acid removal, Mn〇2 , Ruthenium tetroxide, a phase transfer catalyst, such as chromic acid or a peracid salt supported on a polymer, 匚 12-pyridine. H202, ammonium molybdate, NaBr02-CAN, NaOCl dissolved in HOAc, chromite copper'copper oxide, Raney nickel, acetic acid free, Meerwin-Pondrof-Verley reagent (with another ketone Third aluminum butoxide) and N-succinimide bromide. Organometallic carbon-containing nucleophiles, such as: Grignard reagents, organolithium, dialkyl lithium copper or R ^ SiMes dissolved in TBAF and ketones with appropriate aprotic solvents at the appropriate temperature Coupling produces 2, -alkylated sugars. For example: RiMgBr / TiCU or WMgBiVCeCh can be used as described by Wolfe et al., 1997, J. Org. Chem. 62: 1754-1759. Alkylated sugars can be protected by O: \ 88 \ 88427 D0C -65- 200423945 methods familiar to those skilled in the art, if necessary, protected with appropriate protecting groups, preferably fluorenyl, substituted alkyl Or silane groups, such as Greene et al., Protective Group in Organic Synthesis, John

Wiley and Sons, Second Edition, Teaching in 1991. The protected sugar, if necessary, can then be coupled to the throat or by methods well known to those skilled in the art. Dense σ test basis, such as T〇wnsend Chemistry of

Teaching in Nucleosides and Nucleotides, Plenum Press, 1994. By way of example, acidified sugars can be dissolved in a suitable solvent at a suitable temperature, such as tin tetrachloride, titanium tetrachloride, or trimethylsilyhriflate coupler to Shixiyan test group. Alternatively, the halo sugar can be coupled to a silylated base in the presence of trimethyl si lyltri flat e. The following Scheme 1 illustrates an alternative synthesis method of a protected sugar coupled to a base 'which is a carbon atom instead of a nitrogen atom attached to the base. Scheme 1: Alternative sugar synthesis and coupling

The production of a sugar in the above scheme 1 can start from the commercially available D-nuclear bran, by

Mandal S R ^ ^ Temple people, Synth. Commum ·, 1993, 9, p. 1239

O: \ 88 \ 88427.DOC -66- 200423945. Protecting hydroxyl groups to form b sugars is described in WiUy, DR et al., Tet. Lett., 1990, 31, p. 4787. The preparation of c ^ d sugar is based on the method described in Carbohydr. Res., 2001, 33, p. 165 and the method described herein. R in the e sugar may be hydrogen, an alkyl group, a substituted alkyl group, a dilute group, a substituted alkenyl group, an alkynyl group, or a substituted alkynyl group. Particularly preferred r groups are methyl, trifluorofluorenyl, alkenyl and alkynyl. 6 Sugars are prepared by using a modified Grignard reaction in RMgBr or other suitable organometallic reagents as described herein (no titanium / fluorene required). Finally, the preparation of the i-sugar used in the subsequent puppet reaction was performed using the same protection method as the above-mentioned b-sugar. Lithification is described in Seel a17. Subsequently, any nucleosides can be protected by methods known to those skilled in the art, such as Greene et al., Protective Group in

Organic Synthesis, John Wiley and Sons, Second Edition, Teaching in 1991. In a specific embodiment, the 2, -C-branched ribonucleoside system is desired. 2 · Linear method: modification of pre-formed nucleosides The key starting material for this method is appropriate substituted nucleosides with 2, _〇1 ^ and. The nucleoside can be purchased or prepared by any known means, including standard coupling techniques. The nucleoside may be protected with an appropriate protecting group, if necessary, preferably with a fluorenyl group, a substituted alkyl group, or a silane group, such as

Greene et al., Protective Group in Organic Synthesis, JOE: n

Wiley and Sons, Second Edition, Teaching in 1991. Properly protected nucleosides can be oxidized to compatible sugars at a suitable temperature by dissolving in a compatible solvent and a suitable oxidant. Possible oxidants are, for example L ··

O: \ 88 \ 88427.DOC -67- 200423945

Dess Martin reagent, dissolved in DMS〇 AC20 + dcc, 5 free oxidized d (DMS〇, chloracetone 'triethylamine), cut ⑽ reagent (mixture of chromic acid and sulfuric acid), CoUins, s reagent (dipyridine Cr (VI) oxide), corey, s reagent gas chromate) &quot; specific dicomplex, acid dicomplex, potassium short acid, Mn〇2, tetra Ruthenium oxide, a phase transfer catalyst, for example: chromic acid or permanganate supported on a polymer, pyridine. Determination, h. Ammonium molybdate, NaBKVCAN, lutetium dissolved in H〇Ae, copper ore, copper oxide, thunder = acetic acid free, Meerwin_p〇ndr〇f-Verley reagent (with the first class of another class Aluminum tributoxide) and N-succinimide bromide. Coupling an organometallic carbon-containing nucleophile such as: Linolin formula, organolithium, lithium dialkyl copper sulfide, or RLSiMe3 dissolved in TBAF with a suitable aprotic solvent at the appropriate / m degree To produce a suitably substituted nucleoside. The nucleosides can then be protected by methods familiar to those skilled in the art, such as Greene et al., Protective ^ 〇 叩 沁 〇 哪 仏

Synthesis, John Wiley and S., 2nd Edition, 丄 &quot; ^ 不彰 ^ ο In a specific embodiment, 2, the heart branched ribose nuclear bitter system is as desired. In another embodiment, L_epimer is the desired one. Therefore, _, which can correspond to the L_ epimer of the present invention, can be started from the ㈣ nucleoside L-epomer, and the general method for preparing B · 3, C-branched ribonucleosides according to the same general method as described above. Synthesis of i, -C-branched ribonucleosides with the following structures:

O: \ 88 \ 88427.DOC -68- X200423945 R2

OH OH la W〇

OH OH lb where R, R2, W, X, Y, and z, such as μ, +, and A e do not have the same meanings as above, can be prepared by one of the following general methods. 1. Convergence method. Glycosylation of nucleobases with appropriate modified sugars. The key starting material for this method is the appropriate substituted sugars, which have 3, -OH and 3'-H, and have appropriate departures. Group (leavingg_p), for example: an acid group, methoxy group or gas, erbium, fluorine or fluorene. The sugar can be purchased or prepared by any known means &apos; including standard deviation epimerization, substitution, oxidation, and reduction techniques. The substituted sugar can be purchased again or prepared by any known means, including standard deviation epimerization, substitution, oxidation, and reduction techniques. The substituted sugar can be oxidized to 3, -modified sugar in a compatible solvent at a suitable temperature by a suitable oxidizing agent. Possible 14 daggers are, for example: Dess-Martin perylene reagent, soluble kDMSC ^ Ac20 + dcc, oxidant (DMSO, chloracetin, triethylamine), Jones reagent (mixture of chromic acid and sulfuric acid) Coiuns, s reagent (dipyridine Cr (VI) oxide), ~ Seven reagents (pyridine gas chromate), pyridinium dichromate, acid dichromate, potassium permanganate, Mη〇2 ' Ruthenium tetroxide, phase transfer catalyst, for example: chromic acid or permanganate supported on polymer, pyridine, ammonium molybdate, O: \ 88 \ 88427.DOC -69- 200423945

NaBr〇2-CAN, NaOCl dissolved in HOAc, chromite copper, copper oxide, Rauniel 'Acetic acid | Bar, Meerwin-Pondrof-Verley reagent (the third aluminum butoxide with another ketone) and N-bromosuccinimide. Coupling organometallic carbon-containing nucleophiles, such as Griner reagent, organic bell, lithium dialkyl copper sulfide or R ^ SiMe3 dissolved in TBAf, with a ketone accompanied by a suitable aprotic solvent at a suitable temperature, Produces branched sugar. For example: RMgBr / TiCl4 or RMgBr / CeCl3 can be used as described by Wolfe et al., 1997, J. Org. Chem. 62: 1754-1 759. 3, -C_branched sugar can be familiarized by them A method well known to the skilled person, if necessary, protected with a suitable protecting group, preferably with a fluorenyl group, a substituted alkyl group, or a silyl group, 卯 Greene et al., Protective Grupup in 〇rganic Synthesis, J 〇hn

Wiley and Sons, Second Edition, Teaching in 1991. The protected sugars can be coupled to purine or pyrimidine bases by methods familiar to those skilled in the art, such as T〇wnsend Chemistry 〇f

Teaching in Nucleosides and Nucleotides, Plenum Press, 1994. For example, the tritiated sugar can be dissolved in a suitable solvent with a Lewis acid at a suitable temperature, such as tin tetrachloride, titanium tetrachloride, or trimethylsilyltrinate, to couple to the sulfonated base. Alternatively, the glycosyl sugar can be coupled to a silylated base in the presence of Ktrimethylsilyltrifiate. Subsequently, nucleosides can be protected by methods familiar to those skilled in the art, such as Greene et al., Protective Group in Organic Synthesis,

John Wiley and Sons, Second Edition, Teaching in 1991. In a specific embodiment, the 3'-C-branched ribonucleoside system is a desired one or the deoxyribonucleoside system is a desired one. To get these nucleosides,

O: \ 88 \ 88427.DOC -70- 200423945 The ribonucleosides generated can be used as needed by those who are familiar with this technology, such as Greene et al., Protective Group in 〇wnic S ^ -S'J〇 hnWileyands〇ns, the second edition, the teaching of the continent § and then return to the house, 2 0H, with appropriate reduction. 2, -Hydroxy may be activated as needed to promote reduction; that is, via Barton reduction. 2. Linear method: Modification of pre-formed nucleosides The key starting material for this method is appropriate substituted nucleosides with 3, -OH and 3, -H. The nucleoside can be purchased or prepared by any known means, including standard coupling techniques. The nucleoside can be protected with an appropriate protecting group, if necessary, preferably with a fluorenyl or silane group, such as Jia et al., Protective Group m Organic Synthesis ^ John Wiley and Sons, 2nd Edition, i99i Teaching . Properly protected nucleosides can be oxidized to 3, _ modified sugars by dissolving in a compatible solvent at an appropriate temperature. Possible oxidants are, for example ^:

Dess-Martin reagent, dissolved in DMS〇 Ac2〇 + DCC, oxygen

Chemical agents (DMSO, grass 1 chloride, triethylamine), Jones reagent (mixture of chromic acid and sulfuric acid), Collins's reagent (dipyridine Cr (VI) oxide), reagent (pyridine chlorochromate), pyridine Dichromate, acidic dichromate, potassium permanganate, Mn〇2, ruthenium tetroxide, phase transfer catalysts, such as chromic acid or permanganate supported on poly characters, dr pyridine, H202 molybdenum Acid money, copper oxide, another ketone

NaBr02-CAN, NaOCl dissolved in HOAc, chromite copper, Raney nickel 'acetate, Meerwin-Pondrof-Verley reagent (third aluminum butoxide) and N-bromosuccinimide. Subsequently, the nucleosides can be protected by those familiar with this art by O: \ 88 \ 88427 DOC -71-200423945, such as Greene et al., Protective Group in Organic Synthesis, John Wiley and Sons, Second Edition, 1991 Teaching. In a specific embodiment, the 3'-C-branched ribonucleoside system is desired. Alternatively, the deoxyribonucleoside system is desirable. To obtain these nucleosides, the generated ribonucleosides can be protected if necessary by methods familiar to those skilled in the art, such as Greene et al., Protective Group in Organic Synthesis, John Wiley and Sons, Second Edition, Teaching in 1991, and then reducing 2, -OH with a suitable reducing agent. The 2, -hydroxyl can be activated as needed to promote reduction; i.e. via Barton reduction. In another embodiment of the present invention, the L-epimer is the desired one. Therefore, the L-epimer which can correspond to the present invention can be prepared from the corresponding L-sugar or nuclear bitter L-epimer as a starting material according to the same general method as described above. C. General synthesis method of purine base of formula la and pyrimidine base of formula lb Purine base of formula I-IVa and pyrimidine base of formula I-IVb used in the above condensation reaction are commercially available or can be obtained by Prepared by procedures known in the art. The preparation of purine bases of formula I-IVa was reviewed by G. Shaw in "Comprehensive Heterocyclic Chemistry", Pergamon Press, Vol. 5, Chapter 4.09, p. 449 and "Comprehensive Heterocyclic 0 ^ 11 ^ 5 讧 7" 11 '',? 6? &Amp; 111〇11-1633, ¥ 〇1.7, chapter 7.11, page 397. ~ Preparation of pyrimidine bases of formula I-IVb was reviewed in Brown D. 'The Chemistry of Heterocyclic Compounds- The Pyrimidinesff1962 and Supplement 15 1970 John Wiley and Sons, New York, Brown D., 'Comprehensive Heterocyclic 0 \ 88 \ 88427 DOC -72- 200423945

Chemistry ’’, pergamon press, νιι 7, chapter 4.09, p. 499 and K. Unheim and Ding Benneche ,, Comprehensive Heterocyclic Chemistry IΓ ,,

Pergamon Press, v0.6, chapter 6.02, p. 93. For example, a suitable purine base of the formula I-IVa can be prepared from the corresponding purine 'wherein the 2, 6 or 8 position of the purine base is an appropriate leaving group, such as: A or sulfonate Was replaced. These purine precursor-carrying leaving groups are commercially available, for example: 6-chloropurine (Aldrich Chemical Company), 2,6-dichloropurine (Aldrich Chemical Company), 2-Ga-6-amino group Purines (Aldrich Chemical Company), 8-bromoadenine (Sigma-Aldrich Co., Ltd.) or obtained by procedures known in the art. For example, the preparation of 2- and 6-chlorine-substituted sigmaine can be performed by using a chlorinating agent, such as oxychlorination, to oxidize the corresponding 2- and 6-fatyl throats respectively (Bakuni et al. , Indian J. Chem., Sect B 1984, 23, 1286, LaMontagne et al., J. Heterocycl. Chem. 1983, 20, 295), and the introduction of bromine into the 8-position of purines can be achieved by using a brominating agent such as ^ (Mano et al., Chem Pharm Bull 1983, 31, 3454) or N-Succinimide (Kelley et al., Heterocycl. Chem. 1990, 27, 1505) by direct bromination. 6-substituents are alkoxy, aryloxy, sh, alkylthio, arylthio, alkylamino, cycloalkylamino, saturated cyclic amino, azaheteroaryl, hydroxylamino, alkoxyamine The preparation of purines of hydrazine, hydrazine and alkylhydrazino can be performed by treating the corresponding 6-halogenated purines with appropriate alkoxides, thiols, amines, nitrogen-containing heterocycles, hydroxylamines and hydrazines (eg, chae et al.) , J Mfd

Chem, 1994, 37, 342; Niebch and Schneider, Z. Naturforsch. B. Anorg. Chem. Org. Chem. Biochem. Biophys. Biol. 1972, 27, 675; LaMontagne et al., Heterocycl Chem 1983 20 295; O: \ 88 \ 88427.DOC -73-200423945

Estep et al. 'J Med Chem 1995, 38, 2582). Similarly, 2-substituted purines can be prepared from the corresponding 2-i-purified purines, for example: 2-substituents can be prepared from homo, aryloxy, SH, alkylthio, arylthio * NR3R4 Corresponding 2-_purified purine treated with alkoxide, thiol or amine (for example:

Barlin and Fenn, Aust J. Chem, 1983, 3 6, 63 3; Nugiel et al., Jorg. Chem, 1997, 62, 201). Similarly, 8 • substituted purines can be prepared from the relative 8-halogenated purines'. For example: 2-substituents are alkoxy, aryloxy, SH, alkylthio, arylthio, or NR3R4. Treat the corresponding 2-bromopurine with an appropriate alkoxide, thiol or amine (Xing et al.,

Tetrahedron Lett, 1990, 31, 5849; Maiio et al., Chem Pharm

Bull 1983, 3 1, 345 4). If the 2, 6 or 8 substituent is a cyclic amine structure, the noise can be prepared from 6-aminopurine by reaction with a suitable dialkylating agent. In some cases where the 6-substituent is a nitrogen-containing heteroaryl group attached via a nitrogen atom, the pyrethroid can be converted from 6-amine by reacting with a biscarbonyl compound or a reactive derivative thereof (eg, acetal). Hypopurine preparation. For example, Pylopyryl-Bibyl can be prepared from the reaction of 6-chloropurine with 2,5-dimethoxytetrahydrofuran, such as

Estep et al., J Med Chem 1995, 38, 2582. D. Heart aryl (heteroaryl) / alkyl substituted thiol and aryl (heteroaryl) / alkyl substituted pyrimidine general synthesis method 6-aryl (heteroaryl) / alkyl substituted The synthesis of purines and 4-aryl (heteroaryl) / alkyl-substituted pyrimidines is shown in Scheme 2. — Scheme 2

O: \ 88 \ 88427.DOC -74-

200423945 As described by Wolfe et al. In J. Org. Chem., 1997, 62, 1754, the commercially available 341 was converted into a V methyl-ribose derivative 342. 6-bromopurine 2'-methyl nucleoside ( 343) was prepared using the procedure used by Wolfe et al. In J. Org. Chem., 1997, 62, 1754 to synthesize 6-chloropurine. 6-aryl substituted purin 2f-fluorenyl nucleoside 344 was synthesized with a commercially available boric acid (r_m in Scheme 2) using the procedure reported by Hocek et al., J. Med. Chem., 2000, 43, 1817. The 6-alkyl-substituted purine 2'-methyl nucleoside 344 was synthesized using a modification of the procedure reported by Bergstrom and Reday in Tet Leu., 1982, 23, 4191. O: \ 88 \ 88427 DOC -75- 200423945 Aryl-substituted 2-amino-thyrin 2, -methyl nucleoside 345 was reported by Laksman et al. In Org. Lett., 2002, 4, 1479 This procedure was modified with a commercially available boric acid (RB (OH) 2 in Scheme 2). The 6-alkyl substituted 2-amino-purine 2-methyl nucleoside 345 was synthesized using a modification method reported by Bergstrom and Reday in Tet. Lett., 1982, 2 3, 4 1 91. In the same way, but using an appropriate pyrimidine base, a 4-aryl (heteroaryl) / alkyl group can be synthesized. dense. set. According to this scheme, the following nucleosides can be prepared.

O: \ 88 \ 88427.DOC '76-200423945 4 4 ηοΊ ο ^ n ^ nh2 HO OH 9- (2f-C-methyl-β-D-ribofuranosyl) -6-phenyl-2-amino Purine 5 D ^ CN HOnoW HO OH 9- (2'-C-methyl-β-D-ribofuranosyl) -6- (3-cyanophenyl) -threon 6 o HO OH 9- (2'- C-methyl-β-D-ribofuranosyl) -6- (pyridin-3-yl) -purine 7 Oo &lt; ^ χχ cut N human% HO OH 9- (2'-C-methyl-β -D-ribofuranosyl) -6- (benz [b] thiophenyl-3-yl) -2-amino group 8 HO OH 9- (2'-C-fluorenyl-β-D-ribofuranose ) -6- (1H-indol-5-yl) -purine 9 HO OH 9- (2'-C-methyl-β-D-furfuryl ribosyl) -6- (naphthalene-2-yl) -Purine O: \ 88 \ 88427 DOC -77- 200423945 10 A. HO OH 9W-C-methyl-β-D-ribofuranosyl) -6- (dibenzoσfon-4-yl) -2 -Amine throat 11 cop HO OH 9- (2'-C-methyl-β-D-ribosyl) -6- (thienthan-1-yl) -threon 13 ^ Tl H0 ^ N νΛνη2 HO OH 9_ (2'-C-methyl-β-D-ribofuranosyl) -6-cyclopropyl-2-aminopurine 14 HO OH% I 9- (2f-C-methyl-β-D -Ranyl ribosyl) -6- (ethynyl) -purine 15 Η〇Ί 0 HO OH 7- (2'-C-fluorenyl southern ribosyl) -4-thiophenyl-3-yl-7Η-pyrrole [ 2,3-d] pyrimidine 16 Η0Π 0 y ^ N ^ NH2 HO OH 7- (2'-C-methyl-β-D-ribofuranosyl) -4-phenylylamine 17 flies. HO OH l- (2'-C-fluorenyl-β-D-ribofuranosyl) -4-thiobenzyl-j-yl-1 Hr ° ^ -2- 嗣 O: \ 88 \ 8S427 DOC -78- 18 HO—] 0% HO OH l- (2'-C-methyl-β-D-17 aspartame ribose) -4-benzyl-1 Η-σ dense bite-2- 嗣 19 § l- (2 * -C-fluorenyl-β-D-ribofuranosyl)-Ιχ ΗΟΠ HO OH 4- (benzo [b] thiophenyl-2-yl) -1H-pyrimidin-2-one 21 l- (2'- C-methyl-β-D-17 riboflavinyl) -H0-i HO OH 4-cyclophenyl-1H-pyrimidin-2-one 200423945 E. N6-substituted adenine and N4-substituted The synthesis of the sigma-pyramid 6-aryl (heteroaryl) / alkyl-substituted purines and aryl (heteroaryl) / synthetic pyrimidines is shown in Scheme 3.

O: \ 88 \ 88427.DOC -79- 200423945 Illustration 3 ΗΝ HO—I Ν ^ Ν

ΗΟ ΟΗ 322 ΗΝ Ν 5 = 0 ΗΟ ~, HO—I α .〇. I / 〇 、

HO ΟΗ

HO ΟΗ ΗΟ—ι _ '' Ν &quot;

ΗΟ ΟΗ 323 ΗΝ &quot;

349 351 ΗΟ—ι β Ν

ΗΟ ΟΗ 324 (^ ~ ΝΗ2

Bz &lt;

〇 〇Βζ ΒζΟ 〇Βζ 341

O: \ 88 \ 88427.DOC

ΗΟ ΟΗ ΗΟ ^ &amp; 325

ΗΟ ΟΗ 326

ΒζΟ ΟΒζ ά〇 ο 0 ΗΝ 347 ΝΗ, ΗΟ ~ ι, Κ, 〇

ΗΟ ΟΗ 352 ΗΟ— | V '〇

ΗΟ ΟΗ 327 ΝΗ, HO ~ I Ν &quot;

ΗΟ ~ ι Ν 八

CH3〇— ^

ΗΟ ΟΗ ΗΟ ΟΗ ΗΟ ΟΗ350 328 -SO-329 200423945 9- (2f-C-methyl-β-D-σ-ribofuranosyl) -6-methylthio-. Polinate 49, 9- (2-C-methyl-β-D-riboflavinyl) -6-methylthio-sigma sigma sigma 347 and 9- (2'-C-methyl-β- D-ribofuranosyl) -6-methylthio-adenine 350 is synthesized by, for example, R. Harry-O'kuru, J. Smith and M. Wolf in J. Org. Chem. 1997, 62, 175 4- The description of 1759 was implemented. The methylthio-purine system uses γ-Z.

Xu, Tetrahedron, 1996, 52, 1073 7-10750; Υ-ZZ · Xu, Q · Zheng

And P. Swann, Nucleosides Nucleotides 1995, 14, 929-934 explain the steps to oxidize methylmethoxanthenyl_puran. The procedure for substituting the amine group with the vermiculite group and the trifluorenyl group can be similar to that of p. Srinastava, G. Revankar, R

Robins and R. Rousseau reported on the procedure for deoxynucleosides in j Med. Chem, 1981, 24, 393-398. 4_triazolyl-uracil and its amine substitution can be used for 2'-deoxythymus as YZ. Xu 'Q. Zheng and P. Swann, J. Org. Chem. 1992, 57, 3 83 9-3 845 The description of pyrimidine is implemented. The bromination of purine nucleosides can be carried out as described in J. Gerster et al., J_ Org · chem. 1968, 33, 1070-1073.

9- (2'-C-fluorenyl-β-D-ribosyl) -N-(2- -methylaminoethyl) -glandular D-Furamiole) -Nό- (2-aminoethyl) adenine

9- (2’-0 · methyl-β-D-sweet ribosyl) -Νό- [2 · (3Η-indol-3-yl) ethyl] adenine

O: \ 88 \ 88427.DOC -81-200423945

25 rUNH2 H0—1H NN HO OH 9- (2'-C-fluorenyl-β-D-ribofuranosyl) -6- [2-Amino-Epiyl-debiloxan-l-yl)]- Throat 26 Hfy, 2 iV HO ~ i N ^ O HO OH 1- (2LC-methyl-β-D-ribofuranosyl) -N4- (aminocarbonylamido) -cytosine 27 0 HN J HO OH l- (2'-C-fluorenyl-β-D-ribofuranosyl)-N4-[(pyridyl) -methyl] cytosine 30 NHj &quot; ~ ^ N &gt; v ^ m HN Nf Ύ N eNi6H 9 HO—η N ^ N HO OH 9- (2Ά-fluorenyl-β-D-ribofuranosyl) -N6-[(adenine-yl) -aminoethyl] adenine 31 OH A: NH &lt;^; HO—i N eight N% HO OH 9- (2, C-methyl-β-Ο- ^ 0 ^ ribosyl) _ #-[(benzene-3,4,5-triol) -fluorenyl ] Adenine 32 h2nV ^ &gt; NH ^ = N HO— | N eight N% HO OH 9- (2'-0fluorenyl-β-D-furfuribosyl) -N6- [l-aminocarbonyl- 2- (3Η-Indol-3-yl) -ethyl] adenine SO: \ 88 \ 88427 DOC -82- 200423945 33 HO-1 N ^ N HO OH 9- (2'-C-methyl-β -D-ribofuranosyl) -6- (1,3,4,9-tetraaza-0-carboline-2-yl) throat 34 (V HO—i HO OH l- (2'-C- Methyl-β-D-ribofuranosyl) -N4- [l-aminocarbonyl-2- (3H-indol-3-yl) -ethyl] cytosine ^ I 35; ψ; NH NH Hon 〇 ^ 0 HO OH l- (2f-C-methyl-β-D-ribofuranosyl) -4- (pentafluorophenyl-hydrazino) · pyrimidin-2-one 37 OH ixrc? H. Resources HO OH 1-(2'-C -Methyl-β-D-ribofuranosyl) 4- [4- (3,4-dihydroxy-syl) -6,7-dihydroxy-3,4-dihydro-1H-isoquinoline- 2-yl] -pyrimidin-2-one 38 HO-, 〇 ^ 0 HO OH 1K-fluorenyl-β-D-ribofuranosyl) -N4- [2- (3H-indol-3-yl) -ethyl ] Cytosine 39 ~ NH: HN ^ 〇C-〇HO OH l- (2'-C-methyl-β-D-ribofuranosyl) -N4- (2-aminoethyl) cytosine : \ 88 \ 88427.DOC -83-200423945

40 〇γΝΗ2 hnV Λ HO—! NO HO OH 1-(2'-C-methyl-β-D-ribofuranosyl) -N4- (aminocarbonyl-isopropyl-methyl) cytosine 00 .hV HN 〇κ 丨 丄 9- ( 2'-C-fluorenyl-β-D-ribofuranosyl)-53 HO— N ^ N N6-{[(3H-indol-3-yl) -acetic acid] -hydrazine} adenine HO OH 54

9- (2T-methyl-β-D · ribofuranosyl) -Νό- [2- (5-fluoro-benzimidazol-1 -yl) -ethyl] adenosine 2Η Ν «Ν. 55 HO -

HO OH

(/ N1 ji N eight N 9- (2'-C-fluorenyl-β-D-ribofuranosyl) -6-hydrazino-purine 56

Methyl-β-D-ribofuranosyl) -N6- (2,2,3,3,3, -pentafluoropropyl) purine O: \ 88 \ 88427.DOC -84- 200423945 57 0 &lt; / NY ^ n H. Fei eight '' HO OH 9- (2'-C-fluorenyl-β-D-ribofranosyl) -6-pie bite-1 group) mouth Yin 106 Η A HN Η0Π 〇i HO 〇H 9- (2 '-C-f-based-β-D-ribofuranosyl) -6-p- (1H-imidazolyl) -ethyl] purine 107 ho ^ oh 9- (2'-C-methyl-β-D -Ribofuranosyl) -6- (acridinyl) purine 108 QHolv N HO OH 9- (2'-C-methyl-β-D-ribofuranosyl) -6- (° Bilobit -1-yl) purine 110 </ NxV H〇1 ° JN 〇H (TC-fluorenyl-β-D-ribofuranosyl) -hypoxanthine 112 ΗΠΠi HO 〇H 9- (2'- C-methyl-β-D-ribofuranosyl) -6-fluorenylhydrazinopurine O: \ 88 \ 88427.DOC -85-200423945

According to the above steps and this .. ▲, the well-known steps and their derivatives from fluoromethylfuranyl ribose groups such as Li are derived. As illustrated, 2, -C 'species can be prepared. , Including them, can be made according to the above steps and the well-known steps in this technique

Step compound as described by Devos4 et al. And Sommadossi5 et al. 1-Deazapurine can be as described in Cristalli et al. J. Med. Chem., 1987 30 (9), page 1686 or Seela, F. et al. Nucleosides Nucleotides: 1998, 17 (4), page 729 Preparation and coupling to ribofuranosyl derivatives

σ-voicing nuclear bitter can be prepared and coupled to O: \ 88 \ 88427.DOC -86-200423945 succinyl ribosyl derivatives using the methods and materials described herein.

