ZA200408588B - Nucleoside derivatives for treating hepatitis C virus infection - Google Patents

Description

NUCLEOSIDE DERIVATIVES FOR TREATING

HEPATITIS C VIRUS INFECTION

Field of the Invention

The invention relates to the field of pharmaceutical chemistry, in particular to compounds, compositions and methods for treating hepatitis C virus infections.

References

The following publications and patents are cited in this application as superscript numbers: 1. Chen, ef al., Med. Assoc., 95(1):6-12 (1996) 2. Cornberg, et al., "Hepatitis C: therapeutic perspectives." Forum (Genova), 11(2):154-62 (2001) 3. Dymock, et al., Antivir. Chem. Chemother. 11(2):79-96 (2000) 4. Devos, et al., International Patent Application Publication No. WO 02/18404 A2, published 7 March 2002 5. Sommadossi, ef al., International Patent Application Publication No.

WO 01/90121, published 23 May 2001 6. Ducrocq, C.; et al., Tetrahedron, 32:773 (1976). 7. Rizkalla, B. H.; Broom, A. D., J. Org. Chem., 37(25):3980 (1972). 8. Anderson, G. L.; Broom, A. D., J. Org. Chem., 42(6):997 (1977). 1

Amended sheet 27/02/2007

® 9. Rizkalla, B.

H.; Broom, A.

D., J.

Org.

Chem., 37(25):3975 (1972).

10. Furukawa, Y.; Honjo, M., Chem.

Pharm.

Bull., 16(6):1076 (1968).

11. Ektova, L.

V.; et al, Bioorg.

Khim., 5:1369 (1979).

12. De Clercq, E.; et al., J.

Med.

Chem., 26(5):661 (1983).

13. Robins, M.

J.; Barr, P.

J., J.

Org.

Chem., 48(11):1854 (1983).

14. Griengl, H., J Med.

Chem.,28(11):1679 (1985).

15. Lichtenhaler, F.

W.; Cuny, E., Chem.

Ber., 114:1610 (1981).

16. Hamilton, H.

W.; Bristol, J.

A., J.

Med.

Chem., 26(11):1601 (1983).

17. Seela, F.; Steker, H., Liebigs Ann.

Chem., p. 1576 (1983).

18. Winkley, M.

W.; et al., J.

Heterocycl.

Chem., 8:237 (1971).

19. Barascut, J.

L.; et al., 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.; et al., Helv.

Chim.

Acta, 79:702 (1996).

2 Amended sheet 27/02/2007 i

° 24. De Las Heras, F.; et al, J.

Heterocycl.

Chem., 13:175 (1976). 25. Tam, S.

Y-K.; et al., J.

Heterocycl.

Chem., 13:1305 (1976). 26. Chu, C.

K.; et al., J.

Heterocycl.

Chem., 17:1435 (1980). 27. De Bernardo, S.; Weigele, M., J.

Org.

Chem., 42(1):109 (1977). 28. Saureamid-Reaktionen, L.; Orthoamide, I., Chem.

Ber., 101:41 (1968). 29. Lim, M.-L; Klein, R.

S.; Fox, J.

J., 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, R.

S., Tet.

Lett., 22:25 (1981). 33. Bhattacharya, B.

K.; et al., Tet.

Lett., 27(7):815 (1986). 34. Grisis,N.S.; etal, J Med.

Chem., 33:2750 (1990). 35. Li, N-.S.; Tang, X.-Q.; Piccirilli, J.

A., Organic Letters, 3(7):1025 (2001). 36. Cristalli, G.; et al., J.

Med.

Chem., 30(9):1686 (1987). 37. Seela, F.; et al., Nucleosides Nucleotides, 17(4):729 (1998). 38. Sagi, G.; etal, J.

Med.

Chem. 35(24):4549 (1992). 39. Hawkins, M.

E.; et al., Nucleic Acids Research, 23(15):2872 : | Amended sheet 27/02/2007

® (1995). 40. Mandal, S.B., 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., ef al., J. Chem. Soc. Perkin Trans. I, 2145 (1