Y Benzosialoside can be prepared and coupled to ribofuranosyl derivatives as described by Sagi, G. et al. J. Med. Chem. 1992, d (24), 4549.

(R 'ratios σ and σ can be prepared as described in Tetrahedron 1976, 32, 773 and coupled to ribofuranosyl derivatives.

The 4-pyrimidinylpyridone Sangivamycin analog can be prepared and coupled to a ribofuranosyl derivative as described in J. Org. Chem., 1972, 37, 3980 and J. Org. Chem., 1977, 42, 997.

O: \ 88 \ 88427.DOC -87- 200423945 The 2-pyrimidinylpyridone sangivamycin analog can be prepared and coupled to a ribofuranosyl derivative as described in j. Org. Chem., 1977, 42, 997.

The cardiopyrimidin pyridone Sangivamycin analog can be prepared and coupled to ribofuranosyl derivatives as described in J. Org.

R10 ° dense ° fixed base. ratio. A ketone analog can be prepared and coupled to a ribofuranosyl derivative as described in Chem. Pharm. Bull., 1968, 16, 1076 and J. Org. Chem.

A pyridinyl-tetrahydropyridine can be prepared and coupled to a fructosyl derivative as described in Biorog. Khim., 1979, 5, 1369.

Q

O: \ 88 \ 88427 D0C -88- 200423945 Furan pyrimidine (and tetrahydrofuran pyridine) can be as described in J. Med. Chem., 1983, 26, 661; J. Org. Chem., 1983, 48, 1 854; and J Med. Chem., 1985, 2 8, 1679 was prepared and coupled to a ribofuranosyl derivative.

Pyrazoles can be prepared and coupled to ribofuranosyl derivatives as described in Chem. Ber., 1981, 114, 1610 and J. Med. Chem., 1983, 26, 1601.

R2〇

. Pyrimidine can be prepared and coupled to a ribofuranosyl derivative as described by Liebigs Ann, Chem., 1983, 1576.

three. A pyrimidine can be prepared and coupled to a ribofuranosyl derivative as described in J. Heterocycl. Chem., 1971, 8, 237 and J. Carbohydr. Nucleosides Nucleotides, 1976, 3, 281. O: \ 88 \ 88427.DOC -89- 200423945 〇

It can be determined as Nucleosides Nucleotides, 1989, 8, 1345 and Chem,

Bedch, 1974, 107, 3377 describes the preparation and coupling to ribofuranosyl derivatives. 〇

° Pyridine C-nucleosides can be prepared by coupling ribofuranosyl derivatives to various test groups, such as Angew. Chem. Int. Ed. Engl., 1996, 35, 1968, and 1 ^ 1 ¥. 31 ^ 111. People (^ &, 1996, 79, 702-709).

Q I

° The specific hydrazone diaza-C-nucleosides can be prepared by coupling ribofuranosyl derivatives to various motifs, such as j. Heterocycl. Chem., 1976, 13, 175; J.

Heterocycl. Chem., 1976, 13, 1305; J. Heterocycl. Chem., 1980, 17, 1435; J. chem., 1977, 42, 109.

O: \ 88 \ 88427 DOC 200423945 9-deazapurine C-nucleoside can be prepared by coupling ribofuranosyl derivatives to various bases, such as J. Chem., 1977, 42, 109; Chem. Ber. , 1968, 101, 41; Tet · Lett "1981, 21, 1013; J.〇i * g. Chem. 1967, 32, 1 825; J · Heterocycl · Chem ·, 1978, 1 5, 353; Tet. Lett ·, 1981, 22, 25, Tet · Let ·, 1986, 27, 815; and J. Med. Chem ·, 1990, 33, 2750.

Indole nucleosides can be prepared by coupling ribofuranosyl derivatives to various

Bases, as described by Yokoyama, M. et al., J. Chem 1996, 2145.

Effectiveness, testing and administration The present invention provides compounds having antiviral activity, including anti-hepatitis virus, and compounds that inhibit hcv virus by inhibiting participation in replication factors including:化合 私 7 允 A 4 么 #, ... compounds. Including novel anti-hepatitis C virus inhibition of HCV virus replication by inhibiting the enzymes involved in replication. . Nuclear bitterness. Compounds that can be absorbed into cells and reinhibited are also used as prodrug nucleosides.

Other compounds and treatment

O: \ 88 \ 88427 DOC -91-200423945 In general, the compounds of the present invention can be administered in an effective amount by any acceptable mode of administration for agents of similar utility. The actual amount of the compound of the present invention, that is, the active ingredient, may depend on many factors, such as: the severity of the disease to be treated, the age and relative health of the individual, the potential of the compound used, the route and type of administration, and other factor. The drug may be administered one day or more, preferably one or two times a day. Once the compounds of the general formula Ia, Ib, Ic, Π, ΠΑ, 111 or 1V are effective, they can be about 0.05 to 50 mg per kilogram of the subject's body weight per day; about 0.001 to 25 mg / kg / day is Better, about 0.10 mg / kg / day. Therefore, when administered to a 70 kg patient, the dosage range is approximately daily or even optimal. In general, the compounds of the present invention can be administered as a pharmaceutical composition by any of the following routes: oral, systemic (for example, transdermal, nasal, or suppository or parenteral ( For example, "intramuscular, intravenous or subcutaneous) administration. The preferred method of administration is oral administration using a convenient daily dose therapy, and it can be adjusted according to the condition. The type of the composition can be a tablet , Tablets, capsules: semi-solid, powdered, sustained-release formulations, solutions, suspensions, aqueducts, sprays, or any other suitable composition. Another preferred method for administering a compound of the invention is inhalation. This is an effective method for directly delivering Γ therapeutics to the respiratory tract, especially for the treatment of, for example, qi ... like or related respiratory disorders (see US Patent No. 915). The choice of formulation depends on various Factors, such as drug administration patterns and

O: \ 88 \ 88427 D0C -92- 200423945 Bioavailability of materials. For inhaled delivery, the compound can be formulated as a liquid solution, suspension, spray propellant or dry powder and loaded into a suitable formulation for administration. There are several types of medical inhalation devices-spray inhalers, metered-dose inhalers (MDI) and dry powder inhalers (Dpi). The spray device can generate a high-speed airflow to spray the therapeutic agent (formulated into a liquid type) into a mist and be brought into the breath. MDI s is typically a preparation packaged with compressed gas. At the time of flooding, the device will release the metered therapeutic agent by compressed gas, so: To provide a reliable method for delivering a set amount of reagent. A free-flowing powder that can be dispensed can be dispensed into the patient's breathing airflow during suction through this device. To achieve a free-flowing powder, the therapeutic agent can be formulated with excipients such as lactose. Quantitative therapeutic agents are stored in capsules and dispensed in each action. 〇 Recently, pharmaceutical formulations have been developed specifically for drugs with low bioavailability, which is based on the principle that bioavailability can be increased by increasing surface area, ie, reducing particle size. For example ... US Patent No. 4,107,288 states that a pharmaceutical formulation 'has particles ranging in size from 1,000 nanometers, and the active material in the sweetener is a molecular matrix supported on a cross link. on. U.S. Patent No. 5,145,684 describes the production of a pharmaceutical formulation in which the medicinal ingredient is crushed into nano particles (average particle size / 400 nanometers) in the presence of a surface modifier and sub-dispersed in a liquid medium In this way, the pharmaceutical formulation can show a significantly high bioavailability. , And is generally composed of a compound of formula Ia, Ib, Ic, π, ΠA, ⑴ or ... and at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, can assist administration and are effective for formulae la, lb, Ic, Π, ΙΙΑ,

O: \ 88 \ 88427.DOC -93- 200423945 ⑴ or IV compounds 彡 ㈣ state, liquid, semi-solid, or if the aerosol two doses can be solid excipients for those skilled in the art usually If available, the gaseous solid-drug excipients include: powder, cellulose, lactose, gelatin, malt, rice, flour, chalk 1 :, :: magnesium acid, sodium stearate, monostearate Acid / Shi Yueyue said another cause of soil-this lice sodium, dry skim milk. Liquid grime and semi-solid excipients can be selected from glycerin, propylene glycol, ethanol, and various oils, including those derived from stone; from animals, plants, or synthetics: for example: peanut oil, soybean oil, real oil, sesame oil Wait. Preferred liquids: carriers', especially for injectable liquids, including water, physiological saline, aqueous dextrose and glycerol. Compressed gas can be used to disperse the compounds of the invention in aerosol form. The inert gases suitable for this purpose are nitrogen and carbon dioxide. Other suitable medical excipients and their formulations are described in E w. Martin

Remington's Pharmacetical Sciences (Mack Publishing, 18th ed., 1990). The content of the compound in the formulation can be varied within the full range of use by those skilled in the art. Typically, the formulation may comprise about 0.01-99.99% of the total formulation. (Weight percent) compounds of formulas 13, 11), 1 (:, 11, 11, 8 and 1; [1 or IV, and the remaining ingredients are one or more suitable excipients. Preferably, the presence of the compound The amount is about 1-80 Wt%. Representative formulations containing compounds of formula la, lb, Ic, II, IIA, III or IV are described below. Examples In the following examples, the following abbreviations have the following meanings. Undefined abbreviations O : \ 88 \ 88427.DOC -94- 200423945 is generally accepted as meaning.% M 〇1 = mole percentage AcOEt = ethyl acetate μL = microliter Arg = arginine amino acid residue Boc Py = N-Boc-4-amino-l-methyl ° Bis-Hydroxy-2-lattic acid Boc = third butoxycarbonyl Boc-5-Ain = N-Boc-5-amino-called | σ 朵 -2- Boc-5-Ain-HB A-AMPS = N-Boc-5 -Amino- ° bow | Hout-2 -Weic acid (p -Tranylbenzidine methyl polystyrene) ester Boc-Py- HBA-AMPS = N-Boc-4 -amino-1 -fluorenylsigma biloba-2-endo (P-hydroxybenzylaminofluorenyl polystyrene) ester BOP = benzodisial-1-yl Oxy-tris (dimethylamino) phosphine hexafluorofiller brd = broad doublet brm = broad multiplet brt = broad triplet bs = Singlet peak Bzl = benzyl protecting group cone. =? Agro-dba = Dibenzylideneacetone DCC = Dicyclohexylcarbodiimide DCE = 1, 2-diethylethane DCM = Dichloromethane 5427 DOC -95-200423945

DCU dd DE DIAD DIC DIPEA DMAP DME DMF DMSO DP DPPA dppf dt eq · Et EtOH Fomc g Gly for a; h HBA-AMPS HBTU = N, Nf-dicyclohexyl urea = double peak of double peak = 2- (methylamine Group) Ethylamine = diisopropylazodicarboxylate = N, N′-diisopropylcarbodiimide = diisopropylethylamine = 4-N, N-dimethylaminopyridine = Dimethoxyethane = Ν, Ν-Dimethylformamide = dimethyl amine = 3- (dimethylamino) propylamine = diphenylphosphonium Si azide = 1, Γ-bis (di Phenylphosphine) ferrocene == doublet of triplet = equivalent = ethyl residue = ethanol = dimethoxymethoxy protecting group digram = glycine amino acid residue = hour = ^- Benzamidine-fluorenyl polystyrene = 0-benzotriazol-1-yl-N, N, Nf, N'-tetrafluorenyluronium hexafluoroscale salt O: \ 88 \ 88427.DOC -96 -200423945 HPLC = LC / MS = liquid chromatography / mass spectrometry Lys = Amino acid residues M = Molar concentration mM = 4 Molar concentration m = Multiplet Mef = methyl Residues

MeOH = methanol mg = milligram min. = Minute mL = milliliter

= Millimeter mmol MMT mp mp d MS for; N NMR Np Npc (Et) Npc (Me) Npc (Pr) = millimoles = monomethoxytrytil (p-anisyldiphenylfluorenyl) protecting group = Decomposition melting point = mass spectrometry = normal = nuclear magnetic resonance spectrum = 4-nitrophenyl residue = 4-stilbyl-1-ethyl-1 Η-mouth ratio 17 each-2-Wei acid residue = 4- stilbyl- 1-methyl-1Η- ° ratio σ each of 2-weileric acid residues = 4-shishoyl-1-propylhex-2-acid residue

O: \ 88 \ 88427 DOC -97- 200423945

Pfp Phe psi Py Pyr Pzl-Gu- (Boc): q rpm Rt rt st t-Bu TEA TFA THF TLC Z ν / ν ν / ν / ν BSA TMSOTf nm Dipentafluorophenyl residue = phenyl residue = Pounds per square inch = 4 -Amino-1 -methyl-1Η-° Specific Hexa-2-Weic acid residue: ° Ratio σ fixed = N, N'-bis (third butoxycarbonyl) -1Η-pyridine Azole-1 formazan: quadruple peak: revolutions per minute: retention time: room temperature: singlet peak: triplet: third butyl protecting group: triethylamine = trifluoroacid = tetrahydrofuran = thin layer color Analysis = benzyloxycarbonyl protecting group = volume / volume = volume / volume / volume = bis-trimethylsilylacetamide = tri-fluorenylsilyltrifluoromethanesulfonate = nanometer O: \ 88 \ 88427.DOC -98- RP HPLC = reverse phase HPLC NBS = N-succinimide bromide NIS = N-succinimide iodide DI = deionized NMP = N-fluorenyl σ biluo burnt powder 1 PPA = Polyacrylic acid Hex = Hexane DMEM = Dulbeco's Modified Eagle's Medium 200423945 In the NMR data, the unit of chemical shift is ppm and the unit of coupling constant (J) is Hertz (Hz) ). All melting points are uncorrected. In the following examples and procedures, starting materials and reagents can be purchased from any of Aldrich, Lancaster, Sigma, Specs, TCI, Maybridge, Frontier Scientific, and Bachem. The term "Aldrich" means that the compound or reagent used in the step was purchased from Aldrich Chemical Company (Milwaukee, WI 53233 USA); the term "Lancaster" means that the compound or reagent used in the step was purchased from Lancaster Synthesis Company (NH 03087 USA); &quot; Sigma &quot; — The word refers to the compound or reagent used in the step was purchased from Sigma (St. Louis M0 63178 USA); "Maybridge," the word refers to the compound used in the step Or reagents were purchased from Maybridge Chemical Company (Trevillett, tintagel, Cornwall PL34 OHW UK); and the term nTCIn means the compound or reagent used in the step was purchased from TCI America (Portland OR 97203) Frontier Scientific Means that the compound or reagent used in the step was purchased from Frontier Scientific O: \ 88 \ 88427.DOC -99- 200423945 (Utah, USA); &quot; Specs "means the compound or reagent used in the step Purchased from the Netherlands; and "Bachem," which means that the compound or reagent used in the step was purchased from Bachem (Torrance, California, USA). [Embodiment] The following Those mentioned in the examples are compounds and intermediates which can be used to make the compounds of the present invention. Example 1 'Methylfurfuryl ribosyl) -6 • Synthesis of 9- (2'-C-methyl U) -Synthesis of ribofuranosyl-6-bromopurine (4 丨) can be used in R · Harry-CVkurii, J. Smith, and M · Wolf J · 〇rg ·

Chem. 1997, 62, 1754-1759. Example 2 Synthesis of 9- (2'-C_methyl_p-D_ribofuranosyl) + (thiophenyl-3_yl) threonine. Toluene (10 ml) was added to a solution containing 9- (2,- C-methyl-β-D-ribofuranosyl) -6-bromothranine (41) (1 mmol), K2C03 (200 mg, ι · 5 mmol), 3 • sulfur Phenylboronic acid (1.5 mmol) and Pd (PPh3M 59 mg, 0.05 mmol) were placed in an argon-diagonal flask and the mixture was placed at 1000. Stir under argon for 8 hours. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was chromatographed on a silica gel column. The residue was dissolved in 10 ml of NH3 saturated MeOH and placed in a sealed tube at 55. (: Reaction for 12 hours. The reaction was cooled and concentrated in vacuo. The product was separated by silica gel column chromatography (chloroform / methanol / ammonia 9: 1: 05 Wv / v). Example 3 O: \ 88 \ 88427. DOC 100- 200423945 Methyl-β-D-ribofuranosyl) _n2_Isobutyridine_Uridine (42) Synthesis of 9- (2'-C-methyl-β-D-ribofuranosyl) -N2_ The synthesis of isobutyramine-bird bitter (42) can be described using the general procedures in R. Harry-O'kuru, J. Smith, * M. WolfJ. Org. Chem. 1997, 62, 1754-1759 and borrowed Separated by hplc. Example 4

Synthesis of 9_ (2 ^ C-methyl + D_ribofuranosyl) _2_amino_6_phenylpurine _Isobutyrin_guanosine (42) (1 mmol) was dissolved in dichloromethane (10 ml) in argon and 2,6-di · second-butyl-4-methylpyridine ( 3 millimoles). The solution was cooled to and trifluorosulfonic anhydride (3 mmol) was added and the reaction was warmed to room temperature. After 12 hours, the mixture was concentrated in vacuo and chromatographed on a silica gel column (ethyl acetate / dichloromethane). The product was dissolved in toluene (10 ml) and K2C03 (2%) was added.

Wide grams, 1.5 millimoles), phenylboronic acid (1.5 millimoles) and Pd (PPh3) 4 (59 mg '0.05 millimoles) and the mixture at 100 t: Stir in argon for 8 hours. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was chromatographed on a Shixi gel column. The residue was dissolved in 10 ml of NH3 saturated

MeOH was reacted in a sealed tube at 55 ° C for 12 hours. The reaction was cooled and concentrated in vacuo. The products were separated by silica gel column chromatography (chloroform / methanol / ammonia 9: 1: 0.5 v / v / v). Example 5 Synthesis of 9- (2'-C-methyl_p-D_ribofuranosyl) _pyrimidine (43)

O: \ 88 \ 88427.DOC -101-200423945 9- (2'-C-methyl-β-D-ribofuranosyl) · uracil (43) is synthesized as in R.

Hairy-O'kiiru, J. Smith, and M. Wolf J. Org. Chem. 1997, 62, 1754-1759. Example 6 Synthesis of l- (2f-C_methyl-β-D-ribofuranosyl) thiobenzyl-1H-pyrimidinone (17) 9- (2'-C -methyl-β- D-ribofuranosyl) _uracil (43) (丨 mole) dissolved in dichloromethane (10 ml) in argon and added 2,6-di-third-butyl-4-fluorenyl Attachment (3 millimoles). The solution was cooled to zero and trifluoromethanesulfonic anhydride (3 mmol) was added and the reaction was warmed to room temperature. After 12 hours, the mixture was concentrated in vacuo and chromatographed on a silica gel column (ethyl acetate / dichloromethane). The product was dissolved in toluene (10 ml) and K2co3 (200 mg, 1.5 μmol), phenylboronic acid (1.5 mmol), and pd (pph 59 mg, 0.5 mg) were added. (5 mmol) and the mixture was stirred at 100 ° C for 8 hours under argon. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was chromatographed on a silica gel column. The residue was dissolved in 10 ml of Nh3 saturated MeOH and placed in a sealed tube at 55. (: Reaction for 12 hours. The reaction was cooled and concentrated in vacuo. The product was separated by silica gel column chromatography (gas-form / methanol / ammonia 9: 1: 0.5 v / v / v). Example 7 1_ (2 '_C-fluorenyl_β_ι &gt; -furanyl ribosyl) _4 · Cyclopentyl_1H pyrimidine_2_one (21) Synthesis of 9- (2'-C-methyl-β-D-ribofuranosyl ) _Uracil (43) (1 mmol) Dissolved in dichloromethane (10 ml) in argon and added 2,6-di-third-butylmethyl ° pyridine (3 mmol) .The solution was cooled to 0 ° C and trifluoroarsonite yellow O: \ 88 \ 88427.DOC -102 · 200423945 gadolinium anhydride (3 mol) was allowed to return to room temperature. After 12 hours, The mixture was concentrated in vacuo and chromatographed on a silica gel column (ethyl acetate / dichloromethane). The product was dissolved in anhydrous THF (10 ml) and Pd (PPh3) 4 (59 Mg, 0.05 mol). Cyclopentylzinc bromide was added mol, 0.5 M was dissolved in THF) and the reaction was stirred at room temperature for 18 hours. The mixture was evaporated in vacuo and the residue was separated on a silica gel column. The residue was dissolved in 10 ml of NH 3 saturated MeOH and reacted in a sealed tube at 55 ° C for 12 hours. The reaction was cooled and concentrated in vacuo. The products were separated by silica gel column chromatography (chloroform / methanol / ammonia 9: 1: 0.5 v / v / v). Example 8 Synthesis of 9- (2'-C-methyl_β-fluorenylfurfuryl ribosyl) toromethanine (49) The synthesis of _ 曱 sulfur_sigh (49) is as described in R. Harry CTkuru, J. Smith, and M. Wolf J. Org. Chem 1997, 62, 1754-1759. Example 10 9- (2'-C-methyl-β-D-biting ribose group) _6_ [2- (111- 味 哈 _4-yl) -ethyl] purine (106) Synthetic Compound 1 06 Series As described in Example 9, step 4 was synthesized from histamine and nucleoside 5}. MS 361.45 (M + H)

Hi-NMR ^ DMSO ^): 0.8 (s, 3H, 2, -CH3), 3.25-3.45 (ιη, 4H, fluorenyl), 3.53-4.05 (m, 7H, sugar) , 5.99 (s, 1H, 1, -H), 7.48 and 9.09 (s, 1H, purine), 8.35 and 8.65 (3, 0.77 :, imidazole). Example 11 O: \ 88 \ 88427 DOC -103-200423945 9- (2'-C-methyl-pD-sweet ribosyl sulfonylaminoethyl) Synthesis of glandular (23) 7 The nucleoside ( 51) (1 mmol) was dissolved in morphine (5 ml), ethylene diamine (5 mM) was added and the reaction mixture was kept at room temperature overnight. The solvent was evaporated; the product (23) was separated by silica gel column chromatography (chloroform / methanol / ammonia 9: 1: 05. Example 12 9- (2, -C-methyl-PD · Ribosyl) _6_ [2_ (1H indole_3yl) ethyl] Synthetic compound 24 of purine (24) was synthesized from tryptamine and nuclei as described in Example 9, Step 4. MS 410.38 (M + H) H ^ NMRPMSO ,: 0.76 (s, 3H, 2, -CH3), 2.60-4.10 (m, sugar and methylene), 5.98 (S, 1H, Γ-Η), 6.80 (d, 1H, ten flowers) ), 7 4H, called Hou), 8.35 and 8.68 (s, 1H, purine), 9.02 (s, 1h, nh). Example 13 9- (2'-C_methyl-β-D- Ribofuranosyl) _6_ [Bibirolidinyl 2-methanamine-purine (25) Synthetic compound 25 is synthesized from L-proline amide and nucleoside 51 as described in Example 9 and Step 4. &quot; Human MS 380.35 (M + H) H ^ NMRCDMSO-d ^: 0.86 (s? 3¾ 2 ^ CH3)? 2.25-3.95 (m5 4H? 3 · 1〇_4 · 1〇 (ΐη, sugar and pyrrolidine) , 5.98 (s, 1H, rH), 8-35 and 8.68 (s, 1H, throat), 9.25 (s, ih, amidine).

O: \ 88 \ 88427.DOC -104- 200423945 Example 14 1- (2 ', 3', 5, _tri-〇-benzyl-2, -C-methyl-PD-ribofuranosyl) brain, pyrimidine Synthesis of (47) 1- (2 ', 3', 5, -tri-0-benzyl-2, -C-methyl-β-D-ribofuranosyl group> Urea σ dense

Synthesis of pyrimidine (47) such as R. Harry-O’kuru, J. Smith, and M. Wolf J

Org. Chem. 1997, 62, 1754-1759. Example 1 Synthesis of 1-yl) uracil (52) r, 2f, 4'-trisial (60 mmol) was suspended in anhydrous acetonitrile (20 ml) at 0 C. Slowly add phosphorus oxychloride (15 mM) with rapid stirring, and then add triethylamine (50 mmol) dropwise. The reaction mixture was stirred at 0 ° C for 30 minutes and nucleoside (47) (15 mmol) was added. The reaction was terminated with 50 ml of a saturated solution of sodium bicarbonate within 1 hour. The product was extracted with 50 ml of chloroform. The organic extract was washed with 5% sodium bicarbonate, water, dehydrated with magnesium sulfate and evaporated. The product was isolated by silica gel column chromatography (toluene / ethyl acetate). Example 16 Synthesis of l- (2'-C-fluorenyl_p_D · furan ribosylaminocarbonylcarbonyl) _cytosine (26) A nucleoside (52) (1 mmol) was dissolved in 95% pyridine ( 5 ml), glycine donutamine (5 mM) was added and the reaction mixture was kept at 55 ° C for 16 hours. The solvent was evaporated. The product (26) was separated by silica gel column chromatography (gas-form / methanol / ammonia 9: 1: 0.5 v / v / v). Example 17 O: \ 88 \ 88427.DOC -105- 1- (2'_C_methyl-β-D-furfuryl) -N4-[(^ b pyridyl) -methyl] cytosine ) Synthesis The nucleoside (52) (1 mmol) was dissolved in 95%. To pyridine (5 ml), add pyridin-1-yl-methylamine (5 mM) and keep the reaction mixture at 55 ° C for 16 hours. The solvent was evaporated. The product (27) was separated by Shixi gel column chromatography (chloroform / methanol / ammonia 9: 1: 0.5 Wv / v). Example 18 Synthesis of 2f-C-methyladenosine (50) Preparation of 2-C-methyladenosine (50) is as described in r. Harry-O’kuru, J.

Smith, and M. Wolf J. Org. Chem. 1997, 62, 1754-1759. Example 19 Synthesis of 2-C-fluorenyl-8-brookline nucleoside (28) Mole (2 ml) was added to 50 ml of water and stirred vigorously at room temperature for 3 minutes. Nucleoside (50) (5 g) was suspended in 30 ml of water and Bγ2 water was added in portions at a rate that would cause the yellowness of the reaction mixture to disappear during each addition / month. The total amount of ΒΓ2 water was 45 ml. The solid was collected by filtration and carefully washed with ice water to pH 5.5 °. The residue was recrystallized from hot water to produce 60% of the target product. Example 21 Synthesis of 5- (2-C_methyl_p_D_ribofuranosyl) _5pyrrole [3,2_midpyridylamine (80) As described on this page. Example 22

\ 88 \ 88427.DOC -106- &gt; Hydrogen-The 4-Amino-8- (2, _ (% methyl certain β h β-furfuryl ribosyl) -5-oxy-5,8- «« Synthesis of vanadyl carboxylic acid amine (81) for the preparation of the title compound can be used »The method is similar to the method of 3985 for Rizkalla7. Example 23 2,4-m (2, cardiac methyl · p_D㈣ ribosyl) Synthesis of 5-oxyl from mono-nitrogen "specific bite [2,3_d] bite_5 edge acid amine (82)

The title compound can be prepared by methods similar to those described on page 999 of Anderson 8. Example 24 4-Amino_8- (2'-C_methyl_p_D_ribofuranosyl) _inoxy_7,8_dihydro_ Howl [2,3- (1) pyrimidine_5_ Synthesis of the title compound of the amidine carboxylate (83) can be performed by a method similar to that described on page 1000 of Anderson 8. Example 25

2,4-diamino_8- (2f-C-methyl_β-0-ribofuranosyl) -7 · oxy_7,8_ dihydro-pyridine [2,3-d] pyrimidine-5- The synthesis of the title compound of the amidine carboxylate (84) can be performed by a method similar to that described in Anderson 8 1000. Example 26 8- (2'-C-methyl-β-D-bite ribose) -2-Palanyl-4,5-dioxy-3,4,5,8-tetrahydro-pyridine [ Synthesis of 2,3_d] pyrimidinecarboxylic acid amidoamine (8S) 1. 2-4,5-dioxy · 3,4,5,8-tetrahydropyridine [2,3-d] pyrimidine, & Synthesis of Ethyl Acetate O: \ 88 \ 88427.DOC -107- 200423945 As described in Beta · Rizkalla and AD Broom, J. Org. Chem ·, 1972, 37 (25), 3980-3985 Synthesis 4 , 5-Dioxy-3,4,5,8_tetrahydro_pyridine [2,34] pyrimidine-6_carboxylic acid ethyl ester. Step 2. 8- (3,4-bis-benzyloxy_5_benzyloxymethyl_3_methyl_tetrahydro_furan_2_yl) _2,4,5 · monooxy_3, 4,5,8_ Tetrahydro specific bite [2,3_d] Synthesis of ytterbium-6 diethyl etherate The product (0.2 g, 0.71 mmol) from step 1 above was dissolved in anhydrous acetonitrile. ( 3.5 ml) of the suspension, BSA (0.385 ml, L56 mmol) was added and the mixture was refluxed under argon for 30 minutes. The resulting solution was cooled to room temperature, and tetra-o-benzylmethyl heptane (0.32 g, 0.55 mmol) dissolved in anhydrous acetonitrile was added, and TMS 0Tf (0.5 13 ml, 2.84 millimoles). The resulting reaction mixture was heated at reflux for 2 hours. The reaction was allowed to cool to room temperature and then concentrated in vacuo to an oily residue. The oily residue was dissolved in EtOAc and washed with 1x saturated> ^ 11 (: 03) and the aqueous layer was re-extracted 2x with EtOAc. The organic layers were combined, washed with h20, brine, and NajO4 Dehydrate and concentrate in vacuo. The crude reaction was purified by silica gel chromatography with 10% methanol in dichloromethane. The appropriate fractions were collected and _ strips were issued in dioxane. Bubble to give 0.406 g (100%) of the title compound. Step 3. 8- (3,4-dihydroxy-5_hydroxymethyl-3_methyl-tetrahydro-furan_2_ Synthesis of 2-methylthio-4,5_dioxy_3,4,5,8_tetrahydro-pyridine [2,3_d] pyrimidinecarboxylate amine (0.2) G, 0.270 mmol) in 40 ml of liquid ammonia and stirred at room temperature for 48 hours. The liquid ammonia was evaporated and all

0 \ 88 \ 88427 DOC -108- 200423945 The yellow oily residue was purified by HPLC using 0-20% buffer B at a flow rate of 10 ml / min. Buffer A _ ..% triethylammonium acetate aqueous solution, buffer B-0.1% triethylammonium acetate iCH3cN solution. The nucleoside-containing fractions were collected and evaporated in vacuo and co-evaporated to dryness with pure wine to obtain 27 mg (25%) of the desired nucleoside. MS: 397 · 13 (Μ-Η) H1-NMR (DMSO-d6): 0.8 (s? 3H, 2f-CH3) 5 2.5 (s? 3H? 2'-CH3), 3.0-4.0 (m, 4H, sugar), 5.0-5.5 (m, 3H, -0H), 6.7 (s, 1H, l'-H), 7.4 (s, 1H, -Ar), 8.8 and 9.2 (s, 2H, -NH2). Example 27 8 "2'-C_methyl_P_D_ribofuranosyl) _8H_e than pyridine [2,3-d] pyrimidine_2,4_ dione (86) Synthesis of the title compound can be similar to Rizkalla7i The method described on page 3979. Example 28 8- (2f-C_methyl_p_D —ribofuranosyl) _1Ηιι 比比 丨 2,3_priming pyrimidine_2, cardiodione (87) Synthesis of the title compound can be similar to Rizkalla7i 3979 As described on this page. Example 29 8 · (2_C_methyl4_D_ribofuranosyl) -4-methylthio_5,6,7,8_tetrahydro- &quot; Bipyridine [2,3-d] pyrimidine (88) The synthetic title compounds can be prepared by methods similar to those described in Biorog · Khim ·, 1979, 5, 1 369. Example 30

〇. \ 88'88427.DOC -109- 200423945 3- (2'-C-methylfurfuryl ribosyl) _6_methyl_3,7a_dihydro-1H_bite% formic acid [2,3-d] Synthesis of pyrimidin-2-one (89) The title compound can be prepared by a method similar to that described on page 666 of De Clercq12. Example 31 3- (2'-C-methylfurfuryl ribosyl) _3,5,6,7a_tetrapyrene · 1H_furanyl [2,3-d] pyrimidine_2_one (90) Preparation and preparation of the synthetic title compound can be performed by methods similar to those described on page 1680 of Griengl14. Example of r- (2'-C-methyl) 33 ribofuranosyl_4_methylthio_7H-pyrrole [2,3-d] pyrimidine (92) can be synthesized by analogy to Seela 17 on page 15 85 And method for the preparation of W compounds Example 34 P_D_ribofuranosyl) -4-methylthio-1H-pyridine [2,3-d] This can be done in a manner similar to that described on Seela 17, 1 5 85. 3- (2'cardiomethyl, the title compound and its methods. Example 35 Synthetic preparation of ribofuranosyl) -3Η- [1,2,4] triazole [l, 5-a] enone (94) By similar to that described on page 239 of Winkley 18

O: \ 88 \ 88427.DOC -110- 200423945 Example 36 3-methyl-8- (2'-0methyl_β_ϋ_ribofuranosyl) _2_methylthio-3H, 8H_pyridine-4,7 -Synthesis of diketone (95) The title compound can be prepared by a method similar to that described on page 2875 of Hawkin 39 et al. Example 37 Synthesis of 5- (2'_C-methyl-β-D · ribofuranosyl) _pyridine · 2-ylamine (96) The title compound can be prepared by substituting it as shown in Figure 1 The sex f sugar is coupled to a test base prepared by method 22 · 23 similar to that previously described. Example 38 Preparation of 5_ (2'_C-methylfuranosylpyridyl-2-ylamine (97)) The preparation of the title compound can be performed by coupling the alternative f sugar prepared to The test group was prepared by a method similar to that described above. 8 (2 C_methyl U · ribofuranosyl) -pyrazole [1,5 ^] [1,3,5] triazin-4-yl The synthesis of amine (9 8) and the preparation of the title substance can be prepared by the following explanation:

The 1'f sugar is coupled to A soil prepared by a method similar to that described by Tam25 et al. On page 1307. Other pyrazole triazine C-nucleosides, for example: Compound 9 (and 100 disks are available) ^ Technology 24_27 uses this glycocalyx and other well-known examples 41

O: \ B8 \ 88427.DOC -111-200423945 9- (2'-C-trifluoromethyl_p_D_sucrose ribosyl) n6 (2aminoethyl) adenine (62) Preparation can be performed by methods similar to those described by u35 et al. Trifluoromethylated sigmatofuranosyl derivatives can be coupled to various test groups. ❹: Compounds 63, 64, 66 and 67 can be prepared by the techniques described herein and methods well known in the art. . Example 42 1- (2'_C-vinylpyrene rabbit ribosyl) _1] 0 [_benzobenzoxazole (synthesized title compound can be prepared by a method similar to that described by Sagi38 et al. And illustrated herein Ethylene can be coupled to a variety of bases, such as compound 68. Preparations can be prepared by the techniques described herein and methods well known in the art. Example 43 1 (2 C Ethynyl squeezable ribosyl) _113 [_ Benzimidazole (79) Synthesis The title compound can be prepared by a method similar to that described by Sagi38 et al. And described herein. Ethyl can be lumped. Derivatives are coupled to various bases, for example, compounds 74-76 can be prepared by the techniques described herein and methods well known in the art. Example 44 1_ (2-C_methyl · β · ϋ · riboflavin The basic compound of the compound _4 and ^ 4 (iq4) can be prepared by a method similar to that described by Jia-43 and others. The preparation of other nuclear cores can be achieved through pure ribose sugar biological coupling O: \ 88 \ 88427.DOC -112 · 200423945 to various indole, for example: Preparation of compound 105 The technique described in the method and the method well known in the art 43. Example 45 9 (2-methyl-ribofosyl) -6- (11 yacridyl) sigh (107) of the synthetic compound 107 series Synthesized from azetidine and nucleoside 51 as described in Example 9, Step 4. MS 323.32 (M + H) H1-NMR (DMSO-d6): 0.76 (s, 3H? 2J-CH3) 9 3.25 -3.45 (m? 4H? Arylene), 3.10-4.10 (m, sugar and acridine), 5.98 (s, 1H, Γ-Η), 8.35 and 8.68 (s, 1H, purin). Examples 46 9- (2, (!! _ fluorenyl_0-〇_sucrose ribosyl) _6_ (| 1 biloxo-1_yl) whine (108) synthetic compound 10 8 is as in Example 9 The description in step 4 was synthesized from bilobit and nucleoside 5 1. MS 336.32 (M + H) H ^ NMRpMSO-de): 0,77 (s, 3H, 2'-CH3), 2.00 (m, 4H, α-pyrridine), 3.43-4.14 (m, sugar and pyrrolidine), 5.98 (s, 1H, Γ-Η), 8.36 and 8.72 (s, 1Η, purine). Example 47 9_ (2f-C- Methyl-β-D · furfuryl ribosyl) _6_ (tripidine_1_yl) Synthetic compound 57 (7) is as described in Example 9, step 4 from pyrrolidine to nuclear 5 1 0 . \ 88 \ 88427 DOC -113-200423945 Synthesis. MS 350. 37 (M + H) H ^ NMRPMSO-c ^): 0.78 (s, 3H, 2 '-(: Η3), 1.62 (m, 6H, piperidine), 3.43-3_88 (m, sugar and piperidine), 4.01-4.02 (d, 1H, 3, -H), 5.97 (s 1H, Γ-Η), 8.28 and 8.58 (s, 1H, purine). Example 48 9_ (2f-C-methyl-β-D. Furfuryl ribosyl via aminoamino group) sigh (109)

And 9- (2 ^ C-fluorenyl-β-D-ribofuranosyl) _hypoxanthine (11〇) Sulfofluorenyl 51 (0.2 mmol) was dissolved in 3 ml of absolute alcohol Add an amine solution (as prepared by PKChang, J. Med. Chem., 1965, 8, 884) (2 mM) and reflux the mixture for 1 hour and concentrate in vacuo. The residue was dissolved in DMF (5 ml) and purified by HPLC using 20-100% B at a flow rate of 10 l / min over 30 minutes. A-0.2% triethylammonium acetate aqueous solution, buffer B-0.2% triethylammonium acetate CH3CN solution.

The mixture containing the protected nucleosides 109 and 110 was separated and evaporated, dissolved in MeOH and HCl / MeOH at 0. (: Treated for 5 minutes and precipitated a mixture of nucleoside 109 and 110 (3: 1) with ether. The mixture was separated by HPLC at 0-20% B within 30 minutes, and the buffer system was as described above. Related The fractions were combined, evaporated, co-evaporated with water (3 X 10 mL), dissolved in methanol (1 mL) and precipitated with ether (35 mL) to give a white solid. 9- (rC-fluorenyl D-furan Ribosyl) -N6- (hydroxyamino) thyrine (109) MS: 283 · 19 (M + Η),

Xmax 26 1.5 nm O: \ 88 \ 88427.DOC -114- 200423945

Hl-NMR (DMSO-d6): 0.68 (s5 3H, 2f-CH3)? 3.81-4.04 (m, 2H? 5, -H), 4.07 (t, 1H, 4, -H), 4.17-4.20 (d , 3'-H), 6.06 (s, 1H, 1, -H), 8.06 and 8.53 (s, 1H, purine). 9- (rC-methyl-β-D · ribofuranosyl) -hypoxanthine (110) MS: 298.38 (M + H) 5 λϊηαχ 249.5 nm H ^ NMRPMSO-c ^): 1.09 (s, 3H, 2 '-CH3), 3.85-4.24 (π, 3H, sugar), 6.16 (s, 1H, Γ-Η), 8.21 and 8.62〇, 1H, hypoxanthine). Example 49 Synthesis of 9_ (2'_0 methyl sucrose ribosyl) _6_methoxyamino group (in) Compound 111 was synthesized as described in Example 9 and step 4 from methoxy amine and nuclear bitter 51. MS 312.41 (M + H) H! -NMR (DMSO &lt; d6): 0.91 (s5 3H? 2f-CH3) 5 3.82-4.04 (m5 7H5 sugar), 3.95 (3, 0-0: 113), 6.01 (5 , 111, 1, -11), 8.22 and 8.88 (3,1115 adenine). Example 50 9- (2'-C_fluorenyl-β-D · ribofuranosyl) -6-hydrazinopurine (55) Synthesis of nucleoside 55 is as described in Example 9, step 4 by suinonyi derivative 51 and Hydrazine Synthesis. MS 297.3 1 (M + H) H'-NMRCDMSO-dG): 0.8 (s5 3H5 2f-CH3)? 3.80-4.00 (m5 7H5 sugar), 6.02 (3, 1 ^ 1, 1'-11), 8.47 and 8.77 (3,1 ^ purine).

O: \ 88 \ 88427.DOC -115- 200423945 Example 51 9- (2 '-(: _ methyl-fen-0-ribofuranosyl) -6- ~ methylhydrazinopurine (112) synthetic nucleoside 112 is derived from sulnonyl derivative 51 and hydrazine as described in Example 9, Step 4. MS 313.72 (M + H)

Hl-NMR (DMSO-d6): 0.68 (s, 3H? 2f-CH3) 5 3.80-4.00 (m5 7H, sugar), 3.88 (s, N-CH3), 5.90 (s, 1H, Γ-Η), 7.68 and 8.21 (s, 1H, purin). Example 52 9- (2, _C-methyl-β-D-ribofuranosyl) -6- (3,6_dihydro_2H-pyridin-1-yl) purine (113) Synthetic compound 113 is as in Example 9 The description in step 4 was synthesized from 3,6-dihydropyridine and nucleoside 51. MS 348 · 32 (M + Η) rf-NMRpMSO-dS): 0.88 (s, 3Η, 2, -CH3), 3.10-3.40 (m, 6Η, CH2-tetrahydropyridine), 3.80-4.00 (m, 7H , Sugar), 5.80-5.98 (m, 2H, CH-tetrahydropyridine), 6.01 (s, 1H, Γ-Η), 8.23 and 8.48 (s, 1H, purine). Example 53 9- (2'-C-fluorenyl-β-D-ribofuranosyl) -6- (3,4-dihydro-111-isoquinolin-2-yl) purine (114) It was synthesized as described in Example 9, Step 4 from 3,4-dihydroisoquinoline and nucleoside 51. MS 398.53 (Μ + Η) O: \ 88 \ 88427.DOC -116- 200423945

Hl-NMR (DMSO-d6): 0.88 (s? 3H, 2f-CH3) 5 2.25-2.31 ^ 2.90-3.00 (m? 2H, fluorenyl), 3, 10-3, 40 (m, 6H , CH2-tetrahydropyridine), 3.80-4.00 (m, 4H, sugar), 5.20-5.35 (m, 3H, OH, sugar), 6.01 (s, 1H, Γ-Η), 7.16-7.25 (m, 4H , Benzene), 8.27 and 8.53 (s5 1H, purine). Example 54 Synthesis of 9- (2f-C-methyl-β_0_squeezable ribosyl) -6_ (l, 3,4,9-tetrahydro_β_carbolin-2-yl) purine (33)

Compound 33 was synthesized from 3,4-dihydroisoquinoline and nucleoside 51 as described in Example 9, Step 4. MS 437.43 (M + H)

Hi-NMRCDMSO-dS): 0.89 (s, 3H, 2, CH3), 2.98 (m, 2H, methylene), 3.40-4.00 (m, tetrahydropyridine sugar and methylene), 4 05 (d, 3, -Η), 6.05 (s, 1H, Γ-Η), 6.90_7.05 (m, 2H, aryl), 7.29-7 · 40 (ιη, 2H, aryl), 8 32 and 8-65 (s, 1Η, purine) 10.99 (s, 1Η, ΝΗ). Example 55 Synthesis of 7- (2'-C_methylfurfuryl ribosyl) -4_ via aminoamino ratio [2,3-d] Φ Pyrimidine (117) · Steps 1 · 7- (2T_C -Methyl-β-D-sucrose ribosyl) _4_gas-orbilo [2,3-d]; The synthesis of pyrimidine (141) is as described in WO 02/057287, p 27-30. Step 2. 7- (2T-C-methyl-ribose ribosyl) -4-merylamino- «Bilo [2,3-d] pyrimidine (117) The nucleoside 141 (300 mg, 1 mmol) Mol) was dissolved in absolute alcohol (10 ml), a hydroxylamine solution (as prepared by PKChang, J. Med. Chem., 1965, 8, 884, 5) (10 mM) was added and the mixture was refluxed for 1 hour Reconcentrate in vacuo at O: \ 88 \ 88427 DOC -117- 200423945. The residue was purified by HPLC using 0-30% B at a flow rate of 10 ml / min for 30 minutes. A-0 · 2% triethylammonium acetate aqueous solution, buffer solution B-0.2% acetic acid and diethyl ether solution. The relevant fractions were combined, evaporated, co-evaporated with water (3 x 10 ^: liter), dissolved in methanol (1 mL) and precipitated with ethyl scale (35 mL) to give 11 7 white solid. Example 56

Methylfuryl ribosyl) -4-methoxyamino group pyrrole [2,3-d] pyrimidine (118) Synthesis of nucleoside 118 was prepared from nucleoside 141 (Example 55, step 丨) with methoxyamino group Substituted via amine. Example 57 The synthesis step of l- (2f-C-methylcresyl ribosyl) _4_ several aminoamino groups «specific [3,4-dj pyrimidine (120) is called 1, 2, 3, 5-di- 〇_benzyl_2'_methyl_1,5-dihydropyridine [3,4-d] pyridin-4-one (142) Synthesis of nucleoside 142 is as described in Example} *, Substitute 6-bromopurine to 1,5-dihydro- ° ratio 嗤 [3,4- (1] continued-4-one. _ Step name 2. 2,3,5_dibenzyl_2 ' _Methyl gas ratio [3, 'd], Synthesis of bite w-4-one (143) · Dissolve nucleoside 142 in toluene, add 10 equivalents of sociC2 solution and mix the mixture at 50 Heated at ° C for 2 hours. The solvent was evaporated in vacuo and the residue was co-evaporated with toluene and purified by silica gel flash chromatography (toluene_ethyl acetate, 9: 1 Wv). The relevant fractions were evaporated and dissolved. In 10 ml of methanol and add 5 ml of NH4OH. The reaction mixture was left at room temperature overnight and O: \ 88 \ 88427.DOC -118- 200423945 Example 5 5 'Step 2 Description The separation of the title nucleoside by HPLC. Step 3 1 • Synthesis of methyl-β-D-ribofuranosyl) _4_hydroxyamino group, synthesis of biazole [3, 'd] pyrimidine (12〇)' in step 2 Saying The core 143 is converted into bitter nucleation Pu 120. Example 58 1 (2 methyl_β-β_ribofuranosyl) _4_methoxyaminopyrazole [3,4_d] Synthesis of pyrimidine (119) Nucleoside 119 was prepared from nucleoside 143 (Example 57, step 3) Substituting hydroxylamine with a methoxyamine group. Example 59 Synthesis of 7_ (2'heart methyl_p_D_ribofuranosyl) _5-qi-4_hydroxyamino group ^ pyrrole [2,3-d] pyrimidine (123) Synthesis of nuclear bitter 117 (0.1 milli Mol) was dissolved in dmf (0.5 ml) and cooled to 0 ° C. Then, 1 succinimide chloride (NCS) (0.1 mmol) dissolved in dmf (0.5 ml) was added dropwise, and the reaction was stirred at 30 ° C for 30 minutes and allowed to cool at room temperature for 30 minutes. The reaction was quenched with methanol (5 mL) and concentrated again. Column chromatography with MeOH / DCM gave 123. Example 60 Synthesis of 7- (2'-C-fluorenyl_β-0_ribofuranosyl) -5_smellol hydroxyamino ^ pyrrole [2,3-d] pyrimidine (124) The preparation is the same as that of 123, and the NCS is replaced with brominated succinimide (NBS). Example 61 7- (2'-C-fluorenylribofuranosyl) _5 • methyl_4_hydroxyamino_pyrrole O : \ 88 \ S8427.DOC -119- 200423945 [2,3_d] Synthesis of pyrimidine (125) Step 1: Dissolve nucleoside 141 (1 mmol) in DMF (5 ml) and cool to 0 ° C. Then, NBS (immol) dissolved in DMF (5 ml) was added dropwise, and the reaction was stirred at 0 ° C for 30 minutes and at room temperature for 30 minutes. The reaction was quenched with methanol (50 ml) and concentrated again. The column chromatography (SiO2) was performed on MeOH / DCM to obtain 7-bromo-6-gas-7-deazapurine nucleoside.

Step 2: Dissolve the nucleoside (0.5 mmol) from step 丨 in a 10% dioxane aqueous solution (2.5 ml) and add potassium carbonate (1.5 mmol) and tetrakis (triphenyl scale) Acid) | 'Add trimethyl boroxine (0.5 mmol). The reaction was refluxed for 18 hours, filtered through celite and concentrated. Column chromatography (SiO2) with MeOH / DCM gave 7-fluorenyl-6-gas-7-deazapurine nucleoside. Step 3: Nucleoside 125 was synthesized as described in Example 55, Step 2, using hydroxylamine. Example 62 Synthesis of 7- (2methyl_p_D_bitose ribosyl) -5-ethyl-4 · Arylamido-πbilo [2,3-d], 唆 (128) Step 1: From Example 61, the nucleoside (0.1 mmol) from step 1 was dissolved in THF (1 ml) and tetrakis (triphenylphosphate) palladium was added. An ethyl acetate was added to the reaction, and the reaction was heated under reflux for 6 hours. The reaction was stopped with NH4C1 and the extraction was shaken. Column chromatography (SiO2) was performed on MeOH / DCM to obtain 7 • ethyl-6-chloro-7-deazapurine nucleoside. Step 2: Nucleoside 128 was synthesized as described in Example 55, Step 2 using amines. Example 63 O: \ 88 \ 88427.DOC -120-200423945 7- (2'-C-methylfuranyl ribosyl) -5-cyano-4-hydroxyamino-pyrrole [2,3-d] pyrimidine ( 126) Synthesis Step 1: The nucleoside (0.5 mmol) obtained in Example 61, Step 1 was dissolved in THF (5 ml) and tetrakis (triphenyl acid) was vigorously charged into 1 bar. Zinc cyanide was added to the reaction and the reaction was heated under reflux for 6 hours. The reaction was stopped with NH4C1 and the extraction was shaken. Column chromatography (SiO2) was performed with MeOH / DCM to obtain 7-cyano-6-gas-7-de-mouse sigmaine. Step 2: Nucleoside 126 is as described in Example 55 and Step 2. Synthesis using hydroxylamine 0 Example 64 7- (2 ^ C-methyl-β-D-sweet ribosyl) _4. [2,3-d] Synthesis of pyrimidine 5-carboxyamidoamine (127) Step 1: The nucleoside (0.5 mmol) obtained in Example 63, Step 1 was dissolved in absolute alcohol (10 ml) And saturated with anhydrous HC1. The reaction was stirred at room temperature overnight and reconcentrated. The residue was redissolved in ethanol (1 ml) and water (1 ml) was added and the reaction was stirred for 2 hours. The solution was concentrated and subjected to column chromatography (SiO 2) with MeOH / DCM to obtain 7-formamidine chloride-7-deazapurine nucleoside. Step 2: Nucleoside 127 was synthesized as described in Example 55, Step 2 using hydroxylamine. Example 65 7_ (2'-C-fluorenylribofuranosyl) _ 5-bromo-4-methoxyamino_pyrrole [2 The synthetic nucleoside 129 of, 3-d] pyrimidine (129) was synthesized from ι18 as described in Example 60. O: \ 38 \ 88427.DOC -121-200423945 Example 66 7- (2'-0 methylfuranyl ribosyl) -5-methyl-4-methoxyamino_pyrrole [2,3_d] pyrimidine (130) The synthetic nucleoside 130 was synthesized as described in Example 55, Step 2, using methoxyamine instead of Mamine. Example 67 7- (2, C-methylfuranyl ribosyl)-5-cyano-4-methoxyamino group ^ Birrole, [2,3_d] Synthesis of pyrimidine (131) φ will be obtained as explained in Example 66 From Example 61, the nucleoside of step 2 was converted to 13 1. ♦ Example 69 7_ (2′-0methyl-pD-furfuryl ribosyl) _ 4-methoxyamino ^ bilo [2,3-d] pyrimidine 5-carboxyamidoamine (132) was synthesized as in Example 66 The description converts the nucleoside from Example 63, Step 2 to 132. Example 70 The synthesis of l- (2'-C-methyl_p_D_furfuryl ribosyl) -3-benzyl 4-hydroxyamino ^ pyrazole [3,4_d] pyrimidine (133) was as described in Example 60. Nucleoside 12 was converted to 133. Example 71 \ l- (2'-C-methyl-p_D_ribofuranosyl) methyl_4_hydroxyamino_pyrazole · [3,4_d] pyrimidine (134) Synthesis Under the conditions in 61, nucleoside 134 was synthesized from 143. Example 72 Synthesis of (methylribofuranosyl) -3-cyano-4-hydroxyaminopyrazole [3,4_d] pyrimidine (135)

O: \ 88 \ 88427.DOC -122- 200423945 143 Synthesis of nucleoside 135. Use the conditions described in Example 0, Example 73 Synthesis of 1_ (2'_C-methyl # and ribose) -4-transylaminopyridine [3,4-d] pyrimidinemethoxamine (136) Using the conditions described in Example 64 Φ α μ J64, a nucleoside 136 was synthesized from 143. Example 74 Synthesis of K2 C methyl) _3bromo-4-methylpyridine I-pyrazole ^^ 1 ^ · A (137) Instructions for use are shown in Example 6 [Synthesis of nucleus from 119 in conditions of + μ μ 1 Glucoside 137. Example 75 1 (2 C methyl-p_D_ribofuranosyl) _3_methyl_cardioxymethoxyamino ^ pyrazole [3, 'd] pyrimidine (138) Synthesis and use are described in Example 6 1 φ +, ′ Under the conditions in bl, nucleoside Π8 was synthesized from 143, and hydroxylamine was substituted with methoxyamine. Example 76 (fluorenyl sucrose ribosyl) _3_cyano-4-methoxyamino-pyridine [3,4_d] pyrimidine (139) Synthesis of the conditions described in Example 63, nuclear bitter from 143 139. Substitute the amine with methoxyamine. Example 77 Synthesis of 1- (2'cardiomethyl_p_D · sweet ribosyl) _cardiolamine aminoazole []] 'pyridin-3-carboxamide (q4〇) Use the conditions described in Example 64 , Synthesis of nucleosides from 143, hydroxylamine substituted with methoxyamine.

0 \ 88 \ 88427 DOC -123-200423945 Example 78 Synthesis of 2-C-methyl_p_D_furyl ribosylthiomethylpurine (i5〇) r Tanno D h 卞 丞 2-C · methylfuranyl-6-thiomethyl_purine Synthesis of 6, methylthio group (1.43 g, δ · 6 mmol) was suspended in 100 ml of To anhydrous CH3CN, bis-trimethylsuprylamine acetate (BSA) (5 ml, 20 mmol) was added and the mixture was refluxed until a clear solution was formed (about 30 minutes). Add 1,2,3,5-tetrabenzyl_2, _c_fluorenylribofuranose (4 g, 6.9 mmol) and then add trimethylsilyl trifluoromethanesulfonate (TMSOTf) (5 ml ). The mixture was refluxed for * hours and the disappearance of sugar was controlled by TLC in burned ethyl acetate (1: 1 v / v). 10% NaHC03 was added and the benzylated nucleoside was extracted with ethyl acetate. Water was extracted with organics (2 x 30 ml) and separated. The combined organic fractions were washed with water, dehydrated with NkSO4 and evaporated. Separation by silica gel chromatography using 5% ethyl acetate in toluene as the eluent gave the title nucleoside in 74% yield. MS: 625.72 (M + H); HLnMRCCDCW: 1.59 (s, 3H, 2, -CH3), 2.74 (s, 3H, SCH3), 4.70- 4.80 &amp; 5.90-5.00 (m, 3H, H-4, and H-5, a, b), 6.23 (d, 1H, Η · 3), 6.80 (s, ih, Hl,), 7.25-8.20 (m, 15H, benzyl), 8.20 &amp; 8.80 (s, 2H, purine). Step 2. Synthesis of methyl-β-D-ribofuranosyl-6-thiomethyl-purine The compound isolated in step 1 was dissolved in methanol saturated with K2CO3. After 20 minutes, the solvent was evaporated and the title compound was purified by flash chromatography with chloroform / 100% methanol. MS: 313.38 (M + H); O: \ 88 \ 88427.DOC -124- 200423945

Hi-NMI ^ DMSO-c ^ O.SWs, 3H, 2, -CH3), 2.82 (s, 3H, SCH3), 3.62-4 · 15 (m, 4H, sugar), 5.23-5-31 (m, 2H, sugar), 5.40 (s, 1H, H-3,), 6.01 (s, 1H, Η-Γ), 8.20 &amp; 8.80 (s, 2H, purine). Example 79 Synthesis of 2′-C · fluorenyl β-D-ribofuranosyl-6-phenyladenine (155)

6-phenyladenine (315 mg, 1.5 mmol) was suspended in 20 ml of anhydrous CHsCN, BSA (0.4 ml) was added and the mixture was refluxed until a clear solution was formed (about 30 minutes). After adding 1,2,3,5-tetra-0-benzylmethyl-β-D-ribofuranose, trimethylsilyl triflate (0.2 ml) was added. The mixture was refluxed for 4 hours and the disappearance of sugar was controlled by TLC in hexane-ethyl acetate (1: 1 v / v). 10% NaHC03 was added and the benzylated core was extracted with ethyl acetate. The water was separated with organics (2x30 ml). The combined organic fractions were washed with water, dehydrated with Na2SO4 and evaporated. The residue was dissolved in 20 ml of NH3 / methanol and left overnight at room temperature. The reaction mixture was concentrated and purified by silica gel chromatography using ethyl acetate / isopropanol / water (H2, upper phase) as the eluent. The title nucleoside was dissolved in methanol and precipitated with ether to give 75% yield. MS: 358.5 1 (M + H); H ^ NMR (DMSO-d6): 0.81 (s, 3H, 2, _CH3), 2.82 (s, 3H, SCH3), 3.80-4.20 (m, 4H, H-4 , And H-5, a, b, H05,), 5.20-5.41 (m, 3H, H-3 ,, HO-2 'and HO-3'), 6.01 (s, 1H, H-1 '), 6.90-7.10 (t, 1H, 4-phenyl), 7.28-7.32 (t, 2H, 3, 5-phenyl), 7.90 (d, 2H, 2,6-phenyl), 8.40 &amp; 8.62 (s, 2H, purine), 9.90 (s, 1H, NH). Example 80 2'-C-methyl-β-D-taste ribose- 6- (2-dimethylamino-ethylamino) O: \ 88 \ 88427 DOC -125-200423945 Purine synthesis procedure Synthesis of I 9_ (5'_〇_monomethoxytriphenylmethyl_2, cardiomethylfurfuryl) -6 • (methylthio) Compound 15〇 (1.5 g, 5 mmol) ) Dissolved in 30 ml of anhydrous pyridine, p-methoxyphenyl gasified diphenylphosphonium (7.5 mmol) was added and the reaction was kept at room temperature for 2 days. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was washed with 10% NaHC03, water, dried over Na2S04- and evaporated. The crude oil was purified by silica gel chromatography using 5% methanol in chloroform. The fractions containing the title nucleoside were combined, evaporated and freeze-dried from benzene to produce 2.1 g (74%) of the desired nucleoside product as a white solid foam bed. MS: 585.96 (M + H); HLNMR (CDC13) · 0.99 (s, 3H, 2, -CH3), 2.76 (s, 3H, SCH3), 3.80 (s, 3H, CHr dibenzylmethyl) , 3 50-3 55, 4 &amp; 4.20-4.30 (m, 4H, sugar), 5.30 (d, 1H, H-3,), 6.08 (s, 1H, H1,), 7.20-7.50 (m, 14H, triphenylfluorenyl), 8.20 &amp; 8.68 (s, 2H, purine). Step 2-Synthesis of 9_ (5, -0-monoethoxytriphenylmethyl K • methyl_ ribosyl) -6_ (methylthio) purine_ The nucleoside (2 (G, 3.4 mmol) was dissolved in 5 ml of anhydrous acetonitrile, 8.2 ml of 1 M 3-chloroperoxybenzoic acid was added, and the reaction mixture was left at room temperature for 1 hour. The reaction mixture was partitioned between water and chloroform. The organic layer was washed with 10% NaHC03, water, dehydrated and evaporated to give the title compound in 95% yield. MS: 617.83 (M + H). Step 3. 9- (2f_C-methyl-β-D-ribofuranosyl) _6- (2_dimethylamino_ 0 \ 88 \ 88427 DOC -126- 200423945 ethylamino) 9- (5'-〇-monoethoxytriphenylmethyl-2, -C-methyl-β-D-ribofuranosyl) -6- (methylthio) purine (0.2 millimoles ) Dissolved in 3 ml of anhydrous acetonitrile and added 2-monomethylamino-ethylamine (2 mmol). The mixture was refluxed for 1 hour

And concentrated in vacuo. The residue was dissolved in DMF (5 ml) and purified by HPLC using 20-100% b at a flow rate of 10 ml / min for 30 minutes. A-0.2% triethylammonium acetate aqueous solution, buffer B-o.2% triethylammonium acetate CHgCN solution. The protected 9_ (2'-C-methyl-β-D-ribofuranosyl) -6- (2-dimethylamino-ethylamino) purine was evaporated and dissolved in

Treat the title compound with HCl / Me0H at TC for 5 minutes in MeOH and precipitate with ether. The title product is isolated by HPLC at 0-20% B in 30 minutes (buffer system is as described above). Relevant divisions were combined, evaporated, co-evaporated with water (3 x 100 mL), dissolved in methanol (1 mL) and precipitated with ether (35 mL) to give the title compound as a white solid. (Yield 9- ( 5, _〇_monoethoxydibenzylmethyl_2'-C-methyl-β-D-ribosyl) -6- (methylthio) 55% of thymine) MS: 617.83 (M + H). H ^ NMRCDMSO-d ^: 0.78 (s? 3¾ 2 ^ CH3) 5 1.62 (m? 6¾ 2.76-2.88 (s: attached, methyl-N), 3.25_3.45 (m, volume , Methylene), 3.53_4.io (m, 7H, sugar), 59 places, Γ-Η), 8.35 and 8.65 (s, 1H, purine). Example 81 9_ (2f-C_ The synthesis of the methyl succinyl ribosyl) benzo benzoate (60) The title compound was prepared as described in Example 79 above, using benzimidazole as a heterocyclic group.

0 \ 88 \ 88427.DOC -127- 200423945 MS 267.32 (M + H) H! -NMR (DMSO-d6): 0.81 (s, 3H? 2, -CH3) 3 3.68-4.20 (m? 4H5 sugar), 5.25-5.30 (m, 2H, sugar), 5.40 (s, 1H, H-3,), 6.10 (s, 1H, Η-Γ), 8.87, 9.00 &amp; 9.10 (3s, 3H, purine). Example 82 Synthesis of 9_ (2'-C_methyl-β-D-ribofuranosyl) -6- (2- (lH-imidazole_4-yl) -ethylamino) purine (156)

Compound 156 is as described in Example 80, Step 3, using 2- (2H-imidazol-4-yl) -ethylamine and 9- (5f-0-monomethoxytriphenylmethyl-2, -C- Synthesis of fluorenyl-β-D-ribofuranosyl) -6- (methanesulfonyl) purine. MS 376 · 78 (Μ + Η) H1-NMR (DMSO-d6): 0.80 (s? 3H? 2f-CH3), 3.25-3.45 (m, 4H5 methylene), 3.53-4.05 (m, 7H, sugar ), 5.99 (s, 1H, 1, -H), 7.48 and 9.09 (s, 1H, purine), 8_35 and 8.65 (bs, 0.7H, imidazole). Example 83 Synthesis of 9- (2'-C-methyl-β-D-ribofuranosyl) -6- (2-piperidin-1-yl_ethylamino) cinine (157) As described in Example 80, Step 3, from 2-piperidin-1-yl-: ethylamine and 9- (5 ^ 0-monomethoxytriphenylmethylmethyl-β-D-ribofuran · sugar ) -6- (methylsulfonyl) purine synthesis. MS 293.58 (M + H)

Hi-NMR (DMS 0-d6): 0,88 (s, 3H, 2'-CH3), 1.40 (bs, 2H, fluorenylene), 1.65-1.82 (m, 4H3.25-3.45 (m, 4H , Methylene), 3.1 (M.15 (m, 10H, sugar & piperidine), 5.99 (s, 1H, Γ-Η), 8.35 (s, 1H, purine), 8.60 (bs, 1.5 · Purine &amp; NH) O: \ 88 \ 88427 DOC -128-200423945 Example 84 9- (2'-C-methyl-β-D-ribofuranosyl) -6- (cyclopropylamino) The title compound was synthesized as described in Example 80, Step 3, using cyclopropylamine and 9- (5'-〇-monomethoxytriphenylmethyl-2f-0 methyl ID-ribofuranosyl ) -6- (Methanesulfonyl) purine synthesis. MS 322.43 (M + H) H1-NMR (DMSO-d6): 0.88 (s? 3H? 2, -CH3)? 0.21-0.32 (m5 5H5 ring Propane), 3.53-4.05 (m, 7H, sugar), 5.99 (s, 1H, Γ-Η), 8.68 and 8.99 (s, 1H, purine). Example 85 9_ (2, -C-methylfurfuryl) ) -6- (Cyclopentylamino) Hornin (159) Synthesis of the title compound is as in Example 80, the description of step 3 'from pentamylamine and 9- (5'-〇_monomethoxytriphenyl Stilbene _2'-0 methyl deca-ribose (sulfuribosyl) -6- (arsonite S preparation) MS 350.64 (M + H) H1-NMR (DMSO-d6): 0.88 (s? 3H? 2'-CH3)? 1.47-1.65 (m? 9H? Cyclopentane), 3.86-4.86 (m, 7H , Sugar), 6.10 (s, 1H, lf-H), 8.47 and 8.79 (s, 1H, purine), 11.5 (s, 1H, NH). Example 86 9- (2, -C- Synthesis of methyl_p_D_ribofuranosyl) -6_ (cyclohexylamino) vocal (l58) The title compound is shown in Example 8 and the description of step 3 is' from cyclohexylamine and 〇 88 88884 DOC -129 -200423945 9- (5 Ά-mono 曱 oxytriphenylmethyl K-methyl-β-D-ribofuranosyl) -6- (methylsulfonyl) purine synthesis. MS 364.64 (M + H)

Hl-NMR (DMSO-d6): 0.86 (s? 3H5 2? -CH3)? 1.30-1.42 (m? 10H, methylene), 2.58-2.62 (m, 1H, sulfenyl), 3.86-4.86 ( m, 7H, sugar), 6.10 (s, 1H, Γ-Η), 8.24 and 8.98 (s, 1H, purine), 11.5 (s, 1H, NH). Example 87 Synthesis of 9- (2'_C • fluorenylfuryl ribosyl) _6_ (6_fluoro-1,3,4,9 · tetrahydro-β-carbolin-2_yl) purine (163) As described in Example 80, Step 3 -2'-C-fluorenyl-β-D-ribofuranosyl) -6- (methylsulfonyl) purine synthesis. MS 455.69 (M + H) H1-NMR (DMSO-d6): 0.82 (s, 3H, 2f-CH3), 1.10-1.40 (m, 6H, methylene), 3.00-4.00 (m, 6H, sugar) , 4.18-4.21 (d, 1H, H-3 '), 6.05 (d, 1H, H-lf), 6.90-6.95 (m, 1H, indole), 7.30-7.35 (m, 2H, indole), 8.3 &amp; 8.67 (s, 1H, purine), ii.5 (s, 1H, NH). Example 88 Synthesis of 9- (2'-C-fluorenyl_p_D_ribofuranosyl) -6_ (3,6-dihydro_2H-pyridinyl) purine (164) The title compound is as in Example 80. Procedure The explanation of 3 is based on Ribosyl) -6-(Oxidite yellow g blue group) synthesized by vocalization.

O: \ 88 \ 88427.DOC -130- MS 348.49 (M + H); HLNM ^ DMSO-dS): 0.90 (s, 3H, 2'-CH3), 1.50-1.63 (m, 2H, methine) , 2.10_3.20 (m, 6H, tetrahydropyridine), 3.80-4.10 (m, 3H, sugar), 5.20-5.40 (m, 3H, sugar), 6.00 (s, 1H, Η-Γ), 8 · 22 &amp; 8.55 (s, 1H, purine). Example 89 1 * (2 -C -methyl-β -D -taste ribose) -5 -aminobenzosalan and l- (2'-C-methyl_pD-ribofuranosyl) _6- Synthesis steps of aminobenzimidazole GL048950 1. l- (2'-C-methyl-β-D-ribofuranosyl) -5-nitrobenzimidazole and l- (2'-C-methylfuran Ribosyl) -6-nitrobenzimidazole Synthesis The nitronucleoside mixture was prepared as described in Example 79 above, using 5-nitrobenzimidazole as a heterocyclic group, with a yield of 72%. 〇. MS: 310.34 (M + H); H ^ NMRPMSO ,: 0.71 &amp; 0.72 (s, 3H, 2, -CH3), 3.23-4.00 (m, 4H, sugar), 5.19-5.33 (m, 1H, Sugar), 5.41 &amp; 5.50 (2s, 1H, pyrene-3,), 6.05 &amp; 6.13 (2s, 1H, H-lf), 7.80-9 · 00 (4Η, benzoic cr sit). Step 2. Synthesis of l- (2'-C-methylfuranyl ribosyl) -5_aminobenzimidazole and l- (2'-C-methylfuranyl ribosyl) _6_aminobenzimidazole The nucleoside nucleoside mixture prepared as in step 1 above was dissolved in methanol and hydrogenated in 10% Pd / C at 25 psi for 40 minutes. The catalyst was filtered and washed thoroughly with methanol, the solution was concentrated and the residue was purified by column chromatography as described in Example 79 to produce an inseparable mixture of 5- and aminobenzimidazole riboside. MS: 280.32 (M + H);

O: \ 88 \ 88427.DOC -131-200423945 HLNMRPMSO-C ^): 0.84 &amp; 0.87 (s, 3H, 2f-CH3), 3.23-4.00 (m, 8H, sugar), 5.19-5.33 (m, 4H , Sugar), 4.76 &amp; 4.99 (2s, 1H, H-3,), 5.68 &amp; 5.75 (2s, 1H, Η-Γ), 6.49-7.29 (4¾ benzimidazole), 8.21 &amp; 8.29 ( 2s, 1H, NH2). Example 91 Synthesis of 9- (2'-C-methyl-β-D-ribofuranosyl) -6- (tetramethyl-guanidino) purine (178) The title compound is as described in Example 80, step 3, It is synthesized from tetramethylguanidine and 9- (5f-O-monomethoxytriphenylmethyl K-methyl-β-D-ribofuranosyl) -6- (methoxanthanoic acid) purine. MS 380.49 (M + H) H1-NMR (DMSO-d6): 0.90 (s5 3H? 2! -CH3) 5 2.90 (m, 12H5 CH3), 3.20-4.15 (m, 7H, sugar), 6.00 (s, 1H, Η-Γ), 8.48 &amp; 8.85 (s, 1H, purine). Example 92 Synthesis of 2'-C-methylribosyl-purine-6-formamidine (208) Step 1,2,2,3,5, -tetra-0_segment_2, Synthesis of-(: _ methyl_6-methyl nitrite-threonine) 9- (5f-〇-mono-methoxytriphenylmethyl-2, -C-fluorenyl-β-D-furfurylose ) 6-((sulfonylsulfonyl) hexyl) (Example 80, step 1) (624 mg, 1 mmol) was dissolved in 5 ml of anhydrous acetonitrile, and 3 ml of "Zhonghong chloride peroxyl" Benzene I and hold the reaction mixture at room temperature for 1 hour. The reaction mixture was partitioned between water and chloroform. The organic fraction was washed with 10% NaHC03, water, dehydrated and evaporated to produce 6-fluorenylsulfonyl nucleoside Yield, 95%. MS: 657.83 (M + H)

O: \ 88 \ 88427 Dooc -132- 200423945 The σ-Hai product 'was grained in DMF and NaCN (2 equivalents) was added. The reaction was stirred at room temperature for 2.5 hours to obtain a yellow solution. The solution was concentrated in vacuo 'to leave a residue, which was then precipitated with chloroform and water. The organic portion was washed with water, 10% NaHco, and once with water. The chloroform was partially dehydrated and evaporated. Compounds were separated by silica gel column chromatography using 5% methanol in chloroform. The relevant fractions were evaporated to give the desired product as a foam (50%). MS: 604.78 (M + H) -H NMR (CDC13). 1.85 (s, 3H, 2f-CH3), 4.75-5.00 (m, 3H, sweet sugar), 6.07-6.09 (s, 1H, H-3, ), 6.81 (s, 1H, H1,), 7.25-8.20 (m, -15H, benzyl), 8.60 &amp; The step is called the synthesis of 2 2'-C-methylfuranyl-thyrin-6-formamidine. 1'2,3,5-tetrabenzyl-2'-C-fluorenyl-6-methylene Lithos-acid (1Q5 halo) was dissolved in water / methanol / hydrogen peroxide (300 / 〇) 1: 1: 005 v / v / v (20 ml). The solution was adjusted to pH 9 with NH4OH. The mixture was gently heated until a clear solution was obtained and maintained at room temperature overnight. The reaction mixture was evaporated and the residue was purified by RP HPLC as before. The relevant division is evaporated, co-evaporated with water _ and dehydrated to obtain the desired compound in a yield of 60%. _ MS 310.78 (M + H), ~ H1-NMR (DMSO-d6): 0.82 (s? 3H? 2f-CH3) 5 3.80-4.1 6 (m3 4H ?. sugar), 5.28-5.35 (m, 3H, sugar), 6.17 (s, 1H, Η-Γ), 8.74 &amp; 8.86 (s, 2H, purine). Example 94 2- (3,4-dihydroxy-5_hydroxymethyl_3_methyl_tetrahydro-furan_2_yl) _2H_ [1,2,4] triazine-3,5_dione (169 Synthesis of)

0 \ 88 \ 88427 DOC -133-200423945 Step synthesis "'3'5 Tetrabenzyl-2'-C-methyl β-D-sucrose ribose" The title compound was prepared as described above. Steps are called 2 · 2_ (3,4 · Dialkylidyl-methyl_3_methyl_tetrahydrosuccinyl) -2Η- [1,2,4] diazine_3,5-dioxane Synthesis 2H- [1,2,4] triazine-3,5-dione (Aldich) (194 5 mg, in mmol) was dissolved in anhydrous acetonitrile (6 ml). BSA (85 mL, 3.44 ¾ mole) was added using a syringe and the reaction was refluxed at 90 ° C for 45 minutes. Allow the anti-Lu to cool to room temperature. 1,2,3,5-tetrabenzyl-2f-C-fluorenyl β-D-ribofuranosyl sugar (500 mg, 0.861 mmol) was dissolved in anhydrous acetonitrile (6 ml) and added to the reaction mixture in. Then, MSOtf (0.625 ml, 3.44 mmol) was added dropwise via a syringe. The reaction was refluxed for an additional 2 hours at 90 ° C. The mixture was diluted with EtOAc (200 mL) and washed with 200 mL of a saturated NaHC03 solution. The organic layer was extracted with 2 x 100 mL of EtOAc and the combined organic layers were washed with brine and dried over magnesium sulfate. The reaction was subjected to silica gel column chromatography (2: 4: 4

EtOAc: DCM: hexane) was purified to give a white crystalline product (450 mg, 0.79 mmol, 91%). Zero H ^ NMR ^ DCIb): 8.13 (m3 4H) 5 8.00 (dd, 2H) 5 7.63 (dt? 2H)? 7.50 (m? 5H) ?. 7.35 (t, 2H), 7.29 (s, 1H), 7.11 (s, 1H), 6.04 (dd, 1H), 4.85 (dd, 1H), 4.76 (m, 1H), 4.54 (dd, 1H), 1.80 (s, 3H). Step 3. 2- (3,4-Diacryl_5-Ethylmethyl-3-methyl-tetrazyl-tetrazoyl) -2Η- [1,2,4] triazine-3,5_di Ketone synthesis: 35 mg of 2- (3,4-dibenzyl-5-benzyl-methyl-3-fluorenyl-tetrahydrofuran-2-yl) -2fluorene- [1,2,4] Triazine-3,5-dione was dissolved in ammonia-saturated methanol (100: \ 88 \ 88427 DOC -134- 200423945 ml). The reaction was sealed and stirred for 48 hours. The reaction was concentrated in vacuo to an amorphous solid and reprecipitated from methanol and dichloromethane to obtain the product (12 mg, 75% yield). MS: 258.12 (M + H), H ^ NMRCDMSO ^): 7.55 (s? 1H)? 5.95 (s3 1H) 5 5.00 (s5 2H) 5 4.55 (s5 1H). 3.80 (t, 1H), 3.65 (dd , 2H), 3.45 (dd, 2H), 1.02 (s, 3H). Example 95 Synthesis of 5-hydroxymethyl-3-methyl-2 · (6-thiobenzene-3-yl-purine-9-yl) _tetrahydro · sweeten-3,4-diol (1) Step 1 · 2_ (6_bromo-purine-9-yl) _5 · Synthesis of benzyloxymethyl_3_methyl-tetrahydro-furan-3,4-oxybenzyl , 342.3 mg, 1.72 mmol) were dissolved in anhydrous acetonitrile (6 ml). BSA (0.85 ml, 3.44 mmol) was added using a syringe, and the reaction was refluxed at 90 ° C for 45 minutes. The reaction was allowed to cool to room temperature. 1,2,3,5-tetra-O-benzyl-2'-C-methylpD-^-ribose (500 mg, 0.861 mmol) was dissolved in anhydrous acetonitrile (6 ml) and added to the reaction In the mixture. TMSOTf (0.625 ml, 3.44 mmol) was added dropwise via a syringe. The reaction was refluxed at 90 ° C for 3.5 hours. The mixture was diluted with EtOAc (100 mL) and washed with 100 mL of saturated sodium bicarbonate solution. The organic layer was extracted with 2 × 100 ml of EtO Ac and the combined organic layers were washed with brine and dehydrated with magnesium sulfate. The reaction was purified by silica gel column chromatography (filled with 5% EtoAc in DCM and dissolved in 10% EtOAc in DCM) to give an off-white solid (500 mg, 0.76 mmol, 87%).

Hi-NMR (CDC13): 8.75 (s, 1H), 8.40 (s, 1H), 8.12 (dd, 2H), O: \ 38 \ 88427.DOC -135-200423945 8.〇6 (dd, 2H), 8.0Q (dd, 2H), 7.65 · 7 · 35 (η, 1GH), 6_82 (s, 1H), 6.21 (d, 1H), 4.95 (m, 2H), 4.75 (m, 1H), 1.61 (s , 3H). Step 2. 5-benzyloxymethyl-3 -methyl-2- (6-thiophenyl-3-yl-throat_9_yl) _tetrahydro-furan_3,4-oxybenzyl The following reagents were added to the reactor. 2- (6-Bromo-purine-9-yl) -5 -benzyloxyfluorenyl-3 -fluorenyl-tetrahydro-furan-3,4- Oxyenyl (240 mg, 0.365 mmol), 3-thiophene boronic acid (Aldrich, 71 mg, 0.548 mmol), potassium carbonate (76 mg, 0.548 mmol), Pd (PPh3) 4 (42.18 mg, 0.0365 mmol). The reagent was then dissolved in anhydrous toluene (9.6 mL) and stirred at 10 ° C overnight. The reaction was diluted with EtoAc (100 mL) and saturated sodium bicarbonate solution (200 mL) ) Wash 2 ×. The combined organic layers were washed with brine and dehydrated with magnesium sulfate, and concentrated in vacuo. The reaction was purified by silica gel column chromatography (1: 3 EtOAc: hexane), and the fraction was concentrated to Obtained as a brown oil (220 mg, 0.33 mol). Fig. 3.5-Cyclo-3-methyl_2- (6-thiophenyl-3-yl-hex + _9_yl) Tetrahydrofuran-3,4-diol will be obtained from 5-benzyloxyfluorenyl-3 -fluorenyl-2- (6-thiophenyl-3-yl-purine-9-yl)- Tetrahydrofuran-3,4-oxybenzyl (220 mg, 0.33 mmol) was dissolved in ammonia saturated methanol (20 ml) and stirred at room temperature for 48 hours. The reaction was concentrated in vacuo Formation and purification via HPLC (from 0% acetonitrile water / cereal to 100% ethoxylate in 20 minutes. The product was dissolved in 10.5 minutes) to give a yellow oil (92 mg, 0.26 mmol, 79%) MS 349.1 1 (M + H),

Hl-NMR (DMSO-d6): 8.90 (dd? 1H)? 8.86 (dd? 1H), 8.81 (s5 O: \ 88 \ 88427 DOC -136- 200423945 1H), 8.24 (dd, 1H), 7.45 (m , 1H), 6 ″ 7 (s, 1H), 4.53 (d, 1H), 4.18 (d, 2H), 3.98 (dd, 1H), 0.96 (s, 3H). Example 96 5-Synthesis via methyl_3-methyl-2- (6-phenyl-rhyme-9-yl) _tetrahydro-bite-3,4-diol (170) Step 1.5 -Benzyloxymethyl-3-methyl-2- (6-phenyl · purin-9-yl) -tetrahydro-furan-3,4-oxybenzyl The following reagents were added to a reactor based on a single port: From step 1 above, 2- (6-Bromo-purin-9-yl) -5-benzyloxymethyl-3-methyl-tetrahydro-furan-3,4-oxybenzyl (200 mg, (300 mmol), phenylboronic acid (Aldrich, 54.9 mg '0.45 mmol), potassium carbonate (63 mg, 0.45 mmol), pd (pph3) 4 (23 g) (0.02 mg) ). The reagent was then dissolved in anhydrous toluene (6 mL) and stirred overnight at 10 ° C. The reaction was diluted with EtoAc (75 mL) and washed with a saturated solution of sodium bicarbonate (150 mL). 2x. The combined organic layers were washed with brine and dehydrated with magnesium sulfate, and concentrated in vacuo. The reaction was purified by silica gel column chromatography (1: 4 EtOAc: hexane), and the fraction was concentrated to give colorless Oil (153 mg, 0.23 mmol). Step 2. 5-hydroxy-3-methyl-2- (6-phenyl-purine_9_yl) _tetrahydro_furan_3,4- The diol will serve the product from step 1 (153 mg, 0.23 mmol), dissolved in saturated methanol (20 ml) and searched overnight at room temperature. The reaction was concentrated in vacuo to It was purified via HPLC (from 0% acetonitrile in water to 30% acetonitrile in 20 minutes. The product dissociated in 15.3 minutes) to give a colorless oil (61 mg, 0.18 mmol, 78%).

0 \ 88 \ 88427.DOC -137- 200423945 MS 343.1 5 (M + H), HI-NMR (DMSO-d6): 8.93 (s5 1H) 5 8.68 (m? 2H)? 8.60 (s? 1H), 7.52 (m, 3H), 6.23 (s, 1H), 4.47 (d, 1H), 4.15 (dd, 2H), 3.96 (dd, 1H), 0.85 (s, 3H) ° Example 97 Amine_2- (3 , 4-Diacryl-5-acryl-3-methyl-tetrazol-bital-2-yl) _4,5_dihydro-2H- [1,2,4] triazin-3_one ( 174) and 5-amino-2- (3,4-dihydroxy-5_hydroxymethyl-3-methyl · tetrahydro · furan-2-yl) -4,5-dihydro-2H_ [1, Synthesis of 2,4] triazin-3-thione (172) 1. 2- (3,4-dibenzyloxy-5-benzyloxymethyl-3-methyl-tetrahydro-furan-2- Synthesis of _5_thioketone_4,5_dihydro_2H_ [1,2,4] triazin-3-one: 2- (3,4-dibenzyl-5-benzylmethyl-3- Fluorenyl-tetrahydro-furan-2-yl) -2H- [1,2,4] triazine-3,5-dione (450 mg, 0.79 mmol) was dissolved in anhydrous methylbenzyl (25¾ Liters). Lawesson's reagent (161 mg, 0.4 mmol) was added and the reaction was refluxed at 120 ° C for 4 hours. The reaction was then concentrated in vacuo and co-evaporated with dichloromethane, and purified via column chromatography (3: 2: 3 DCM: EtOAc: hexane) to give a yellow oil (160 mg, 0.3 mmol). Moore). Step 2. 5-Amino-2- (3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl) _2H_ [1,2,4] triazine- 3-Ketone The product known from step 1 above was dissolved in ammonia-saturated methanol (25 ml) and stirred overnight at room temperature. The reaction was concentrated in vacuo and purified via column chromatography (1: 9 MeOH: DCM) to give a white amorphous solid (56 mg, 0.02 mmol).

O: \ 88 \ 88427.DOC -138- 200423945 MS 259.12 (M + H),

Hl-NMR (DMSO-d6): 7.49 (s? 1H)? 6.08 (s? 1H), 3.79 (d, 1¾) 3.7 (d, 1H), 3.6 (d, 2H), 3.48 (m, 1H), 0.94 (s, 3H). Step 3. 5-Amino-2_ (3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-granyl) -4,5-dihydro-2H_ [1,2,4 ] Synthesis of triazine-3-thione The title compound was collected in a separate division during the purification of step 2 above.

MS 274 · 09 (M + H), H1-NMR (DMSO-d6): 7.73 (s5 1H), 5.91 (s, 1H) 5 3.81 (dd5 1H), 3.7 (d, 1H), 3.60 (d, 2H ), 3.48 (dd, 1H), 1.03 (s, 3H). Example 98 Synthesis of l- (3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl) -4-hydroxy-1H-pyridin-2-one (177) 1 · benzoic acid 4- (2,4-digas-benzyl) -5- (2,4-digas-benzyloxymethyl) -2_ (4_hydroxyoxy_2H-pyridin-1-yl) -3-methyl-tetrahydro-furan

Synthesis of Esteryl Pyridine-2,4-diol (Aldich, 148 mg, 1.33 mmol) was dissolved in anhydrous acetonitrile (6 ml). Add via syringe: 8.8 (0.66 ml, 2.67 mmol) and allow the reaction to reflux at 90 ° C for 45 minutes. The reaction was allowed to cool to room temperature. 1,2,3,5-tetra-O-benzylmethyl ribose (400 mg, 0.666 mmol) was dissolved in anhydrous acetonitrile (6 ml) and added to the reaction mixture. Then syringobutane (0.482 ml, 2.67 mmol) was added dropwise via a syringe. The reaction was again refluxed at 9 ° C for 3.5 hours. The mixture was diluted with EtoAc (200 ml) and washed with 200 ml of saturated sodium bicarbonate solution. Organic O: \ 88 \ 88427.DOC -139- 200423945 layer It was extracted with 2 × 200 ml of Et0Ac and the combined organic layers were washed with brine and dehydrated with magnesium sulfate. The mixture was concentrated in vacuo. The reaction was purified by silica gel column chromatography (H9 Me0H: DCM) and concentrated under vacuum to A colorless oil (312 mg, 0.82 millimolar, 70%) was obtained. The step size is 2.1 · ((2,4_dikisyloxy)) _ 5_ (2,4_dikisyl_benzyloxymethyl) -1 ^ Synthesis of hydroxy-3-methyl-tetrahydro-furan_2_yl] _4_hydroxy · 1H_pyridine_2_one The product of step 1 (3 12 mg, 0.46 mmol) was dissolved in Potassium carbonate 'saturated methanol (4.6 mL) and stirred at room temperature overnight. The mixture was diluted with EtAc (100-mL) and washed with 100 mL of saturated bicarbonate solution. Washed with brine and dehydrated with magnesium sulfate. The magnesium sulfate was filtered off and the solution was concentrated in vacuo to a white powder (2 65 mg, 0.46 mmol, 1000/0). Step 3. Synthesis of 1_ (3,4_dihydroxy_5_hydroxymethyl_3 • methyl-tetrahydro-furan_2_yl) _4_hydroxy-1H-nb bitone. The product of step 2 (265 mg, · 46 millimoles) was dissolved in DCM (14 pen liters) and the temperature was lowered to -78 ° C. Boron trichloride (i.om, DCM solution, 4.6¾ liter, 4.6¾ mol) was added dropwise In this reaction, the reaction was stirred at -78 ° C for 2 hours and then allowed to warm to -20 overnight. The reaction was stopped with 1: ιOMOH: DCM (20 mL), and then concentrated in vacuo to Brown · colored oil. The product was purified by silica gel column chromatography (1: 4 MeOH: DCM) to obtain a white powder (99 mg, 0.385 mmol, 84%). MS 256.10 (MH), H ^ NMRCDMSO-dG): 7.86 (d? 1H)? 6.06 (s, 1H), 5.86 (dd? 1H) 5 5.54 (d? 1H)? 5.12 (dd, 2H), 5.00 (s, 1H), 3.78 (m , 2H), 3.64 (dd, 2H), 0.86 (s, 3H). Example 99 O: \ 88 \ 88427.DOC -140- 200423945… -methoxy-… -yl) -5, methyl · "tetrahydroanhydro-3,4-diol Synthesis Step 1.2- ( 2_ 气 _6_ 甲 备 | 'Human-based ... 24 1 ^) o, 4-: qi_solenyloxy) (, oxetyloxymethyl) -3-methyl-tetrahydro -...- alcoholΊ , Luanshuo 033 liters) of methyl methyl bis- (2,4-dichloro, tick). Soil-2-C-methyl fucofranose (400 mg, 0.8 mmol) solution in HBr (dissolved in 30% by weight in acetic acid, milliliters) was added dropwise at 0 ° C. The resulting solution was blended for hr at ot 'for another 3 hours at room temperature, concentrated in vacuo and mixed with Anhydrous toluene (3x20 ml) was co-evaporated. The oily residue was dissolved in anhydrous acetonitrile (15 ml) and added to 2,6_dichloro. Sodium sulphate solution (the preparation was made by 2,6 -Dichloro-9H-purine (455 mg, 2.4 mmol) and sodium anhydride (60%, dissolved in mineral oil, 110 mg) in anhydrous acetonitrile (l) for 4 hours). The combined mixture was stirred After 24 hours, it was evaporated to dryness. The residue was diluted with EtOAc (75 mL) and water (75 mL). The aqueous layer was removed and EtAc (2 × 50 mL) was re-extracted. The combined organic fractions were washed with brine (100 liters) and dehydrated with sulfuric acid. The product was subjected to Shixi gel column chromatography (1: 1 EtOAc: hexanes). ) Purified to give an amorphous solid (400 mg, 0.61 mmol). Step 2-2- (2-Ga-6-methoxy-purine-9-yl) -5-methyl- Synthesis of 3-methyl-tetrahydro-furan-3,4-diol The product obtained from step 1 was dissolved in dichloromethane (6 ml), and the temperature was lowered to -78 ° C. Syringe trichloride (1.0 M, dissolved in DCM, 6.1 ml, 6.1 mmol) was added dropwise to the reaction in a syringe. The reaction was stirred at -78 ° C for 2 hours and then warmed to- Overnight at 20 ° C. The reaction was stopped with 1: 1 MeOH: DCM (30 ml) O: \ 88 \ 88427.DOC -141-200423945 and stirred at -20 ° C for 15 minutes. The solution was dissolved in NH4OH. And concentrated in vacuo to beads. The product was purified by Shixi gel column chromatography (1: 9 MeOH: DCM) to give a white solid (161 mg, 0.48 mmol, 79%). MS 331 · 09 (Μ + Η), H1-NMR (DMSO-d6): 8.76 (s? 1H)? 5.92 (s? 1H), 5.40 (s? 1H)? 5.24 (t? 2H)? 4.09 ( s, 3H), 3.99 (m, 1H), 3.92 (m, 1H), 3.69 (m, 1H), 0.77 (s, 3H). Example 100 φ 7- (3,4 · Dihydroxy-5-hydroxymethyl_3-methyl-tetrahydro-furan-2-yl) -4-oxo-4,7_dihydro_3H-pyrrole [2,3-d] Synthesis steps of pyrimidine-5-formamidine (203) 1. 5-Bromo-7- (3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan -2_yl) -3,7-dihydro-pyrrole [2,3-d] pyrimidin-4-one Synthesis of 7- (3,4_dihydroxy_5_hydroxyfluorenyl-3-methyl- Tetrahydro-furan-2-yl) -3,7-dihydropyridine [2,3-d] pyrimidin-4-one is dissolved in DMF. NBS was added and the reaction was stirred at room temperature. The completed reaction was concentrated to a solid, dissolved in EtO Ac and washed with water. The organic layer was washed with brine and dried over magnesium sulfate. The solution was concentrated in vacuo to a solid. Step by step 2 · 7_ (3,4_dihydroxy_5_hydroxymethyl-3-methyl-tetrahydro-furan-2- · yl) _4_oxy_4,7-dihydropyrrole [2,3_d ] Synthesis of pyrimidine methyl nitrite The product from step 1 above was combined with Zn (CN) 2, Pdz (dba) 3, dppf, and zinc powder dissolved in DMF. The reaction will be at 120. [Under reflux. The completed reaction was purified by silica gel tube chromatography to obtain the product. 1 Spiro 3.Hydroxymetholium-Dongjiamou-tetrahelium-furoline_2-

O: \ 88 \ 88427 D0C -142-200423945 dihydro-3H-pyrrole 2,3_dl pyrimidine-5-A The product obtained from the above step 2 is dissolved in HC1 saturated ethanol and placed in a chamber, or Taxes have fought. The reaction was concentrated to dryness. Step 4. 7_ (3,4_dihydroxy_5_hydroxymethylmethyl · tetrahydro_furan_2_yl) _4 · oxy_4,7 · dihydro-3H-pyrrole [2,3-d] Synthesis of pyrimidine-5 · formamidine The product from step 3 above was dissolved in liquid ammonia and heated in a bomb reactor overnight. The reaction was concentrated to obtain the final product. Example 101 2- (4-Amino-5-furan-2-yl-pyrrole [2,3-d] pyrimidin-7-yl) -5-hydroxymethyl-tetrahydro-sweeten-3,4 · diol (204) Synthesis Step 1.4_ 气 -5- 破 _711_11 Billo [2,3- (1) Synthesis of biting dissolves heart chloride · 7Η- growl [2,3-d] pyrimidine (TCN) DMF. Add NIS 'and stir the reaction at room temperature for 1 hour. Then dissolve the reaction in EtOAc, wash with brine, and dehydrate with magnesium sulfate. The solution is concentrated to give an orange solid. Step 2 · Synthesis of 4-airfuran_2_yl_7H_pyrrole [2,3-d] pyrimidine The product obtained from the above step 1 was dissolved in dioxane and the following reagents were added: 2-furanboronic acid (Aldrich), Potassium carbonate, and tetrakis (triphenylphosphate) palladium. The reaction vessel was sealed and heated at 10 ° C overnight. The reaction was filtered through celite and purified by HPLC to give a yellow solid. Step 3. 7- [3,4-bis- (2,4-digas-benzyloxy-5_ (2,4-dichloro_benzyloxymethyl) -tetrahydro-furan_2_ylbu 4_gas_5 · furan Synthesis of -2_yl_711_pyrha [2,3-d] pyrimidine at 0 ° C in methyl-3,5-bis- (2,4-diO in anhydrous dichloromethane : \ 88 \ 88427.DOC -143-20042394 5: :) 2 C methyl-Bu D-ribofuranose solution was added dropwise with HBr (30% 'combined with Sa acid, 1 liter). The resulting solution was stirred at room temperature for one hour: at room temperature Stir for 3 hours', evaporate in vacuum and co-exist with anhydrous toluene. Dissolve the oily residue in anhydrous acetonitrile and add to the solution of the sodium salt in step i (the preparation is made with sodium anhydride (6 〇%, dissolved in mineral oil) = Stir in hot acetonitrile for 4 hours). Dissolve the combined mixture for 2 hearts], ^ Resume to dryness. Et0Ac and water, release the residue. Remove the aqueous solution The layers were re-extracted with EtOAc. The combined organic fractions were washed with brine and dried over magnesium sulfate. The reaction was purified through a silica gel column. Step 4 2- (4 • Ga-5-furan-2-yl-pyrrole [2 , 3-d] pyrimidin-7-yl) -5- via synthesis of methyl-tetrahydro-bite-3,4-diol The product of step 3 above was dissolved in dichloromethane and the temperature was reduced to _ 78 c. Boron trichloride was added dropwise to the reaction. The reaction was stirred at -78 for 2 hours, and then overnight at -20 ° C. The reaction was terminated with 1: 1 MeOH: DCM and stopped at -20 ° Stir for 15 minutes at C. Use nh4OH to react And then concentrated in a vacuum to a solid. The product was purified by a silica gel column. The step is called 5 · 2_ (4_amino_5-crean-2 · yl- «bilo [2,3_d] pyrimidine Based on the synthesis of methyl-tetrahydro-squeezed-3,4-diol, the product of step 4 above was dissolved in liquid ammonia and sealed in a bomb reactor. The reaction was stirred at 80 ° C overnight. The solution was concentrated to give the product. Example 102 2- (4-Amino-5-oxazole-2.yl-pyrrole [2,3-d] pyrimidin_7 • yl) -5-hydroxyfluorenyl_tetrahydrofuran-3,4 · di Synthesis of alcohol (205) 1. Synthesis of 4-chloro-5-oxazole_2-yl-7 基 -pyrrole [2,3_d] pyrimidine O: \ 88 \ 88427.DOC -144- 200423945 Slightly [2,3 piperidine (prepared as above) was dissolved in thf. Put Tetrakis (triphenylsuccinic acid)! Bar and tributyltin. Xanthine is added to the reaction mixture. The reaction vessel was sealed and heated at 100 t overnight. The compound was purified on a silica gel column. Step 2.7- [3,4-Bis_ (2,4_digas-benzyloxy) (2,4_digas_benzyloxymethyl) _tetrahydrofuran_2-yl] · 4_qioxazole_2_s_7H _Pyrrole ^, ^ Pyrimidine is synthesized at 0 ° C and is dissolved in anhydrous dichloroformamidine methyl_3,5_bis_ (2, 'dichloro-benzyloxy) -2-C-methyl- HBr (30% by weight, dissolved in acetic acid, 1 ml) was added dropwise to the β-D-ribofuranose solution. The resulting solution was stirred for 1 hour at the bottom, and then stirred at room temperature for 3 hours, evaporated in a vacuum and contacted with The anhydrous residue is co-evaporated. The oily residue is dissolved in anhydrous acetonitrile and added to the sodium salt solution of step 1 above (the preparation is made with sodium anhydride (60%, dissolved in Shiguang oil) in anhydrous Stir in acetonitrile for 4 hours). Stir the combined mixture for 24 hours and evaporate to dryness. Dilute the residue with EtOAc and water. Remove the aqueous layer and re-extract with EtOAc. Wash the combined organics with brine and wash with The magnesium sulfate was dehydrated. The reaction was purified through a Shi Xisheng column. Steps were called 3.2 · (4- -qi_5_ bite-2 -yl-11-bilo [2,3_d] bite-7-yl) _5 -Methyltetrahydrofuran-3,4-diol is synthesized by the above step 2 The product was dissolved in dichloromethane and the temperature was lowered to 8 t :. Boron trichloride was added dropwise to the reaction. The reaction was stirred at 81: 2 hours, and then at -20 ° C overnight. : MeOH: DCM terminated the reaction and stirred at -20 ° C; stirred for 15 minutes. The reaction was neutralized with NH4OH, and then concentrated in vacuo to a solid. The product was purified by a silica gel column. O: \ 88 \ 88427 DOC -145-200423945 Step 4. 2- (4-Amino-5_furan-2-yl-pyrrole [2,3_d] pyrimidinyl) -5 hydroxymethyl-tetrahydro-furan_3, Synthesis of 4-diol The product from step 3 above was dissolved in liquid ammonia and sealed in a bomb-type anti-deer device. The reaction was pulled off at 80 C. The solution was concentrated to obtain the desired product. Example 103 4-Cyclopropylamino-1- (3,4 · dihydroxy-5-hydroxymethyl-3-methyl-tetraammine_bite-2-yl) _1Η_Continue Lake 2-Meng (206) The synthesis step is called 1 · 1- (3,4-monooxy-5-benzyloxymethyl-3-methyl-tetrahydro_sweet • 2-yl) -1Η-pyrimidine-2,4 dione. Synthesis The 1Η-pyrimidine-2,4-dione (Aldrich) was dissolved in anhydrous acetonitrile. BSA was added using a syringe, and the reaction was refluxed at 9 ° C for 45 minutes. The reaction was allowed to cool again But it's too warm. Dissolve 1,2,3,5_tetra_0-benzyl-2'-C_fluorenyl β-D-ribofranose in anhydrous acetonitrile and add it to the reaction mixture. Then inject TMSOTf was added dropwise to the cartridge. The reaction was refluxed for another 2 hours at 90 ° C. The mixture was diluted with EtOAc and washed with saturated sodium bicarbonate solution. The organic layer was extracted 2x with EtoAc and the combined organic layers were washed with brine and dried over magnesium sulfate. The reaction was purified by silica gel column chromatography to obtain the desired product. Step 2. 1- (3,4-Dibenzyloxy-5-benzyloxymethyl_3_methyl-tetrahydro-furan-2_yl) -4-thio_3,4_dihydro-1H -♦ 唆 _2_ 嗣 Synthesis The product from step 1 above was dissolved in anhydrous toluene. Lawesson's reagent was added and the reaction was refluxed at 120 ° C for 4 hours. The reaction was concentrated in vacuo and co-evaporated with dichloromethane, and purified by Shixi gel column chromatography to obtain the product. O: \ 88 \ 88427.DOC -146- 200423945 Step 3. 4-cyclopropylamino 4- (3,4-dibenzyloxy_5_benzyloxymethyl_3_methyl-tetrahydrofuran Synthesis of _2_yl) -lH-pyrimidin-2-one The product from step 2 above was dissolved in absolute ethanol. Cyclopropylamine (Aldrich) 'was added and the reaction was refluxed overnight. The reaction was concentrated in vacuo and purified via silica gel column chromatography to obtain the product. Step 4 4-cyclopropylamino-l- (3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro · squeezing_2 _ *)-1H_pyrimidine_2_one Synthesis The product from step 3 above was dissolved in methanol saturated with ammonia and stirred at room temperature. The reaction was concentrated in vacuo and purified via silica gel column chromatography. 0 Example 104 1- (3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro · furan_2_yl) -4 -Synthesis of hydrazino-3,4_dihydro_1H-pyrimidin-2-one (207) 1.1- (3,4-dibenzyloxy_5_benzyloxymethyl-3-methyl- Synthesis of tetrahydro-furyl 4-hydrazino_3,4_dihydro_1Η [_pyrimidin-2-one will be soluble in 1- (3,4-dibenzyloxy-5-benzyloxyfluorenyl group -3-fluorenyl-tetrahydro-furan-2-yl) -4-thioxo-3,4-diargon-1fluorene-pyrimidin-2-one solution, add hydrazine (35% by weight, soluble in water) The reaction was refluxed overnight, then concentrated and purified via silica gel column chromatography. Step 2. 1- (3,4-dihydroxy-5-hydroxymethyl-3-fluorenyl · tetrahydro_furan-2-yl ) -4_Synthesis of 3,4-dihydro-1H-, bitan-2-one The product from step 1 above was dissolved in methanol saturated with ammonia and stirred overnight at room temperature. The reaction was concentrated in vacuo and purified via silica gel column chromatography to obtain the desired product.

O: \ 88 \ 88427.DOC -147- 200423945 Example 106 8_ (3,4-dihydroxy-5-hydroxymethyl-3_methyl · tetrahydro_furan-2_yl) _4,5_dioxy Synthesis of 3,4,5,8-tetraargon-pyridine [2,3-d] pyrimidine-6-carboxylic acid amide (161) Oxymethyl_3_methyl · tetrahydro_furan-2_yl) -2-methylthio-4,5-dioxy_3,4,5,8_tetrahydro ^ pyridine [2,3- d] Ethyl pyrimidine-6-carboxylate (0.2 g, 0.27 mmol) was dissolved in 30 ml of ethanol and Raney nickel (0.55 g wet weight and pre-treated with DI water followed by alcohol) and The suspension was heated at reflux for 24 hours. An additional 18 grams of Raney nickel (wet scale, pretreated as described above) was added and the reaction was refluxed for another 24 hours. The suspension was filtered while hot and the Raney nickel was washed with hot alcohol. The filtrate was concentrated in vacuo and 1 liter of DMSO was added to dissolve the nucleosides and then diluted with ammonia-saturated methanol (30 ml). The reaction was allowed to stir at room temperature overnight and then concentrated in vacuo and separated with HPlc 0-20% buffer B at a flow rate of 10 ml / min within 30 minutes. Buffer solution A-0.1% triethylammonium acetate aqueous solution, buffer solution β- ···% triethylammonium acetate in CHsCN. The nucleoside-containing fractions were collected and evaporated and dried by co-evaporation with pure wine to obtain 7 mg (10%) of the desired nucleus: g :. MS: 351.16 (MH) H1-NMR (DMSO-d6): 0.8 (s5 3H, 2? -CH3)? 3.0-4.0 (m5 4H3 sugar), 5.0-5.5 (m, 3H, 0H), 6.7 (s 1H, 1'-H), 7.6 (s, 1H, -A0, 8.4 (s, 1H, -Ar), 90.0 and 9.2 (s, 2H, NH2). Example 107 4-amino-8 -(3,4-dihydroxy · 5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl) -2-methylthio-8Η-pyridine [2,3-d] pyrimidine-7- Synthesis of ketone (165) 0 \ 88 \ 88427 DOC * 148- 200423945 Step scale 1 · 4-amino-2-methylthio- 811-11 than 唆 [2,3-d] Bite -7-hole Synthesis of 4-amino-2 -methylthio-8H- ° ratio. Synthesis systems such as [2,3 -d] Sporodine-7- _ such as G. L. Anderson and SG Richardson J. Heterocyclic Chem · 1985 , 22, 1735-1737. Step 2. 4-Amino-8- [4 (2,4-Diaminobenzyloxy) -5_ (2,4-Diaminobenzyloxymethyl) -3-Amino- Synthesis of 3-methyl-tetrahydro-sulfur-2-yl) -2-methylthiopyridine [2,3-d] pyrimidin-7_one will be dissolved in dichloromethane (15 ml). -Amidino-3,5-bis- (2,4-dichloro-benzyloxy) -2-C-methyl-β-D-ribofuranose (0.5 g, 1.0 mmol) was cooled to 0 ° C and dropwise add HBr (30% by weight, dissolved in acetic acid, 1.25 ml Mao 6.27 mole) and the mixture was stirred at ° billion billion one hour and then allowed to warm to room temperature and stirred for 2 hours. The resulting translucent brown solution was concentrated in vacuo and co-evaporated with anhydrous toluene (3 x 15 ml) to give a brown oil. This oil was dissolved in DMF (8 ml) and added to 4-amino-2-methylthio-8H-pyridine [2,3-d] pyrimidin-7-one (by dissolving in DMF in situ ( 40 ml) of this substance (0.624 g, j · 0 耄 mol) and NaH (60%, dispersed in mineral oil, 0.132 g, 3.3 mmol) at room temperature for 3 hours to produce ) The resulting reaction was stirred at room temperature for 24 hours and then concentrated in vacuo. The crude product was purified by silica gel column chromatography 'using 5% methanol in dichloromethane as the eluent. The appropriate fractions were collected and concentrated in vacuo to give 340 mg (51%) of a yellow oil. Step 3. 4-Amino-8- [4 (2,4dihydroxy-5_hydroxymethyl) -3-methyl-tetrahydro-squeeze_2_yl) -2_methylthio-811- ° Synthesis of Biyodo [2,3- (1) Bite-7-one The product of Step 2 above (0.34 g, O: \ 88 \ 88427.DOC -149- 200423945 0.5 06 millimolar) solution in dry ice / BCl3 (1M, dissolved in dichloromethane solution at -78 ° C and stirred for 1.5 hours, cooled to -78 ° C in an acetone bath and added dropwise '5.0 · 〇. Ml, 5.0 mmol). The solution was stirred at -20 ° C for 20 hours. The reaction was placed on ice> closed and ammonia water was added and stirred at room temperature for 10 minutes. The resulting solution was washed with methyl chloride. Boron salt and concentrated in vacuo. The residue was dissolved in DM SO (j mL) and diluted with% 0 (2 mL).

The product was separated by HPLC with a 15/0 B gradient over a period of 30 minutes at a flow rate of 10 ml / min. Buffer solution A-0 · 1 / 〇 Diethylammonium acetate aqueous solution, and buffer B_00% triethylammonium acetate CH / N solution. The nucleoside-containing fractions were collected and concentrated in vacuo. The residue was then sunk with chloroform and decanted to obtain 20 mg ($%) of the desired nucleoside.

MS: 355.12 (M + H). HLNMRpMSC ^): 0.9 (m, 3H, 2'-CH3), 2.5 (m, 3H, -CH3), 3.5-4.2 (m, 4H, sugar), 5.0-5.5 (m, 3H,- OH), 6.3 (d, 1H, -Ar), 7.1 (s, 1H, 1'-H), 7.8 (s, 2H, code), 8.0 (d, 1H, -Ar). Example 108 Amine-8_ (3,4_dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl) _8H-pyridine [2,3-d] pyrimidin-7_one Synthesis step of (182) 1.4-amino 8- (3,4-dihydroxy-5-hydroxymethyl-3-fluorenyl-tetrahydro-furan-2-yl) -8H_pyridine [2,3 -d] Synthesis of pyrimidine-7-one in 4-amino 8- (3,4 · dihydroxy-5-hydroxyfluorenyl-3 -fluorenyl-tetrahydro-squeak) dissolved in EtOH (20 ml) Alan-2-yl) -2 -fluorenylthio-8Η-σΛ σdefinite [2,3-d]. dense. Raney nickel (1.0 g) was added to the solution of 7-ketone (5 mg, 0.042 mmol) in DI solution and pretreated with DI water and then alcohol, and the suspension was heated under reflux for 20 hours. \ 88 \ 88427 DOC -150- 200423945 hours. The suspension was filtered while hot and the Raney nickel was washed with hot alcohol. The filtrate was concentrated in vacuo. The crude reaction was dissolved in DMS0 (2 ml) and diluted with H2O (3 ml) and purified by HPLC 13% B gradient at a flow rate of 10 ml / min in 30 minutes. Buffer A-0.1% triethylammonium acetate aqueous solution, Buffer B-0.1% triethylammonium acetate CH3CN solution. The nucleoside-containing fractions were collected and concentrated in vacuo. The residue was precipitated with dichloromethane and decanted to give 2.5 mg (15%) of the desired nucleoside. , MS: 309 · 12 (M + Η). Meixiang Example 109 # 2- (6-Amino-8-methyl-purine_9_ylhydroxymethyl_tetrahydro_furan_3,4_ diol The synthesis step is called 1.8-methyl-9H- Purine-6-ylamine Synthesis Add 4,5,6-triaminopyrimidine sulfate (30 g, 13.4 mmol) and acetamide (1.0 g, 16.9 mmol) to In a 25 ml pressure-resistant bomb container and heated to 240 ° C for 6 hours. The crude product was cooked in Η20 for 1 hour and filtered through a small piece of diatomaceous earth. The filtrate was concentrated and subjected to HPLC to (M0 % Relief Solution B, purified in 30 minutes at a flow rate of 10 ml / min. Buffer A-0.1./❶Triethylammonium acetate aqueous solution, Buffer B-0.1% triethylammonium acetate · of CHsCN solution. The nucleoside-containing fractions were collected and concentrated in vacuo to give 225, milligrams (11%) of the compound. MS: 150 · 08 (M + Η). Step 2. Ν, Ν-dimethyl · Ν The synthesis of,-(8-methyl-9Η_purin-6-yl) formamidine will be dissolved in MeOH (14 ml) and dioxane (7 ml) in the above step 1 of 0 \ 88 \ 88427.DOC- 151-200423945 n, n dimethyl dimethyl was added to the suspension of the product (225 mg, 丨 51 mmol) Acid dimethyl dimethylacetate (0.8 ml, 4.52 mmol) and the mixture was heated at reflux for 24 hours. The resulting yellow solution was concentrated in vacuo to a yellow oil. This oil was combined with methane (2χ 1 5 Ml) were co-evaporated and maintained under high vacuum for 2 hours. The crude product was used directly in step 3 without further purification. Step 3. 2- (6-amino-8-methyl-purinyl) protected by benzyl ) _Synthesis of 5-hydroxymethyl-tetrahydro · crean-3,4-diol in a bath of 1,2-dichloroethane (10 ml) of the product from step 2 above BSA (0.8 ml, 3.322 mmol) was added to the solution) and heated under reflux in argon for 1.5 hours. The solution was cooled a little and added to dichloromethane (10 ml) Β-D-ribofuranosyl 1-acetic acid 2,3,5-tribenzyl acetate (.691 g, 1.37 mmol), and then immediately added DMS MSTF (i ml, 5.48 mmol) The reaction was heated to reflux for 24 hours, then another 0.5 ml of TMSOTf was added, and the reaction was refluxed for another 48 hours. The reaction was cooled to room temperature, diluted with dichloromethane, and saturated with NaHCOK 1x7. 5 ml) was washed. The aqueous layer was extracted with dichloromethane (2 x 50 ml) and the combined organic layers were washed with Η20 (1 x 75 ml), brine φ t liter, dehydrated with NkSO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography using 5% methanol in dichloromethane as the eluent. Collect the appropriate fractions and concentrate in vacuo to obtain the desired compound. MS: 649 · 21 (M + Η) 〇 Step 4. 2- (6-Amino-8-methyl-purine-9-yl) -5-hydroxymethyl · tetrahydro-furan-3,4 · di Synthesis of Alcohol The product of Step 3 above was dissolved in 7M ammonia in MeOH (30 ml) and

O: \ 88 \ 88427.DOC -152- 200423945 Stir at room temperature for 24 hours. The reaction was concentrated and the residue was dissolved in dms0 (iml) and water (4ml) and purified by * HPLCa0-10% buffer b in 30min at a flow rate of ml / min. Buffer A-0.1% triethylammonium acetate aqueous solution, and Buffer B-0.1% triethylammonium acetate 2CH3Cn solution. The nuclear bitter fractions were collected and concentrated in vacuo to give 6Q mg (16% from step 3) of the desired compound. MS ... 282 · 09 (M + H). H-NMR (CD3OD). 2.6 (s? 3H5 -CH3) 5 3.6-5.0 (m? 5¾ 5.9 (d, 1H? Lf-H), 8.1 (s, 1H, -Ar). Example 110 Amine methyl 5_hydroxymethyl Mou_3_ Jia Mou · Four Qi-Wu Wuji j, 4_Two drunk He Rong Manhui 1. 2_ (6_amino_8_methyl-purine) protected by 2,3,5 triple protection Ha_9_. Based on a 5_methyl_3-methyl1hydro_pyran_3,4_di 醢 之 会 # in N dissolved in 1,2-digas ethane (10 ml) To a solution of N, dimethyl-N, _ (8-methyl-9H-purin-6-yl) fluorene (1.71 mmol) (crude product of Example 10, step 2) was added BSA (1.0 Ml, 4.05 mmol) and heated under argon at reflux for 1.5 hours. The solution was cooled slightly and 1,2,3,5_ dissolved in 1,2-dichloroethane (10 ml) was added. Tetra-0-benzyl_2, -C-methyl β-D-ribofuranose (0.750 g '1.29 mmol), and TMS 0f (1.5 ml, 8.3 mmol) was added immediately. The reaction was heated Reflux for 24 hours. The reaction was cooled to room temperature, diluted with dichloromethane, washed with saturated NaHC03 (1x75 mL). The aqueous layer was extracted with dichloromethane (2x50 mL) and h2O (1 &gt; &lt; 75 ml), saline (1 x 70 millimeters) ) The combined organic layer was washed, dehydrated and then to Na2S04 concentrated in vacuo

O: \ 88 \ 88427.DOC -153-200423945, the crude product was purified by silica gel column chromatography, and 5% methanol in methylene chloride was used as the eluent. The appropriate fractions were collected and concentrated in vacuo to give the title compound. Buzen 2 · 2 (6-Aminomethyl-Aroyl) -5-By synthesis of methylmethyl_tetrahydro · furan_3,4_diol Dissolve the compound from step 1 in 7M ammonia MeOH (30 ml) and stirred at room temperature for 24 hours. The reaction was concentrated and the residue was dissolved in DMSO (1 ml) and water (4 ml) and analyzed by HPLC with 0-10% buffer solution B-B at a flow rate of 10 ml / min for 30 minutes. purification. Buffer solution A_〇ιι% φ triethylammonium acetate aqueous solution, buffer solution B-1. 1% triethylammonium acetate CHsCN solution. The nucleoside-containing fractions were collected and concentrated in vacuo to give 60 mg (16% from step 1) of the desired compound. MS: 296_13 (M + H). tf-NMRCCDsOD): 1.05 (s, 3H, -CH3), 2.6 (s, 3H, -CH3), 3.6-4.2 (m, 4H, sugar), 6.1 (s, 1H, Γ-Η), 8.7 (s , 1H, -Ar). Example 111 · 2- [6-Amino-8- (N'-methyl-hydrazino) -purine-9-ylbutan 5-hydroxymethyl-tetrahydro-furan-3,4-diol (185) Synthesis 1 To a solution of 8-bromo adenosine (Aldrich, 0.1 g, 0.289 mmol) in DMF-methyl hydrazine (0.15 ml, 2.89 mmol) was added and the mixture was heated to 8 5 ° C for 3 hours. The crude product was purified by column chromatography on Shixi gel, washed with 2.5% methanol in dioxane and dissolved in 20% methanol. The appropriate fractions were collected and concentrated in vacuo to give 90 mg (100%) of the title compound. 0 \ 88 \ 88427 DOC -154- 200423945 MS: 312.16 (M + H).

Hi-NMR (DMS 0-d6): 3.05 (s, 3H, -CH3), 3.4-4.2, 4.85 (m, 5H, sugar), 5.0-5.2, 5.9 (s, 3H, -OH), 4.7 ( m, 2H, NH), 6.35 (s, 1H, Γ-Η), 6,9 (s, 2H, -NH2), 7.95 (s, 1H, -A0. Example 112 2- (6-amino- Synthesis of 8-fluorenoxy-purine-9-kib 5-hydroxymethyl-tetrahydro-furan-3, 'diol was synthesized in 8-bromo adenosine (Aldrich, 0.1 g, dissolved in MeOH (25 ml), 0.289 mmoles) was added to sodium methoxide (0.1 g, 181 mmoles) and the mixture was heated to 85 C for 2 hours. The reaction was terminated with Dow_X 500 resin (h +), filtered and treated with Me OH (15 ml) was washed Dow-X, and then washed with 7M ammonia methanol solution (15 ml). The filtrate was concentrated and purified by silica gel column chromatography using 20 ° /. Dissolved in dichloromethane Methanol was used as the eluent. Appropriate fractions were collected and concentrated in vacuo to give 81 mg (94%) of the title compound. MS: 298 · 10 (Μ + Η) ° H1-NMR (DMSO-d6): 4.1 (S ) 3H, -CH3)? 3.4-4.2, 4.85 (m? 5H, sugar), 5.1-5.5 (m, 3H, -0H), 5.7 (d, 1H, Γ-Η), 7.0 (s, 2H, -NH2), 8.0 (s, 1H, -Ar). Example 1 13 7- (3,4-dihydroxy-5_hydroxymethyl_3_methyl_tetrahydrofuran · 2-yl) _3,7_dihydro-nbpyridine [2,3-d] pyrimidin-4-one ( 188) was synthesized in 2- (4-amino-sigma [2,3-d] pyrimidin-7-yl) -5-hydroxymethyl_ dissolved in NMP (2 ml) and acetonitrile (2 ml). To a solution of 3-methyl-tetrahydro-furan-3, diol (0.09 g, 0.321 mmol) was added acetaldehyde chloride (50% water-soluble O: \ 88 \ 88427 DOC -155- 200423945 solution '). 40.8 μl '〇_321 millimoles) and the mixture was heated to 50. (: lasted 24 hours. The reaction was concentrated in vacuo, diluted with H20 and by hplc, gradient 2¾ buffer B, to Purify within 30 minutes at a flow rate of 20 ml / min. Buffer A-0.1% triethylammonium acetate aqueous solution, buffer ^ _0.1% triethylammonium acetate CHsCN solution. Collect the nucleoside-containing differentiation, The title compound was 53 mg (59%) in vacuo / MS. MS ·· 2 8 2 · 1 0 (M + Η) 0H1-NMR (DMSO-d6): 0.65 (S) 3H, 2f-CH3) 3 3.5-4.0 (m5 4H3 · sugar), 6.1 (s, ih, l'_H), 6.5 (d, 1H, -Ai〇, 7.5 (d, 1H, _Ar), 7.9 (s , ^ 1H, -Ar), 11.95 (s, 1H, -NH ). Example 114 Synthesis of Amino-9- (3,4_dihydroxyhydroxymethyl_3_methyl · tetrahydro_furan · 2_yl) · 7,9_dihydro · thyrin-8-one (173) Step 1.Difluoroacetic acid 5_ [8_bromo-6- (2,2,2-trifluoro_ethylamidoaminopurine)

Pyridyl group] Synthesis of _4_methyl_3,4_bis- (2,2,2_trifluoro_ethoxyltetrahydro · sweet-2-ylmethyl vinegar (14.5 ml) of a solution of 8_ desert glandular urn, A. 2.89 ^ mole, was added with trifluoroacetic anhydride (1 () ml, 57 · mmol) and stirred for 4 hours. This was transparent The solution was concentrated in vacuum and co-evaporated with chlorochlorin (3 × 15 ml) and foamed to obtain 2 g (100%) of the 3 desired compound, which did not need to be purified—it was used directly in the step. 2. Step 2. 6-amino_9- (3 4--S: a: c 乂 (, 4-hydroxymethyl_3-fluorenyl-tetrahydroranyl) -7,9-di The synthesis of hydrogen_purine · 8_one is in the product of Gu Yu anhydrous acetic acid +!. The product of v step 1 (1.05 g, 1.45 mmol:

O: \ 88 \ 88427.DOC -156- 200423945 ears) solution (in a pre-dried and triangle flask cooled in argon) was added with Cul (13.7 mg, 0.0725 mmol), TEA (3 67 ml, 〇 · 4 μ), tetrakis (dibenzyl phosphate) palladium (83 mg, 5 mol%), and trimethylsilylacetylene (0.4 # liter, 2.90 mmol). The reaction was heated to 80 t: for 20 hours, cooled, passed through thin diatomaceous earth and concentrated in vacuo to an oil. The crude product was purified by silica gel chromatography using EtOAc: MeOH: CH2C1 of 1: i.6: 4 as the eluent. The appropriate fractions were collected, concentrated in vacuo to an oil, and precipitated with alcohol / diethyl ether to give 250 mg (61%) of the title compound. MS: 284.11 (M + H) OH NMR (DMSCM6): 3.2-4.2, 4.85 (m, 5H, sugar), 5.0-5.3 (m, 3H, -OH), 5.7 (s, 1H , Γ-Η), 6.6 (s, 2H, -NH2), 8.0 (d, 1H, -Ar), 10.4 (s, 1H, -NH). Example 115 2- Via synthesis of methyl-5_ (1,33,5,6-tetra322-38-indan-6-yl) _tetrahydro-squean-3,4-diol (186) To a solution of DMF (2 ml) in diubercidin (Sigma, 0.03 g, 0.113 mmol) was added gasified acetaldehyde (14 ml, 0.226 mmol) and heated to 50 ° C for 20 hours. The reaction was concentrated in vacuo and purified by silica gel column chromatography using 20% fluorenyl alcohol in methanol as the eluent. Appropriate fractions were collected and concentrated in vacuo to give 30 mg (94%) of the title compound. MS: 291.12 (M + H). H ^ NMRCCDSOD) ··· 3.7-4.6 (m, 5H, sugar), 6.25 (d, 1H, Γ-Η), 6.85 (d, 1H, -Ar), 7.45 (d, 1H, -Ar), 7.6 ( d, 1H, -Ar), 8.95 (s, 1H, -Ar). Example 116 OA88 \ 884r7.DOC -157- 200423945 via methyl_3_methyl-2- (1,38,5,6-tetra323-35_indene-6_yl) -tetrahydrofuran-3 Synthesis of 1,4-diol (166) in 2- (4-aminobilo [2,3-d] pyrimidin-5-hydroxyamidino-3-methyl-tetrahydrofuran dissolved in DMF (12 ml) -3, a solution of cardiodiol (0.7 g, 0.25 mimol) in a solution of 7.0 microliters of acetaldehyde chloride (50% aqueous solution, 35 microliters, 275 mmol). After the last addition, the mixture was stirred for 2 hours and concentrated in vacuo and purified by silica gel column chromatography 'using 20% methanol in methylene chloride as the eluent. Collect the appropriate distinction 'Concentrated in vacuo to give 71 mg (94%) of the title compound. MS: 305.1 1 (M + Η). H ^ NME ^ eOD) · 0.8 (s, 3Η, 2'-CH3), 3.7 -4 · 2 (m, 4Η, sugar), 6.4 (s, 1Η, Γ_Η), 6.85 (d, 1H, -Ar), 7.45 (d, 1H, -Ar), 7.7 (d, 1H, -Ar) , 7.9 (d, 1H, ★), 8.95 (s, 1H, -Ar). Example 117 Synthesis of 2- (4_amino_6-methylpyrrole [2,3-d] pyrimidinyl) _5_hydroxymethyl_tetrahydro_furan-3,4-diol (219) Step 1. Synthesis of 6-methyl-7H-pyrrole [2,3-d] pyrimidin-4-ylamine NfNf-diamidinofluorenamine difluorenyl acetal (equivalent) was added to 2,6-dmf Diamine pyrimidine and heated to 80 ° C. The resulting monoprotected compound was purified and converted to hydrazine with NaNO2, 6N HC1, 0t :, and then SnCl2-2H2O. In hydrazine in EtOH Acetone and tea are added to the mixture and refluxed. The obtained hydrazone is heated in the presence of PPA to form the desired product. Step 2. 2- (4-Amino-6-methyl · pyrrole [2,3-d] pyrimidine- 7-yl) -5 · Hydroxymethyltetrahydro-furan-3,4-diol Synthesis O: \ 88 \ 88427.DOC -158- 200423945 The title compound was prepared as in step 2 and step 3 of Example 107 Illustrate the use of β-DlO-methyl-2,3,5, -tris (2,4-digas benzyl) -ribofuranose and the compound obtained from step 1 above. Example 118 2_ (4-amino-6 -Synthesis of methyl-2-bilo [2,3_d] pyrimidine_7_yl) -5-hydroxyfluorenyl-3-fluorenyl-tetrahydro-furan_3,4-diol (220) The product of step 1 is silylated and reacted with 1- -3,5-bis- (2,4-dichlorobenzyloxy) -2-C-methyl ribofuranose, as described in Example 2 steps 2 and 3. See Example 119 4-Amine group_ 8- (3,4-Dimethynyl via methyl_3_methyl-tetrahydro_sweetness_2 monomethylthio-7-oxy-7,8-dihydro-pyridine The synthesis step of (230) is called 1. 4-amino-2-methylthio-4_oxy-7,8-dihydro-piperidine-6-carboxylic acid ethyl acetate synthesis of 4-amino-7- The synthesis of ethoxy-7,8-dihydro-piperidine-6-carboxylic acid ethyl ester is as described in M .: Ott and W. Pfleiderer Chem. Ber. 1974, 107, 339-361. Procedure 2 · 4-Amino_8_ (3,4-dihydroxy · 5_hydroxyfluorenylmethyl_tetrahydro_furan-2-yl) -2-methylthio_7_oxyocta, 8-dihydro _Pyridinylcarboxylic acid sulfonamide synthesis silanizes the product of step 1 above and condenses with 1,2,3,5-tetra-o-benzyl-2, -C_fluorenyl-β-D-ribofuranose See Example%, steps 2 and 3) to give the title compound.

O: \ 88 \ 88427.DOC -159- 200423945 Example 120 4-Amino-8- (3,4-dihydroxy_5-hydroxymethyl_3_methyl-tetrahydro-furan-2-yloxy _7,8_ Synthesis of dihydro-pyridine-6-carboxylic acid sulfamidine 4-Ramin-8- (3,4-dihydroxy-5-hydroxymethyl-3 -methyl- Tetrahydro-furan-2-yl &gt; 2-fluorenylthio-7-oxy-7,8-dihydro-pyridin-6-carboxylic acid sulfonamide (see Example 108, step 1) to give the title compound. Example 121 4-Amino-8- (3, 'dihydroxy · 5-hydroxymethyl · tetrahydro_furyloxy-5,8-dihydropyridine [2,3-d] pyrimidine-6-carboxylic acid Synthetic steps of hydrazine (225) 1. Synthesis of 4-Gas_5-oxy_5,8_dihydro-pyridine [2,3_d] pyrimidine-6_carboxylic acid ethyl acetate. Treatment of 2-methyl with Raney nickel Thio-4,5 -dioxy-3,4,5,8 -tetrahydro-roar [2,3-dp bite-6-carboxylic acid ethyl ester to remove the thiomethyl group. The resulting The product was refluxed in POCl 13. Step 2-4-Amino-8- (3,4-di-acryl-5-methyl-tetrahydro-cret-2-yl) -5-oxy · Synthesis of 5,8-dihydro-pyridine [2,3-d] pyrimidin-6-carboxylic acid amidoamine Silanizes the product of step 1 above and combines it with 丨, 2,3,5-tetra-0-benzyl -2, -C-methyl-β-D-ribofuranose and treatment with liquid ammonia See Example 26, steps 2 and 3.) Example 122 4-Amino-8_ (3,4-dihydroxy_5_hydroxymethyl_3_fluorenyl-tetrahydro-furan-2_yl) -811_pyridine Synthesis of [2,3_ (1) pyrimidin-5-one (22 6) 1. 1.4 gas-8H-e specific bite [2,3_d] Bite of _5 · ketone synthesis will be 4-chloro-5- Oxy-5,8-dihydrobipyridine [2,3-d] pyrimidinecarboxylic acid ethyl ester soap O: \ 88 \ 88427.DOC -160- 200423945 and was further heated by quinoline in the presence of copper. Decarboxylation to give the title compound. 2. 4-amino-8- (3,4-dihydroxy-5_hydroxymethyl-3-fluorenyl-tetrahydro-furan_2_yl) -8H_pyridine [ Synthesis of 2,3-d] pyrimidin_5 ketone Silanizes the product of step 1 above and reacts with 1,2,3,5-tetra-0-benzyl-2, -C-methyl 4-D-furan Ribose condensation and treatment with liquid ammonia (see Example 26, steps 2 and 3). Example 123 2_ (2,4_Digas_5Η · pyrrole [3,2_d] pyrimidine_7-yl) -5-hydroxymethyl_ Synthesis of 3 • methyl-tetrahydro-furan_3,4 · diol (183) in a single step 1.4- (2,4-digas_benzyloxy) -5- (2,4-digas- Synthesis of benzyloxy) _2- (4,6_imidazole [4,5-c] pyridin-1_yl) _3_methyl_tetrahydro-furan-3-ol, such as R · J · Rousseau * RKRobins , J. Heterocycl.Chem · The description of 1965, 2, 196-201 synthesizes 4,6-dichloroimidazole [4,5-c] pyridine. In a solution of 4,6-dichloroimidazole [4,5-c] pyridine (400 μg '2.1 mmol) dissolved in 30 ml of anhydrous acetonitrile in argon, sodium hydride (60%) was added at room temperature. / (), 93 2 Aike, 2.3 millimoles). The solution was stirred for 4 hours. Methyl_3,5-bis- (2,4-digas-benzyloxy) -2-(::-methylhydrazone-〇- To a solution of ribofuranose (35 0.6 mg, 0.7 mmol) was added dropwise 6 equivalents of 30% HBr dissolved in 0 ° C at 0 ° C. The solution was stirred at 0 t for 1 hour. The mixture was stirred at room temperature for 3 hours. The solution was concentrated in vacuo and co-evaporated with benzene. The residue was dissolved in 10 ml of anhydrous acetonitrile and added to the sodium salt solution prepared above. O: \ 88 \ 88427 .DOC -161-200423945 The combined mixture was stirred at room temperature for 24 hours and evaporated to dryness. The residue was bathed in ethyl acetate and washed with water). The water was decanted twice with ethyl acetate. The combined organic layers were washed with brine and dehydrated with anhydrous sodium sulfate. The solvent was removed in vacuo. Final purification using column chromatography to give 252 mg (0.386 mmol, 54.65%) of 4- (2,4-dichloro-etooxy) -5- (2,4-dichloro-benzyloxymethyl) Yl) -2- (4,6-imidazole [4,5-c] pyridine-b-yl) -J-fluorenyl-tetrazol-σfuranol. Step 2. 2_ (2,4_Digas-5Η_ ° Bilo [3,2_d] Hydro_7_yl) _5_Methyl-3-methyl-tetrahydro-furan-3,4_diol Synthesis The product from Step 1 (252 mg, 0.39 mmol) was dissolved in dichloromethane (10 ml) and the temperature was reduced to -78 ° C. Boron trichloride (1.0 M, dissolved in dichloromethane, 3.9 ml, 3.9 mmol) was added dropwise to the reaction. The reaction was stirred at -78 ° C for 2 hours and then allowed to warm to -20 ° C overnight. The reaction was stopped with 1: 1 methanol: dichloromethane (20 ml) and stirred at -20 ° C for 15 minutes. The reaction was neutralized with NH4OH and concentrated in vacuo to a solid. The product was purified by silica gel column chromatography to obtain a white compound (60 mg). MS: 334.08, 336.08 (M + H). H ^ NMRCCDSOD): 8.90 (s5 1H)? 7.87 (s? 1H)? 5.97 (s, 1H) 5 4.02-4.07 (m3 3H), 3.84-3.89 (m, 1H), 0.88 (s, 3H). Example 124 2- (4-Amino-2_gas-5H · 11 ratio [3,2-d] Houdian-7_yl) -5-Methyl-3_methyltetrahydrofuran-3,4_di The synthesis of alcohol (187) will be 2- (2,4-digas-5H-. Than [3,2-d] pyrimidin-7-yl) -5-hydroxymethyl-3-methyl-tetrahydro- Osan-3,4-diol (183) (40 mg) in a metal pressure-resistant elastic container O: \ 88 \ 88427.DOC -162- 200423945

Skewered and cooled the trough to -80 C (C / dry ice bath). Ammonia (5 ml) is condensed from the air tank until liquid splashes from the existing needles ^ Seal the bomb container. The reaction was heated to 135 t for another 2 days. Evaporation of dichloromethane showed almost complete reaction. After passing through a column (chloroform: methanol 5: 1), 20 mg of the product was obtained. MS: 315.08 (M + H) ttf-NMI ^ CmOD): 8.53 (s, 1H), 6.99 (s, 1H), 5.83 (s 1H), 5 54 (d, 1H), 4.02-4.09 (m, 3H), 3-84-3.89 (m, 1H), 0.88 (s, 3H). Example 125 2- (4_Amino-5H_0Bilo [3,2-d] Mouth bite-7-yl) _5_ Via methyl 3methyl · Tetrahydro_furan_3,4_diol (201) Synthesis The compound 1 87 (40 mg) was dissolved in a mixture of ethyl acetate and methanol and 100 mg of 10% Pd / C and 2 ml of an equivalent sodium hydroxide solution were added. The RP-payable product was evaporated for 3 hours at 40 p s i and evaporated and purified by a second column chromatography (2.1 aerosol-methanol) to give 24 mg of the pure title product. MS 281.11 (M + H). H ^ NMRCCDSOD): 8.60 (s, 1Η), 7.70 (d, 1Η), 6.99 (d, 1Η), 5.91 (s, 1Η), 4.02- 4.09 (m, 3H), 3.84_3.89 (m, 1H ), 0.88 (s, 3H). Example 126 Synthesis of 4-Gas_7-fluoro-l- (2'-C-methyl-β-D-ribofuranosyl) imidazole [4,5-c] pyridine (213) -7-Fluoro-imidazole [4,5-cp than pyridin-1-yl) _4_ (2,4_digas_benzyloxymethyl) _3_fluorenyl-tetrahydro-furan-3-ol Synthesis O: \ 88 \ 88427.DOC -163-200423945 such as M.-C. Liu et al., Nucleosides, Nucleosides &amp; Nucleic

The description in Acids 2001, 20 (12), 1975-2000 synthesizes 4-Pygium fluorinated imidazole [4,5-c] ° ratio. In a solution of 1-methyl_3,5_bis- (2, cardiodichloro-benzyloxy) -2-C-fluorenyl-β-D-ribofuranose dissolved in anhydrous dichloromethane, HBr (30 ° / 0 weight ratio, dissolved in acetic acid, i ml) was added dropwise thereto. The resulting solution was added at 0. Stir at 0 ° C for 1 hour and then at room temperature for 3 hours, evaporate in vacuum and co-evaporate with anhydrous toluene. The oily residue was dissolved in anhydrous acetonitrile and added to sodium chloride-7-fluorinated miso [4,5-c] pyridine sodium salt solution ('chloro-7-fluorinated imidazole [4,5-c ]. It is prepared by stirring bismuth with sodium hydride (60% dissolved in mineral oil) in anhydrous acetonitrile for 4 hours. The combined mixture was allowed to stir at room temperature for 24 hours, and then treated to dryness. The residue was diluted with ethyl acetate and water. The aqueous layer was removed and re-extracted with ethyl acetate. The combined organic fractions were washed with brine and dried over magnesium sulfate. The reaction was purified using silica gel column chromatography to give the title product. Step 2. Synthesis of 4-Gas-7-Fluoro-1- (2'-c-methylfuranyl ribosyl) imidazole [4,5-c] pyridine. The product from step 1 above is dissolved in dichloromethane and The temperature dropped to 8 ° C. Trichloro code (1.0M, dissolved in dichloromethane) was added dropwise to the reaction. The reaction was stirred at -78 C for 2 hours and then warmed to -20. 〇 Overnight. The reaction was terminated with}: methanol · -mastrin. Disturb down for 15 minutes. Use N Η 4 Ο Η to neutralize the reaction and condense it in a vacuum + i Λ to concentrate it in a vacuum. The product was purified by silica gel column chromatography to obtain the title compound. Example 127 Amino 7fluoro 1- (2-heart methyl-β each chewing ribosyl) tastes sharp [4,5 ...

O: \ 88 \ 88427.DOC -164- 200423945 Synthesis of tonidine (214) Suspension of compound 2 1 3 in anhydrous hydrazine was refluxed for 1 hour. The reaction mixture was evaporated to dryness in vacuo and the residue was co-lossed with wine and deoxygenated water. The crude intermediate was dissolved in deoxygenated water, Raney nickel catalyst was added, and the mixture was stirred under reflux for 8 hours under hydrogen. The reaction mixture was then filtered through celite while the catalyst was washed with hot water. The filtrate was evaporated to dryness and purified via column chromatography to give the title compound. Example 128 ^ 2- (4-Amino_5H-pyrrole [3,2_d] pyrimidin_7_yl) _5_hydroxymethyl-3_methyl- # tetrahydro-furan_3,4_diol (215 ) 'S synthesis step 1.3 · 4-bis- (2,4-digas-benzyloxy) _5_ (2, cardiodigas_benzyloxymethyl) -2 -methoxy-3 -methyl-tetra Hydrogen-biting taste 2.3 grams of 1-methyl-3,5-bis- was dissolved in 25 ml of DMF. To this solution was added NaH and heated to 60C. After the evolution of hydrogen gas ceased, 2,4-agascarki-chlorine was added dropwise at 40 ° C. The mixture was stirred for another 16 hours, and then 5 ml of methanol was added. Column chromatography (9 ·· 1 ethyl acetate / hexane) φ gave 1.77 g of product. ® Step Weighing 2 · 3,4-Bis- (2,4-Digas-Benzyloxy) _5_ (2,4-Digas-Benzyloxymethyl) · -3 -Methyl-Diazine-Bite Drink- 2-net * The product from step 1 (1.42 g) was dissolved in 40 ml of dioxane. To this solution was added 40 ml of 4N HC1 and heated to 100. (After 3.16 hours, the solution was adjusted to pH 11 with saturated NaHC03 and extracted with EtOAc (3 x 100 ml). The combined organic fractions were dehydrated and evaporated with NajCU. The crude mixture was dissolved in 15 ml of anhydrous Dichloromethane was added and 1. 4 6 6 g (1.6 oz O: \ 88 \ 88427.DOC -165- 200423945) of Dess Martin periodinane was added. After stirring for 1 day, the mixture was poured into 40 ml of 9 g NaHSCb Saturated NaHC03. Extracted with EtoAc (3x 100 ml), the organic layer was dehydrated and subjected to column chromatography (19: 1 Hex / EtoAc) to give 0.72 g of product. Step 3. Nf- (7-brook-5Η-σbilo [3,2-d] bite-4-yl) dimethylformamidine_ (2, 'digas-benzyloxymethyl) -3-methyl-di Hydrogen-furanone such as Montgomery and Hewson, J. Org · Chem "1965, 30, 1528-1531 The synthesis of 5Η-σΛ 17 each [3,2-d] ° dense. 4-Amine. [3,2-d], 4--4-ylamine was dissolved in dichloromethane and cooled to 0 ° C. In this solution was added bromine dissolved in dichloromethane through another funnel. After confirming the completion of the reaction by LC, it was extracted with EtOAc, dried over sodium sulfate and passed through a column. The product was dissolved in DMF and 1.2 equivalents of DMF dimethyl acetal was added. The reaction mixture was heated to 80. (: Until TLC confirmed the reaction was complete, evaporated, and chromatographed to give the title product. Step 4 2- (4-Amino-5H-pyrrole [3,2_d] pyrimidin-7-yl) _5_hydroxyfluorenyl-3_methyl · tetrahydro_furan_3,4_diol The product from step 3 above was dissolved To the THF solution, add -BuLi at -75X. After 1 hour at -75 ° C, add the lactone solution of the product of step 2 above in -75 ° C at -75 ° C, at this temperature It was stirred for 2 hours and then heated to 0 ° C over the next 3 hours. Saturated NaHC03 was added and the mixture was extracted with ether. The organic layer was washed with brine, dried over MgS04 and concentrated. The residue was dried , Dissolved in CHAh and triethylsilane and added BFsOEt2 dropwise at -75 ° C. The reaction mixture was allowed to warm overnight, the reaction was stopped with IN HC1 and stirred at room temperature for 1 hour. The organic mixture was neutralized with NaOH And 〇: \ 88 \ 88427 DOC -166-200423945

EtOAc extraction. The organic layer was washed with brine, dried over MgS04, concentrated, and purified by column chromatography. The resulting product was dissolved in dichloromethane and the temperature was lowered to -78C. Boron trigas (1.0 M, dissolved in dichloromethane) was added dropwise to the reaction. The reaction was stirred at -78 t for 2 hours and then allowed to warm up to-overnight. The reaction was terminated with 1.1 methanol: dichloromethane and at 20 °. Stir for 15 minutes. The reaction was neutralized with NHUOH and concentrated in vacuo. The product was stirred in ammonia in MeOH overnight. The product was purified via column chromatography. Example 129 Synthesis of 4-Amino-ribofuranosyl) imidazole [4,5_c] pyridine (216) Cardioamino-7-fluoro-1- (β-D.Ribosyl) imidazole [4 Synthesis system such as RR J. Rousseau, LB Townsend, and RK Robins, Biochemistry 1966, 5 (2), 756-760. Example 130 Synthesis of 4-Chloro-7-Fluoro-1- (4-, 7-fluoro-1- (0-〇-sucrose ribosyl)) [4,5-(:) ° bite (217) (0-O-ribofuranosyl) imidazole [4,5-(:] pyridine (217) is synthesized as in M.-C. Liu et al. 'Nucleosides, Nucleosides &amp; Nucleic Acids 2001, 20 (12), 1975 Explanation of -2000. Example 131 4_Amine_7-fluoro- l- (p_D-biting ribose) Miso [4,5-c] fllt ^ (218) i Synthesis of 4-Amine-7-Ga- 1- (β-ϋ-σ ribofosyl) taste. Synthesis of [4,5-(:) 0 than σ-determining (218) is such as MC Liu et al., Nucleosides, Nucleosides &amp; Nucleic Acids 2001, 20 (12), 1975-2000. O: \ 88 \ 88427.DOC -167- 200423945 Example 132 5-Methyl-3_methyl_2- (7_Songji Weijun [4,5-b ] -17 比 唆 -3_ 基) -tetrahydro-furan-3,4-diol (168) The synthesis step is called 1 · -7-nitro-3H_imidazole [4,5_b; G. Cristalli, P. Franchetti, M. Grifantini, S. Vittori, T. Bordoni and c. Geroni J. Med. Chem. 1987, 30, 1 686-1688 Description of Synthesis of 7-nitro-3H-imidazole [4 , 5-b] pyridine. Step 2-5-hydroxymethyl protected by 2,, 3,, 5, _tribenzyl _3-methyl_2_ (7__nitro_3Η · imidazole [4,5-b] pyridine_3_yl) _tetrahydro-furan-3,4_diol combination_ The product of step 1 above ( 1311 mg, 0.8 mmol) was dissolved in 10 ml of anhydrous acetonitrile. 0.5 ml (2.0 mmol) of N, 0-bis (trimethylsilyl) ethane 'was added and the solution was kept at reflux until Clarification-about 15 minutes. Then 'the 1,2,3,5-tetra-0-benzyl-2'-C-methyl β-D-ribofuranose (ribose X) (290 · 3 ^; g' 0.5¾ Moore) and trimethylxanthyl tertate metaxanthate (0.3 ml, 2.0 millimoles) were added to the solution. The solution was kept at reflux for 1 hour. After that, the reaction was cooled to room temperature The reaction was stopped by adding solid sodium bicarbonate (294 mg). The mixture was further diluted with 60 ml of saturated sodium bicarbonate. The product was extracted with chloroform. The organic phase was washed with brine, dehydrated with sulfuric acid, and evaporated. The oily yellow solid product was used immediately in the crude form in the next step. MS ·· 645.23 (M + Na) ° Step 3. 5-Methyl-3-methyl-M7-acyl_imidazole [4,5_b] 〇Specific change_3_yl) -tetrahydro-furan-3, Synthesis of 4-diol O: \ 88 \ 88427 D0C -168-200423945 gas in methanol solution.

The nucleoside in step 2 above was dissolved in 100 ml of 71 μL, and the reaction mixture was kept in a body. The crude mixture was chromatographed on a silica gel column. The fractions containing the title nucleoside were combined and evaporated to give 2 mg (49%) of the desired nucleoside. MS · 311.10 (M + H) 〇 Example 133 2- (7 · Amine-Weijun [4,5-b]-«Specific bite_3_yl) _5_ Via methyl_3_methyl · tetrahydro -Synthesis of bite-3,4-diol (61) 5-hydroxymethyl-3-methyl-2- (7-nitro-imidazole [4,5-b] -pyridine_3_yl) -Tetrahydro-furan-3,4-diol (47.0 mg, 0.15 mmol) was dissolved in 20 ml of methanol. A portion of palladium on carbon (10%) was added to the solution and the reaction mixture was placed in 50 psi of hydrogen for 0.5 hour. The palladium catalyst was filtered off, and the solvent was removed in vacuo. The product was freeze-dried from 1,4-dioxane to give the title nucleoside (34.1 mg, 80%) as a white fluffy powder. MS: 281.16 (M + H). Example 134 Synthesis of 5-light methyl-3 -methyl-2- (4-sonyl-benzobenzo-1 -yl) -tetrahydro-octane-3,4-diol (175) · Synthesis of 4-nitro_1H-benzimidazole as described in Sagi, G, et al., J. Med. Chem., 35, 24, 1992, 4549-4556. Synthesis of 4-nitro-1H-benzimidazole . Step 2. 5-Hydroxymethyl_3_methyl-2- (4-nitro · benzimidazole_1_yltetrahydro-furan-3 protected with 2,, 3 ', 5'-tribenzyl Synthesis of 1,4-diol O: \ 88 \ 88427.DOC -169- 200423945 The product of the above step 1 (130 · 5 mg, 0.8 mmol) was dissolved in ιιο 毫升 of anhydrous acetonitrile. 0.5 ml was added (2_0 millimoles) 2N, bis (trimethylsilyl) ^ and keep the solution under reflux until clear-about 15 minutes. Next, I #} tetrakisyl kappa methyl β · 〇4an Ribose (ribose X) (2δ0.6 mg, 0-5 mmol) and trimethylsilyl trifluorosulfonate (0.3 pen liters, 2.0 mmol) were added to the solution. The solution was kept Reflux for 1 hour. After that, the reaction was cooled to room temperature and stopped by adding solid sodium bicarbonate (294 mg). The mixture was further diluted with 60 ml of saturated sodium bicarbonate. The product was extracted with chloroform. The organic was washed with brine Phase, dehydrated with magnesium sulfate and burst. The oily solid product was used immediately in the crude form in the next step. MS: 680.20 (M + CH3C〇〇). Step 3. 5-hydroxymethylmethyl_2- (4_nitro_benzo Synthesis of azole ^ -yl) -tetrahydro • furan-3,4-diol The nucleoside of step 2 above was dissolved in 100 ml of a 7N ammonia methanol solution. The reaction mixture was maintained at 3 ° C. Overnight. The liquid was removed in vacuo the next day. The resulting crude compound was purified by silica gel column chromatography using 10% methanol in chloroform. The fractions containing the title nucleoside were combined and evaporated to give 12 0.2 Mg (78%) of the desired nucleoside. MS: 368.14 (M + CH3COO). Example 135 2- (4-Amino-benzimidazole 4-yl) _ 5-hydroxymethylmethyl-tetrahydro_furan The synthesis of _3,4_diol (176) will be the nucleoside 5-hydroxymethyl-3-methyl-2- (4-nitro-benzimidazole- 丨 ·) _tetrahydro-σfuran · 3,4-monool (59.3 mg, 0.19 mmol) was dissolved in 20 ml of methanol O: \ 88 \ 88427 DOC-170- 200423945. A portion of the palladium was added to the solution on carbon (10%) to the solution The reaction mixture was placed in hydrogen at 50 psi for 0.5 hours. The palladium catalyst was filtered off and the solvent was removed in vacuo. The product was evaporated from anhydrous wine 3 times to give the title core as a white powder. Bitter (47.5 mg, 89%). MS: 280.1 5 (Μ + Η). Example 136 2- (4-Amino-orbilo [2,3_b] pyrimidin-1-yl) -hydroxymethyl-3-methyltetrahydro-furan-3,4-di Synthetic steps of alcohol (ία) 1. Synthesis of 4-nitro-1H-pyrrole [2,3-b] pyridine, such as Antonini, I, et al., J. Med. Chem., 1982, 25, 1261-1264 Description The synthesis of 4-nitro-1H-pyrrole [2,3-b] pyridine. Step 2 · 4 · (2,4-Digas-benzyloxy) -5- (2,4-Digas_benzyloxymethyl) -3-methyl · 2- (4 2,3-b] 啦 bit-1-yl) _Synthesis of tetra-I-squeezol-3-ol The product of step 1 (188.9 mg, 1.2 mmol) dissolved in 30 ml of anhydrous acetonitrile Sodium hydride was added at room temperature under argon. The solution was stirred for 4 hours. Β-D-1-0-fluorenyl-2,3,5-tris (2,4-dichlorobenzyl) -ribofuranose (riboseγ) (91.5 mg) dissolved in 15 ml of anhydrous dichloromethane , 0.39 mmol) at 0. (: HBr (30%) was added dropwise under argon. The resulting solution was stirred at 0 ° C for 1 hour and then at room temperature for 3 hours, evaporated in vacuum and co-evaporated with anhydrous toluene. The residue Dissolve in 10 ml of anhydrous acetonitrile and add the sodium salt of the product from step 1 above. The combined mixture is allowed to stir at room temperature for 24 hours and evaporated to dryness. The residue is dissolved in EtOAc and washed with water / strip. This water was extracted 3x with EtoAc. The combined organic extracts O: \ 88 \ 88427.DOC -171-200423945 were washed with brine and dehydrated with Na2S04. The solvent was removed in vacuum. Use Shixi hose Column chromatography was performed with 30% ethyl acetate in hexane for final purification. The title nucleoside (102.6 mg, 42%) was isolated as a dark brown oil. MS: 686.04 (M + CH3CO). 3 · 5_ Synthesis of methyl_3_methyl-2_ (4-nitrobilo [2,34] 11 ratio) _tetrahydro_squeak_3,4_diol Synthesis of the above step 2 The product (102.6 mg, 0.16 mmol) was dissolved in 10 ml of CHK12. The temperature was lowered to 78 ° (: and BC13 (0.164 ml, 1.6¾ mole) was added dropwise to the reaction over 5 minutes. in. The reaction was stirred for 2.5 hours at -20 t and the Erlenmeyer flask was left at this temperature overnight. After ~ 20 hours, the reaction Erlenmeyer flask was warmed to room temperature, and 10 ml of methanol was used. : Dichloromethane (1: 1 ratio, 0.016M). Stop the reaction. Set the reaction flask back to 2 (Γ (: ring i 15 minutes and adjust to 27% NKUOH to test conditions. The neutralized crude The reaction was evaporated in vacuo and the product was chromatographed on a silica gel column using 10% methanol in chloroform as the dissolving solvent to give 37.0 mg (73%) of the title nuclear bitter. MS: 31〇.13 (M + H) Step 4. Synthesis of 2- (4-amino-benzimidazolyl) _ 5-hydroxyfluorenylmethyl · tetrahydro-sweet-3,4-diol Nucleosides (24.7 mg, 0.08 mmol) were dissolved in 10 ml of ethyl acetate. A portion of the palladium was added to the mixture on carbon (10%) and placed under hydrogen. 30 minutes. The palladium catalyst was immediately filtered off and the solvent was removed in vacuo. The title nucleoside (20.5 mg, 92%) was isolated as a pink solid.

O: \ 88 \ 88427.DOC -172- 200423945 MS: 280.13 (M + H). Example 137 2- (4,6_Digas-lalo [3,2-c] ° pyridin-1-yl) _ 5-hydroxymethyl-3 -methyl-tetrahydro-furan-3,4_ Synthetic steps of diol (21〇) 1.4, 6_digas_1H_pyrrole [3,2_c] pyridine Synthesis as Scneller, S.W., Hosmane, RS, J. Heterocyclic Chem, 15, 325 ( 1978) 'to synthesize 4,6-dichloro-1H-pyrrole [3,2-c] pyridine. Step 2 · 4_ (2,4_digas · benzyloxy) -5- (2,4-digas_benzyloxymethyl) _ φ 2- (4,6-, — 气-令》 洛 [3 , 2_c] Synthesis of a-bita-1 · yl) -3 -methyl-tetrahydro-succinol The base (1.01 g, 5.4 mmol) prepared in step 1 above was dissolved in 15 ml of anhydrous acetonitrile To the solution was added sodium hydride (60%, 260 mg, 6.5 mmol) under argon at room temperature. The solution was stirred for 4 hours. In a solution of 75¾ liters of anhydrous monochloromethane in methyl-2,3,5-tris (2 4 -dichlorobenzyl) -ribofuranose (sugar Y) (1.11 g, 2.2 mmol). . 〇 0.86 ml of HBr (30%) was added dropwise under the atmosphere. The resulting solution was stirred for 1 hour at room temperature and then for 3 hours at room temperature. The solution was evaporated in vacuo and co-evaporated with toluene. The residue was dissolved in 50 ml of anhydrous acetonitrile-and the sodium salt of the base prepared in the above step was added. The combined mixture was allowed to stand at room temperature for 24 hours' and evaporated to dryness. The residue was dissolved in EtoAc and washed with water. This water was extracted with EtoAe 3 &gt; &lt;. The organic extracts were combined with brine and dried over Na2SO4. The solvent was removed in vacuo. Final purification was performed using a Shixi gel column chromatography with a 30% ethyl acetate solution. The title nucleoside was isolated as a dark brown oil (724 · 3 mg, M%).

O: \ 88 \ 88427.DOC -173-200423945 MS: 708.9555 (M + CH3CO〇) 〇 Step scale 3. 2- (4,6_ digas bilo [3,2_c] pyridine_le group) _5 hydroxyl Synthesis of methylmethyl-tetrahydro-bitter-3,4-diol The product of Step 2 (724.3 mg, l.li mmol) was dissolved in 22.5 ml of CHAh in argon. The temperature was lowered to -78 t and BCldO (98 ml, 1.6 mmol) was added dropwise to the reaction over 5 minutes. The reaction was taxed for 2.5 days at -2 ° C and the amber flask was left at that temperature overnight. After ~ 20 hours, the reaction Erlenmeyer flask was warmed to room temperature, and the reaction was terminated with 10 ml of methanol · chloroform (1.1 ratio '〇.〇16M). Return the reaction cube to a 20 ° C environment for 15 minutes and adjust to 27% NHUOH to verify the condition. The neutralized crude reactant was evaporated in vacuo and the product was subjected to column chromatography on a stone column using 10% methanol in chloroform as a dissolving solvent to obtain 269.5 mg (73%) of the title nucleoside. MS: 333.04 (M + H ”Example 138 2 · (4-Amine-6 · Ga-0Bilo [3,2_c] 0 than 唆 -1_yl) _5_ Via methyl_3_methyl_ tetra The synthesis of hydrogen_furan_3,4_diol (211) will be 2- (4,6-dichloro- ° bilo [3,2-(:) 0 to 12 adi-1-yl) -5- Methyl-3-fluorenyl-tetrahydro-furan-3,4-diol (269.5 mg, 0.81 mmol) was placed in a metal bomb-type reactor and dissolved in liquid ammonia. The reactor was sealed The device was immersed in an oil bath at 13 5 ° C for 5 days. After that, the reactor was cooled to -78 ° C, opened and the liquid ammonia was evaporated. The crude reaction product was subjected to silica gel column chromatography using 20 % Methanol in chloroform solution. 130.0 mg (51%) of the title nucleoside was isolated. O: \ 88 \ 88427 DOC -174- 200423945 Example 139 k (4 · amino- ° pyrrole [3,2_C] pyridine- 1_kib 5_fluorenylmethyl_3_methyl_tetramethylene-furan · 3,4-diol (212, decanted out · 2- (4-amino-6-chloro- ° Bilo [3,2-c]. The ratio of sigma- ^ yl) · 5-Methyl-3-methyl-tetrahydro-furan-3,4-diol was dissolved in 20 ml of methanol and a part of Carbon (10%) and 2 ml of sodium hydroxide (1N). The reaction mixture was placed at 40 psi. After 4 hours, the catalyst was filtered off and the solvent was removed in vacuo. The reaction mixture was purified by dream gel column chromatography using 33% methanol in chloroform as the dissolving solvent. Biological Examples 1 · Anti-C Hepatitis-active compounds can exhibit anti-hepatitis C activity by inhibiting HCV polymerase, by inhibiting other enzymes involved in the replication cycle, or by other pathways. Many analyses evaluating these activities have been published. A general method for assessing severe increases in HCV virus in culture is disclosed by Miies et al. In US Patent No. 5,738,985. In vitro analysis has been published by KFerrari et al.,

Jnl. Of Vir., 73: 1649-1654, 1999; Ishii et al., Hepat 〇gy, 29: 1227-1235, 1999; Lohmann et al., Jni 〇f Bi chem., 274: 10807-10815 , 1999; and Yamashita et al., Jnl. 〇Bi BiChem ·, 273: 15479-15486, 1998 〇97 / 12033, applied by Emory University on September 27, 1996, with C. Hagedorn and A. Reinoldus are the inventors. They claim the priority of USSN 60 / 004,383, filed in September 1995, and describe a HCV polymerase that can be used to evaluate the activity of the compounds described herein. O: \ 88 \ 88427.DOC -175-200423945. Another analysis of HCV polymerase has been issued by Bartholomeusz et al., Atitis C Virus (HCV), pOlymerase ㈣ using cloned HCV non-structural proteins; Antiviral Therapy 1996: l (Supp 4) 18-24. Screening methods for measuring the decrease in kinase activity caused by HCV drugs are disclosed in U.S. Patent No. 6,030,785, which is Katze et al., U.S. Patent No., which is Deivecchi, et. number. The screening method for determining the protease inhibitory activity caused by the proposed Hcv drug is disclosed in U.S. Patent No. 5,861,267 which is Su et al., And U.S. Patent No. 5,739,002 which is ® De Francesco et al., And US Patent No. 5,597,691 to Hughughtori et al. Example 2. Replicon analysis The cell line ET (Huh-Lucubineo-ET) was used to screen compounds of the present invention for HCV RNA-dependent RNA polymerase. The et cell line was passed an RNA replica of I3 89luc-ubi / NS3-3 '/ ET; it had a firefly luciferase-ubiquitin-neomycin phosphotransferase fusion protein and an NS3-5B driven by EMCV-IRES The replicon of the polymerized protein is stably transfected and contains cell cultures of adaptive mutant strains (E1202G, T1280I, K1846T) (Krieger et al., 2001 and unpublished subjects). ET cells were grown in DMEM, and 100/0 · bovine fetal serum, 2 mM glutamine, penicillin (100 μυ / ml) / streptomycin (100 μg / ml), lx were added. Non-essential amine amino acids and 250 micrograms / ml G418 ("Geneticin"). Both can be purchased from Life Technologies (Bethesda, MD). The cells were smeared at 0.5-1 · 0x 104 cells / well on a 96-well plate Incubate for 24 hours before adding the nucleoside analog. Then add 5:50 μM of each compound to the cell: O: \ 88 \ 88427.DOC -176- 200423945. After 48-72 hours, add one Dissolve buffers and matrices to measure luciferase activity (catalog number Glo-lysis buffer-E2661 and Bright-Glo luciferase system E2620 Promega, Madison, WI). Do not allow cells to collect too much during the analysis. Percentage inhibition of day-to-day replication relative to the compound-free control group. Under the same conditions, the cell proliferation reagent, WST-1 (Roch, Germany) was used to determine the cytotoxicity of the compounds. The compounds with antiviral activity but no significant cytotoxicity were determined. IC5G and TC50. Example 3. Selection and cloning of recombinant HCV-NS5b The coding sequence of the NS5b protein was cloned from pFKI3 89luc / NS3-3 '/ ET by PCR, as described by Lohmann, V. et al. (1999) Science 285, 110-113, using the following primers: aggacatggatccgcggggtcgggcacgagacag (sequence 歹丨 j number: 1) aaggctggcatgcactcaatgtcctacacatggac (sequence 歹 J number: 2) The cloned fragment loses 21 amino acid residues at the C-terminus. Embedding the cloned fragment can provide an epitope at the carboxyl end of the protein (Epitope) -labeled (His) 6 in IPTG-inducible expressing plastids. After expressing the recombinant enzyme in XL-1 cells and introducing the expression, the affinity purification was performed on a nickel-NTA column using affinity chromatography. Protein. Storage conditions are 10 mM Tris-HCl pH 7.5, 50 mM NaCl, 0.1 mM EDTA, 1 mM DTT, 20% glycerol, at -20 ° C. Example 4. Analysis of polymerase activity by HCV-NS5b enzyme analysis The radiolabeled UTP is inserted into the RNA product by using a poly-A template (1000-10000 nucleosides) and oligo-Uu primers. Alternatively, a portion of the HCV genome is used as a template and a radiolabeled O: \ 88 is used \ 88427.DOC -177-200423945

However, GTP typically contains 50 mM of the assay mixture

Tris-HC1 (PH 7.5), 5 mM MgClh G. 2 mM EDTA, IQ mM KC1, 1 unit / microliter RNAsin, 1 mM DTT, 10 μM of various NTPs, cK3 ~ P] -GTP, 10 ng / Microliter poly A template and i nano / microliter oligou primer. Test compounds were dissolved in water containing 0-1% DMSO. Typically, the test concentration of the compound is in the range of 1 nM to 100 μM. The reaction begins with the addition of enzymes and is allowed to continue at room temperature or 30 ° C for 1 to 2 hours. The reaction was stopped with 20 microliters of 10 mM EDB A and the reaction mixture was spotted on a DE8 tray to capture the radiolabeled RNA product. After the uninserted NTP was washed with 0.5 mM Na2HP04 (3 times), water (1 time), and alcohol (1 time), the disc was dried and the intensity of the inserted radiation was measured by a scintillation counter. Examples of formulations The following are representative pharmaceutical formulations containing a compound of formula la, lb, Ic, IV, IVA, V or VA. Example 1 Tablet formulations The following ingredients were carefully mixed and pressed into monovalent tablets. Ingredients J, mg_ Compound of the invention 400 Corn starch 50 Croscarmellose sodium 25 Lactose 120 Magnesium stearate 5 Example 2 Capsule formulations The following ingredients were carefully mixed and filled into hard shell gelatin capsules. O: \ 88 \ 88427.DOC -178-200423945 Ingredients Compounds of the invention Lactose, spray-dried stearic acid urinary tablet U :, mg 2400 148 2 Example 3 Suspension formulation A suspension to be administered orally. Dosage gram 0.5 grams 2.0 grams 0.15 grams 0.55 grams 25.0 grams 13.00 grams 1.0 grams 1.0-35 milligrams 0.5 milligrams 0.5 milligrams quantitatively to 100 milliliter Methyl paraben Methyl paraben Propyl paraben Granular sugar sorbitol (70% solution)

Veegum K (Vanderbilt Company) Flavor pigment distilled water Example 4 Formulations for injection Sodium acetate buffer of the compound of the present invention, 0.4M HC1 (1N) or NaOH (lN) water (distilled, sterile) The following ingredients are mixed to form an injectable Of formulations. Ingredients_ Dosage 0.2mg-20mg 2.0ml adjusted to the appropriate pH and quantified to 20ml Example 5 Suppository formulation By combining the compound of the present invention with Witeps〇1⑧h_15 (the diglyceride of saturated vegetable fat S; Riches-Nelson, Inc. New York) mixed to make poultry

O: \ 88 \ 88427.DOC -179- 200423945 A suppository with a weight of 2.5 grams, which has the following components: Ingredient_ Dosage_ 1 Invention compound 500 milligrams

Witepsol® H-15 remaining weight O: \ 88 \ 88427.DOC -180-

Claims (1)

200423945 Scope of patent application: 1. A compound of formula la, lb or Ic, R2 Y! A lb WO R 〇H〇H Ic wherein R and R1 are independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl but Both R and R1 are not hydrogen; R2 is selected from the group consisting of: alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, dilute, substituted alkenyl, O: \ 88 \ 88427.DOC Substituted acylamino guanidinothio thioamino, hydroxy, alkoxy, substituted alkoxy, halo, nitro, sulfo Thioalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and _NR R, wherein R10R4 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, A group consisting of substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hetero%, substituted heterocyclic ring and R3 Forms a heterocyclic ring, substituted heterocyclic ring, heteroaryl, substituted heteroaryl together with R4 and the nitrogen atom bonded thereto The above definition and R5 is selected -nr5nr3r4, where R3 # r4 is a group consisting of free hydrogen and alkyl, O: \ 88 \ 88427.DOC 200423945 w is selected from the group consisting of: hydrogen, phosphate (including monophosphate, Bisphosphate, triphosphate or stabilized phosphate prodrug), phosphonate, prolinyl, alkyl, sulfonic acid, selected from alkyl esters, substituted alkyl groups, alkenyl esters , A group consisting of substituted alkenyl esters, aryl esters, substituted aryl esters, heteroaryl esters, substituted heteroaryl esters, heterocyclic esters, substituted heterocyclic esters, a fat An amino acid, a hydrocarbon, a peptide, and cholesterol; X is selected from the group consisting of: hydrogen, halo, alkyl, substituted alkyl, and -NR3R4, where R3 and R4 is as defined above; Y is selected from the group consisting of: hydrogen, O: \ 88 \ 88427.DOC 200423945 alkenyl 'hydroxyl, thiothio, -NR3R4, where R3 and R4 are as defined above; Z Is selected from the group consisting of hydrogen, halo, meridian, alkyl, Nitrogen, and -NR3R4, wherein R3 and R4 are as defined above; -NR5NR3R4, wherein R3, R4 and R5 are as defined above; and wherein T is selected from the group consisting of: a) 1- And 3-deazopurine: b) a purine nucleoside of the formula: c) benzimidazole riboside: O: \ 88 \ 88427 DOC -4- 200423945 d) 5-pyrrolyl pyridine nucleoside of the formula: R2〇) n or CG〆 (R20) n e) 4-, ° fixed base ° ratio σ fixed sangivamycin analogue f) 2-, olfactory base ° ratio. Ketone 331 ^ ¥¥ 3111 &gt; ^ 11 analogue 〇 human nW • ’g) 4-continuous group ° ratio σ sangivamycin analogue 〇 Q (R21), N N Y, (R10) o h) The analogue of the ratio f of the following formula is: σ 'N N ,, N in. , (R10) o N N O, (R10) P or i J Bulk σ dense group-tetrahydro σ ratio 唆: 〇 'Ν Ν j) The squeaking cry of the following formula (&amp; tetrahydrooctane ° dense σ fixed) O: \ 88 \ 88427.DOC 200423945 R12 Or k). Than suracil Ν 1) The σ Biluo mouth σ is determined by the following formula m) The following three formulae, 唆 N η) Pyridine of the formula: 〇 〇) pyridine C nucleoside of the formula: (P) Pyrazinetriazine C nucleoside of the formula O: \ 88 \ 88427.DOC 200423945 Q, n, n々, n '^ (R10) d (N Y q) indole riboside / r) the base of the formula: s) the base of the formula: R2〇 N Z R22 U) The basis of the following formula: V) Bases of the formula: O: \ 88 \ 88427 DOC w) the test base of the formula '· 1 k n, n々m x) the base of the formula: ΙΛ N y) a base of the formula: Moreover, where = between the bond _ and a ring carbon = double bond is a double bond, then p is 1; if it is a double bond, then ~ is a single bond, but if N, then P is 0 and if Q is a ring Among the carbon two, each P is individually 0 or i; each η is individually 0 or an integer of 1 to 4; each η * is individually 0 or an integer of 1 to 2; L is selected from hydrogen and halogen Group consisting of alkyl, alkyl, substituted alkyl, amine, substituted amine, azide and nitro; Q is selected from the group consisting of hydrogen, halo, = 〇, -〇R &quot;, = N-Rn, -NHR11, O: \ 88 \ 88427.DOC 200423945 diS, -SR, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic ring, and substituted heterocyclic ring Group M; M is selected from the group consisting of = 0, = n_rh and Y; Y is as defined above; R10 is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted A group of cycloalkyl, heterocycle, substituted heterocycle, alkylthioether, substituted alkylthioether, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, but If T is b), S), V), W) or x), then R io is not hydrogen; each R11 and R12 is independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic ring, substituted heterocyclic ring, amino group, and substituted A group consisting of amine, sulfide, substituted sulfide, aryl, substituted aryl, heteroaryl and substituted heteroaryl; each R2G is independently selected from the group consisting of Group: hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, O: \ 88 \ 88427.DOC 200423945 substituted alkynylheteroaryl, substituted heteroaryl, acylamino guanidinothiothioamido, alkoxy, substituted alkoxy, alkylthio R3, R4 and R5 are as defined above; each R21 and R22 are independently selected from the group consisting of Group: -NR3R4, where R3 and R4 are as defined above, -NR5NR3R4, where R3, R4 and R5 are as _C (〇) NR3R4, where R3 and R4 are as defined above, and _C (〇) NR5NR3R4, where R3, R4 and R5 are as defined above; and pharmaceutically acceptable salts thereof; however: 丄) For compounds of formula la, when Z is hydrogen, halo, hydroxy, azido, or -NR3r4, where R3 and R4 are each fluorene or alkyl; γ is hydrogen or O: \ 88 \ 88427 DOC -10- 200423945 -NR3R4, where R3 and R4 are each hydrogen or alkyl; then R2 is not alkyl, alkoxy, halo, hydroxy, CF3, or -NR3R4, where R3 and R4 are each hydrogen or alkyl; 2 ) For compounds of formula la, when z is hydrogen, cyano, hydroxy, azido or -NR3R4, where R3 and R4 are each η or alkyl; Y is hydrogen, halo, hydroxy or alkylthio; then R2 is not a alkynyl group, a substituted alkyl group, wherein the substituted alkyl group is a hydroxy group, an amine group, a thiophene group, a square amine group, an alkoxy group, a alkoxy group, a stilbyl group, a cyanide, a sulfuric acid, a sulfate , Acid, phosphate or phosphonate, with or without protection, halo, hydroxy, alkoxy, sulfanyl, or -NR R4 'where R and R are each hydrogen, Or substituted with a base, amine, alkylamino, arylamine, alkoxy, aryloxy, nitro, cyano, sulfuric acid, sulfate, phosphoric acid, phosphate or phosphonate, with or without protection 3) For a compound of formula lb, when X is hydrogen, radical, alkyl, CF, or -NR3R4, where is hydrogen and R4 is alkyl, then R2 is not alkyl, alkoxy, or radical , Hydroxy, CF3 or -NR3R4, where R3 and R4 are each hydrogen or alkyl; and 4) for compounds of formula lb, r2 is not halo, alkoxy, hydroxy, sulfanyl, or -NR3R4 (where R3 And R4 are each hydrogen, alkyl or hydroxyl O: \ 88 \ 88427.DOC -11- 200423945 group, amine group, amine group, arylamine group, lactate group, oxo group, nitro group, nitro group , Sulfuric acid, sulfate, phosphoric acid, phosphate or phosphonate, with or without protected alkyl group) and further make the compound of formula la, lb or Ic not a) 2- via methyl-5- (6-benzene Yl-l-sigma-9-yl) -tetrahydro-octane-3,4-diol; or 5) 2-Ethyl-5- (6-thiobenzene ~ 3-yl-purine-9-yl ) -Tetrahydro-sweetening_3,4_ diol. 2. A compound of formula II: Where R and R1 are independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, fine group, substituted alkenyl, alkynyl, substituted alkynyl, O: \ 88 \ 88427.DOC -12- 200423945 halogen, azide, amine, and substituted amine; but II and R1 are not both hydrogen; Y2 is CH2, N, s, SO or S02; N and- C (H) b and Y2 together form a hetero. ^, A di-substituted heterocyclic ring, a heteroaryl group, or a, to a substituted heteroaryl group, wherein , 隹 aryl or substituted heteroaryl is even surrounded by # ^ Fang Bao group is optionally with one or more selected from the group consisting of Wang Yi Shao Ji, bad Fuyi, heterocyclic, Fang Mei as hetero # ^ Fang Bao And a heterocyclic group consisting of a cyclic structure (each cyclic structure needs to be selected from 1 to 4 selected from the group consisting of hydroxydentyl, alkoxy, substituted alkoxy, sulfanyl, Substituted sulfanyl, aryl, heteroaryl, heterocyclic, nitro, cyano, carboxyl, carboxylate, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, Substituted acetylene Substituents of the group consisting of amino, amine and substituted amine groups) are fused to form a double or multiple fusion ring system (preferably no more than 5 fusion rings); b is an integer equal to 0 or 1; A, B, D and E are independently selected from the group consisting of> N, &gt; CH, &gt; C-CN, &gt; CN〇2, &gt; c-alkyl, &gt; C-substituted alkyl, &gt;. NHC0NH2, &gt; CC〇NR15R16, &gt; C-C00R15, &gt; C-hydroxyl, &gt; alkoxy, &gt; C-amino, &gt; C-alkylamine, &gt; C-dialkylamino ,> C-halogen, oxazole 1-yl), &gt; C- (1,3 · thiazol-2-yl) and &gt; 〇 (imidazol-2-yl); O: \ 88 \ 88427 .DOC -13-200423945 F system, selected from the group consisting of &gt; N, &gt; CH, &gt; C-CN, &gt; ON〇2, &gt; C-alkyl, &gt; C-substituted alkyl, &gt; c-nhconh2, &gt; C-CONR15R16, &gt; CC〇〇R15, &gt; c-alkoxy, &gt; C- (1,3-bite-2-yl), &gt; c- (l, 3 -4azole-2-yl), &gt; 〇 (imidazol-2-yl) and &gt; 0y, wherein Y is selected from the group consisting of hydrogen, halo, hydroxy, alkyl sulfide and -NR3R4 Group, wherein R3 and R4 are independently selected from hydrogen, hydroxyl Radical, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkyl, aryl, substituted aryl, hetero A group consisting of an aryl group, a substituted heteroaryl group, a heterocyclic ring, and a substituted heterocyclic ring, and if R3 and R4 together with the nitrogen atom bonded thereto form a heterocyclic group, only R3 and R4 One is hydroxy, alkoxy or substituted alkoxy; R15 and R16 are independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkane Group, aryl group, substituted aryl group, heteroaryl group, substituted heteroaryl group, and R and R16 are connected to it by 焉 + J, the original thousand form cycloalkyl group, substituted cycloalkyl group, heterocyclic ring Alkyl, substituted heteropyridine p I '&lt; heterophosphino, heteroaryl, substituted heterosquaryl; O: \ 88 \ 88427.DOC -14- 200423945 w is selected from the group consisting of Group ·· Hydrogen, phosphates (including monophosphates, bisphosphates, triphosphates, or stable and chemical phosphate prodrugs), phosphonates, alkyl, Flavic acid is selected from the group consisting of alkyl, g, substituted alkyl, alkenyl ester, substituted alkenyl ester, aryl ester, substituted aryl vinegar, heteroaryl ester, substituted A group consisting of a heteroaryl ester, a heterocyclic ester, and a substituted heterocyclic ester, a fat, an amino acid, a chloro compound, a peptide, and cholesterol; and a pharmaceutically acceptable salt thereof class. 3 · —Compounds of formula IIA: O: \ 88 \ 88427.DOC -15- 200423945 where R and R1 are independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, fine, substituted alkenyl, alkynyl , Substituted alkynyl, halogen, azide, amine, and substituted amine; but R and R1 are not both hydrogen; Y2 is CH2, N, S, SO, or s02; Heterocyclic Into a group of substituent substitutions) fused N and -C (H) b and Y2 together to form a heterocyclic, aryl or substituted heteroaryl group, in which ^ ring, heteroaryl or substituted heterofluorene 1 «^, Amine group and substituted amine group are combined to form a double or multiple fusion ring system O: \ 88 \ 88427 Γ) ΟΓ ~ 16-200423945 (preferably no more than 5 fusion rings); b is equal to An integer of 0 or 1; W is selected from the group consisting of: hydrogen, phosphates (including monophosphates, bisphosphates, triphosphates, or stabilized structurate prodrugs), phosphonates, 醯Group, alkyl, sulfonate, selected from alkyl esters, substituted alkyl esters, alkenyl esters, substituted alkenyl esters, aryl esters, substituted aryl esters, heteroaryl esters, A group consisting of a substituted heteroaryl ester, a heterocyclic ester, and a substituted heterocyclic ester, a fat, an amino acid, a hydrocarbon, a peptide, and cholesterol; Y is selected from the following Groups consisting of: hydrogen, halo, soy, sulfide, -NR3R4, where R3 and R4 are independently selected from the group consisting of hydrogen, hydroxyl , Alkane O: \ 88 \ 88427.DOC -17- 200423945 group, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy , Aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic ring, substituted heterocyclic ring, and R3 and R4 together with the nitrogen atom bonded to form a hetero group A cyclic group, but only one of R3 and R4 is a alkoxy group, a alkoxy group, or a substituted alkoxy group; Z is selected from the group consisting of: hydrogen, halo, alkoxy, alkyl, and Murine 'and -NR3R4, wherein R3 and R4 are independently selected from the group consisting of hydrogen, hydroxyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl' alkynyl, substituted alkynyl, alkoxy, A group consisting of substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic ring, substituted heterocyclic ring and R3 and R4 are bonded to it The nitrogen atom forms a heterocyclic group, but only one of R3 and R4 is a alkoxy group, an alkoxy group or a substituted alkoxy group; and a pharmaceutically acceptable salt thereof. 4. The compound according to any one of the claims No. 丨 _3, wherein the ruler is hydrogen and R1 is methyl. 5. The compound according to item 丨 or 3 of the scope of patent application, wherein it is hydrogen. O: \ 88 \ 88427.DOC -18-14 The compounds in the scope of patent application No. 1 or 3, wherein Rl3 is hydrogen. 1 group and R ~ compounds selected from the group consisting of: methyl-β-D-ribofuranosyl) -bu (thiobenzene_3_yl) purine · human 9 '(2' carapace N-ribosyl) -6_ (thiobenzene_2 • yl) _amino group 9- (2-C_methyl-β-D-ribofuranosyl) &gt; 6_ (pyrrole_3_yl) · purine; 9_ (2f-C_methylfuryl ribosyl) -6_phenylaminopurine, 9- (2'cardiomethyl-β-D · ribofuranosyl) dong (3-cyanophenyl) ; 9- (2'-C-methyl-β-D-ribosyl) -6-decapyridin-3-yl) "peptin; 9- (2'-C-methyl-β-D- Furyl ribosyl) Winter (benzo [b] thiophenyl jyl) _ Aminopurine; &amp; 9- (2 'Cardinyl ribo ribosyl) Dong (1HH5 · yl) _threonine 9- (2丨 -C_ methyl 9- (2 丨 -C-methyl 2-aminopurine; 9- (2 丨 -C- 曱 9- (2f-C_ methyl 9- (2 丨 -C- 曱 7- (2'- C- 曱 [2,3-d] a dense bite; 7- (2'-C-pyrimidin-2-ylamino-β-D-ribofuranosyl) _6_ (naphthalene_2_yl) _purine; -Β-D-ribofuranosyl) -6- (dibenzofurylhexyl-β-D-ribofuranosyl) _6_ (thienthanyl group) _purine; ribofuranosyl) -6- Cyclopropyl-2-aminopurine Pyridine; group-β-D-ribofuranosyl) -6_ (ethynyl) · purine; group-β-D_ ° ribofuranosyl) -4-thiophenyl-3-yl-7H-pyrrole d] yl-β-D -Ribofuranosyl) _4_phenyl-7Η-σbirrole [2,3- O: \ 88 \ 88427 DOC -19. 200423945 1- (2, C -methyl- β- D-11 ribofuranosyl ) -4 -thiophen-3-yl sigmadin-2-one; l- (2f-C-methyl-β-D-chrysyl ribosyl) -4 -phenyl-1Η-. Dense.- 2-copper; l- (2'-C-methyl-β-D-ribofuranosyl) -4-benzo [b] thiophen-2-yl-1H-pyrimidin-2-one; 1- (2 , C-methyl-β-D-ribofuranosyl) -4-cyclophenyl-1H-pyrimidin-2-one; 9- (2f-C-methyl-β_1furofuranosyl) _Νό- (2-di Methylaminoethyl) -adenine; 9- (2'-C-methyl-β-D-ribofuranosyl) -N6- (2-aminoethyl) adenine; 9- (2'- C-methyl-β-D-ribofuranosyl) -N6- [2- (3Η-indol-3-yl) ethyl] adenine; 9- (2f-C-methyl-β-D-furan Ribosyl) -6- [2-aminocarbonyl- (larolidin-1-yl)]-purine; l- (2f-C-fluorenyl-β-D-ribofuranosyl) -N4- (amino group Carbonylamido) -cytosine; 1- (2 ^ C-fluorenyl-β-D-ribofuranosyl) -N4-[( Pyridin-1-yl) -methyl] cytosine; 9- (2'-C-fluorenyl-β-D-ribofuranosyl) -N6-[(adenine-8-yl) -aminoethyl] Adenine; 9- (2'-C-fluorenyl-β-D-ribofuranosyl) -N6-[(benzene-3,4,5-triol) -fluorenyl] adenine; 9- (2f- C-methyl-β-D-ribofuranosyl) -N6- [1-aminocarbonyl O: \ 88 \ 88427.DOC -20- 200423945 -2- (3H-indole_3_yl) _ethyl ] Adenine; 9- (2'-C-methyl_p_D-ribosyl) -6_ (1,3,4,9_tetrahydrocarbolin-2 -yl). Pyridine; methyl_β_0_ribofuranosyl) _n4_ [Braminocarbonyl-2- (3Η-σbendol-3-yl) -ethyl] pyridine; 1 (2 C-fluorenyl-p_D • Furfuryl ribosyl pentafluorobenzyl_hydrazino) -pyrimidin-2-one; 1 (2 C-methyl ribofuranosyl) _4_ [4_ (3,4_dihydroxy-benzyl) 6,7__ meridyl_ 3, Cardiodihydro, 1H_Isoquinolinyl]; Bu (2-Cardiomethyl n-Ranosyl) _n4 Hepta-Cytosyl &gt; Ethyl] cytosine; Methyl PD-ribofuranosyl) _N4_ (2-Aminoethyl) cytosine; (Methyl P furfuryl) -N4 · (Aminocarbonyl-isopropyl_methyl) cytosine Cardiopyridinyl ribosyl) -N6_ {[(3H 令 朵 -3-yl) -acetic acid] -hydrazine} adenine; fluorenyl PD-ribofuranosyl) -N6_ [2_ (5_fluoro-benzimidazol-1-yl) -ethyl] gland Purine; 9 (2 C-methylsendeca ribosyl) -6-hydrazino-threonine; 9- (2'-C-fluorenyl n # Furnan ribosyl) -N-(2,2,3 , 3,3, -pentafluoropropyl) purine; 9 (2-C-fluorenyl_βheptafuranosyl) _6_ (piperidinyl), purine; 1 (2 C-fluorenyl4) Furyl ribosyl) _ιη_benzimidazole; O: \ 88 \ 88427.DOC -21-200423945 3- (2, C -Fluorenyl-β-D-ribofuranosyl) -3H-imidazole [4,5-b] pyrimidin-7-ylamine; 9- (2'-C-trifluoromethyl-β-D-ribofuranose ) -N6- (2-aminoethyl) adenine; 9- (2'-C-trifluoromethyl-β-D-ribofuranosyl) -N6- [2- (3H-indole-3 -Yl) -ethyl] adenine; p 9- (2'-C-trifluoromethyl-β-D-ribofuranosyl) -6- [2-aminocarbonyl group ... -〇 匕 洛 m)] · ^ 9- (2f-C-trifluoromethyl-β-D-ribofuranosyl) guanosine; l- (2'-C-trifluoromethyl-β-D-ribofuranosyl)- 1Η-benzimidazole; 9- (2'-C-vinyl-β-D-ribofuranosyl) -N6- (2-aminoethyl) adenine; 9- (2'-C-vinyl- β-D · ribofuranosyl) -N6- [2- (3H-indol-3-yl) -ethyl] adenine; 9- (2'-C-vinyl-β-D-ribofuranosyl) -6- [2-aminocarbonylpyrrolidin-1-yl)]-purine; l- (2'-C-vinyl-β-D-ribofuranosyl) -1Η-benzimidazole; ρ 9 -(2, C-ethynyl-β-D-ribofuranosyl) -N6- (2-aminoethyl) adenine; ^ 9- (2, -C-ethynyl-β-D-ribofuranosyl ) -N6- [2- (3H-indol-3-yl) -ethyl] adenine; 9- (2f-C-ethynyl-β -D-ribofuranosyl) -6- [2-aminocarbonyl than pyridin-1-yl)]-purine; 1- (2Ά-ethynyl-β-D-ribofuranosyl) -1Η-benzimidazole ; O: \ 88 \ 88427.DOC -22- 200423945 5- (2, -C-methyl-β-D-ribofuranosyl) · 5Η-pyrrole [3,2-c] pyridin-4-ylamine; 4-amino-8- (2f-C-methyl-β-D-ribofuranosyl) -5-oxy-5,8-dihydro-armidin [2,3-d] pyrimidine-6-carboxyl Acid amide; 2.4-diamino-8- (2'-C-methyl-β-D-ribofuranosyl) -5 -oxy-5,8-dihydropyridine [2,3-d ] Pyrimidin-6-carboxylic acid sulfonamide; 4-amino-8- (2 '-(^-methyl-0-〇-ribosyl) -7-oxy-7,8-dihydropyridine [2,3-d] pyrimidine-5-carboxylic acid sulfonamide; 2.4-amino-8- (2 '-(2-methyl-0-〇-ribosyl) -7-oxy-7, 8-dihydro-σ-pyridine [2,3-d] pyrimidine-5-carboxylic acid fluorenamine; 8- (2'-C-methyl-β-D-ribofuranosyl) -2-fluorenylthio- 4,5-dioxy-3,4,5,8-tetrahydro-anhydropyridine [2,3- (1) pyrimidin-6-carboxylic acid amide; 8- (2f-C-methyl-β- D-Ribosyl ratio. [[2,3-d] 口 密 定 -2,4-diketone; 1- (2 ^ C-methyl-β-D-ribofuranosyl) · 1Η-pyridine [2,3-d] pyrimidine -2,4-diketone; 8- (2, C-fluorenyl-β-D-ribofuranosyl) -4-methylthio-5,6,7,8-tetrahydro-exo sigma [2 , 3-d]. Dense stilbidine; 3- (2'-C-methyl-β-D-ribofuranosyl) -6-methyl-3,7-dihydro-111-furanyl [2,3-d] pyrimidine- 2-keto; 3- (2 丨-(:-fluorenyl + 0-ribofuranosyl) -3,5,6,7 &amp; -tetrahydro-111-furanpyridine [2,3-d] pyrimidine-2 -Ketone; 7- (2'-C-fluorenyl-β-D-ribofuranosyl) -4-methylthio-7H-. Pyrrole [2,3-d] pyrimidine; 200423945 l- (2'- C-methyl-β-D-σ-ribofosyl) -4 -methysalyl-1 基-° specific [2,3- (ί] σ 密 唆; 3- (2, C-methyl-β -D-ribofuranosyl) -3 '-[1,2,4] triazole [l, 5-a]. Migridin-7-one; 3-methyl-8- (2f-C-methyl- β-D-ribofuranosyl) -2-methylthio-3H, 8H-piperidine-4,7-dione; 5- (2'-C-methyl-β-D-ribofuranosyl) -pyridine 2-ylamine; 5- (2'-C-fluorenyl-β-D-ribofuranosyl) _1H_.pyridin-2-one; 8- (2, -C-methyl-β-D-furan Ribosyl) -pyrazole [l, 5-a] [l, 3,5] tris-4-ylamine, 8- (2f-C-fluorenyl-β-D-ribofuranosyl) -3H-. Bidazole [l, 5-a] [l, 3,5] triazin-4-one; 2-amino-8- (2f-C-methyl-β D-bitosylribosyl) -3 Η -° than σ sat [1,5-a] [1,3,5] three -4-ketone; 1- (2, C-methyl-β-D-ribofuranosyl) -4-nitro. Indigo, l- (2f-C-fluorenyl-β-D-ribofuranosyl) Group) -4-aminoindole; 9- (2'-C-methyl-β-D-ribofuranosyl) -6- [2- (1Η-imidazol-4-yl) -ethyl] purine; 9_ (2 '-(3-fluorenyl-3-O-ribofuranosyl) -6- (0 °° D-1-yl) sigh, 9- (2'-C-fluorenyl-β-D -Ribofuranosyl) -6-(. Pyrrolidin-1-yl) purine; (2'-C-fluorenyl-β-D-ribofuranosyl) -hypoxanthine; 9- (2f-C-曱-Β-D-ribofuranosyl) -6-methylpentyl 1-sigma, 9- (2f-C-methyl-β-D-ribofuranosyl) -6- (3,6-di Hydrogen-2Η-pyridin-1-yl) purine; O: \ 88 \ 88427.DOC -24- 200423945 9- (2, -diprazine-bu-[)-ribofuranosyl) -6- (3,4 -Dihydro-11 ~ 1-isoquinolin-2 -ylxanthine; 2 '-('-methyl-β-D-ribofuranosyl-6-thiocarbyl-purine; 2'-C-fluorene -Β-D-ribofuranosyl-uracil; 2LC-methyl-β-D-ribofuranosyl-thymine; 2'-C-methyl-β-D-ribofuranosyl-6-phenyl month Spring purine; 9- (2'-C-methyl-β-D-ribofuranosyl) -6- (2- (丨 1bumidazol-1-4-yl) -ethyl Amine group) sigmaline; 9- (2f-C-methyl-β-D-ribofuranosyl) -6- (2-piperidin-1-yl · ethylamino) purine; 9- (2Ά- Methyl-β-D-ribofuranosyl:)-6- (cyclopropylamino) purine; 9- (2f-C-fluorenyl-β-D-ribofuranosyl) -6- (cyclopentylamine Group) purine; 9- (2 ^ C-methyl-β-D-ribofuranosyl) -6- (cyclohexylamino) purine; 8- (3,4-dihydroxy-5-hydroxyfluorenyl-3 -Methyl-tetrahydro-furan-2-yl) -4,5-dioxy-3,4,5,8-tetrahydro-anhydropyridine [2,3-d] pyrimidine-6-carboxylic acid sulfonamide ; 2- (4-chloropyrrole [2,3-d] pyrimidin-7-yl) -5-hydroxymethyl-3-methyl-tetrahydro-furan-3,4-diol; 9- (2 , -C-fluorenyl-β-D-ribofuranosyl:)-6- (6-fluoro-1,3,4,9-tetrahydro-β-carboline-2 -yl) σ ticket, 9 -(2'-C-fluorenyl-β-D-ribofuranosyl) -6- (3,6-diazepine-1-yl) purine; 4-amino-8- (3,4- Dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl) -2-fluorenylthio-8fluorene "pyridine [2,3-d] pyrimidin-7-one; 5- Fluorenyl-3-fluorenyl- 2- (l, 3a, 5,6-tetraaza-as-indene-6-yl) -tetra-O: \ 88 \ 88427.DOC -25-200423945 hydrogen-squean- 3,4-diol; 5-hydroxymethyl-3-methyl-2- (7 -Nitro-imidazole [4,5-b] -pyridin-3-yl) -tetrahydro-furan-3,4-diol; 2- (3,4-dihydroxy-5-hydroxyfluorenyl-3-methyl) -Tetrahydro-furan-2-yl) -2H- [l, 2,4] triazine-3,5-dione; 5-methyl-3 -fluorenyl-2-(6-phenyl-. Sigma order -9-yl) -tetraaza-octane-3,4-diol; 2-(4-amino group-σbilo [2,3-d] ° ru. -7-yl)- 5-fluorenyl-3 -methyl-tetrahydro-furan-3,4-diol; 5-amino-2- (3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetramethyl Hydrogen-furan-2-yl) -4,5-dihydro-2H- [1,2,4] triazin-3-thione; 6-amino-9-(3,4-dimeryl-5 -Methyl_3-methyl-tetrazyl-pyran-2-yl) -7,9-dihydro-purine-8-one; 5-amino-2- (3,4-dimethyl- 5-Methyl-3-fluorenyl-tetramethylene-pyran-2-yl) -4,5-dihydro-2H- [1,2,4] triazin-3-one; 5-hydroxyfluorenyl- 3-fluorenyl-2- (4-nitro-benzimidazol-1-yl) -tetrahydro-furan-3,4-diol 2-(4-amino-phenylhydrazone. M ° sitting -1- ) -5 -Amidino-3 -methyl-tetramethylene-octane-3,4-diol; 1- (3,4-diamidino-5 _Amidino_ 3 -fluorenyl-tetra Nitrogen-sigmafuran-2-yl) -4 light group-1Η-σbipyridin-2-one; 9- (2'-C-fluorenyl-β-D-sucrose ribosyl) -6- (4 -Amino group) Purine; 2-(4 -Amine-α-Bilo [2,3 · b] ° dense sigma -1 -yl)) -5-Via methyl · 3 -Amino group ~ four Hydrogen-furan-3,4-diol; O: \ 88 \ 88427.DOC -26- 200423945 4-amine -8- (3,4-dihydroxy 0-hydroxymethyl-3-fluorenyl-tetrahydro-furan-2-yl) -8: «-pyridine [2,3-〇1] pyrimidin-7-one ; 2- (2,4-Digas-5Η-.pyrrole [3,2-d] pyrimidin-7-yl) -5-hydroxymethyl-3-fluorenyl-tetrahydro-furan-3,4- Diols; l- (2f-C-fluorenyl-β-D-ribofuranosyl) -5-aminobenzimidazole; and 1- (2'-C-fluorenyl-β-D-ribofuranosyl) 6-Aminobenzimidazole; 2- [6 -Amino-8- (Nf -fluorenyl-Wueiji) -Han-9 -yl] -5-¾methyl-tetrahydro-furan-3 , 4-diol; 2-Methyl- 5- (l, 3a, 5,6-tetraaza-as-Inshen-6-yl) -tetramus-octane-3,4-diol; 7 -(3,4-Dimethyl-5-methyl-3-methyl-tetraaza-pyran-2-yl) -3,7-dihydropyridine [2,3-d] pyrimidine-4 -Ketone; 2- (4-amino-2- [1,2,4] difluoren-1-yl-methylid-5-yl) -5-methyl tetraargon-σfuran-3 , 4-diol; 2-hydroxymethyl-5- (4-methylamino-2- [l52,4] triazol-l-yl-pyrimidin-5-yl) -tetrahydro-σfuran- 3,4-diol; 2 -Methyl-5-[4-fluorenylamino-2-(Nf -methyl-spellyl)-ϋ ϋ -5 _ group)-tetrazine-bitan -3,4-Dioxin, 2- (4-amino-5Η "than [3,2-d] pyrimidin-7-yl) -5- Fluorenyl-3-fluorenyl-tetrahydrofuran · 3,4-diol; 7-(3,4-difluorenyl-5 -transmethyl-3 -methyl-tetramurine-σfuran-2 -Yl) -4 -lactyl-4,7-dihydro-3H-u than [2,3-d] pyrimidine-5- 曱 脒; 2- (4 -amino-5-octane-2- Radical-σBilo [2,3-d] ° Dig σ--7-yl) -5-Acetyl O: \ 88 \ 88427.DOC -27- Radical-Four Star ^ -σfuran-3,4 -Di-Sf ·, 2- (4-amino-5- ° oxaσ-2-yl- ° -ratio [2,3 -d] ° dense σ-7-yl) -5-¾methyl -Tetrahydrofuran-3,4-diol; 4-bad propylamino-1-(3,4-dihalyl-5 -methyl-3 -fluorenyl-tetrazyl i. * · 2 -Base) -1Η-. Dense stilbidine-2 -yan 1, 1- (3,4-dimeryl-5 via methyl-3-methyl-tetrazine-biter 17-nan-2-yl) -4 -pengyi-3,4 -二 鼠 -1Η-. Dense stilbidine-2 -fluorene, 2'-C-methyl-β-D-ribofuranosyl-purine-6-fluorenamine; 9-(3,4 _difron-5-fluorenyl-3 -Fluorenyl-tetrazol-octane-2 -yl) -9 Η 17 17 reams 6-carbothioic acid amine; 2- (4,6-dichloro-methylpyrrole [3,2-c]. Bipyridin-1-yl) -5-hydroxyfluorenyl-3-methyl-tetrahydro-furan-3,4-diol; 2-(4-amino-6-gas-σ ratio [3, 2 -c] ° ratio σ fixed -1 -yl) -5 -Technylmethyl-3 -methyl-tetrahydro-octane-3,4-diol; 2-(4-amino-α-bilo [3 , 2-c] σ ratio. Defining -1 -yl) -5 -Amidino-3 -methyl-tetrahydro-furan-3,4-diol; 4-chloro-7-fluoro-1- (2 '&lt; -methyl-fluorene-0-ribofuranosyl) imidazole [4,5- (:] σ specific bite; 4-amino-7-fluoro-l- (2'-C-methyl-β- D-ribofuranosyl) imidazole [4,5-c] σ specific bit; 2-(4 amine-5 Η-^ bihe [3,2-d] 〇σσ-7 -yl) -5- Via methyl-3 -fluorenyl-tetrahydro-anhydro-3,4-diol; 4-amino-ribofuranosyl) imidazole [4,5-c] pyridine; 4-gas-7-fluoro- 1- (PD-ribofuranosyl) imidazole [4,5- (:]. Pyridine; O: \ 88 \ 88427.DOC -28- 200423945 4-amino-7-fluorofuranyl ribosyl) imidazole [4, 5- c] pyridine; 2- (4-amino-6-methyl "than [2,3-d] pyrimidin-7-yl) -5-hydroxymethyl-tetrahydro-furan-3,4-di Alcohol; 2-(4-amino-6-methyl · σbilo [2,3-d] ° dense ° -7-yl) -5-control methyl-3 _ methyl-tetrahydro-furan -3,4-diol; 4-amino group 8- (3,4-dicontroller-5- via methyl-tetrazine-sigmafuran-2-yl) -7-oxygen * JH group-7 , 8-dihydro-pyridine-6-carboxylic acid sulfonamide;, 4-amino-8- (3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2- ^ Yl) -7-oxy-7,8-di-murine-6-weileric acid amine, 4-amino-8_ (3,4-dicontroller_5-via methyl-3 -Methyl-tetramethylene-pyran-2-yl) -5-oxy-5,8-dihydro-xanthidine [2,3-d] pyrimidin-6-carboxylic acid amide; 4-amino- 8- (3,4-Diacryl- 5- ¾ fluorenyl-tetrachloro-bite. South-2 -yl) -5 -oxy-5,8-dihydropyridine [2,3-d] pyrimidine -6-carboxylic acid amidine; 4-amino-8- (3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl) -8H-u 2,3-d] pyrimidin-5-one; 4 -amino-8-(3,4-dimeryl-5-via methyl-tetramethylene-bitsigma-2 -yl) -8 Η-喋Pyridin-7-one; 4-amino-8- (3,4-diazonyl-5-5-¾methyl-tetra Sulfan-2-yl) -8 '-"pyridine [2,3-d] pyrimidin-7-one; * 4-amino-8- (3,4-diazonyl-5-tetramethyl-tetrazine -Bran-2-yl) -2 -fluorenylthio-8 Η-° than lipidine [2,3-d] hydrazine-7-hydrazone, and 4-amino-8- (3,4- Dimeryl-5-mercapto-3-fluorenyl-tetramurine-octano-2-yl) -2-methylthio-7-lactyl-7,8-diaza-butterfly. Ding-6-Weic acid S blue amine. 8. A pharmaceutical composition comprising a pharmaceutically acceptable diluent and O: \ 88 \ 88427.DOC -29- 200423945 a pharmaceutically effective amount of any one of the compounds in the application range 1-3 or 7 Or a mixture thereof. 9. A pharmaceutical composition comprising a pharmaceutically acceptable diluent and a pharmaceutically effective amount of a compound or a mixture thereof as described in item 5 of the application. 1 10. A pharmaceutical composition for treating mammalian hepatitis C virus, comprising a pharmaceutically acceptable diluent and a pharmaceutically effective amount of any one of the compounds in the scope of application 1-3 or 7 or Its mixture. O: \ 88 \ 88427 DOC -30- 200423945 柒. Designated representative map: (1) The designated representative map in this case is: (none) (II) The representative symbols of the component map are simply explained: 捌, if there is a chemical formula in this case Please reveal the chemical formula that best characterizes the invention: O: \ 88 \ 88427.DOC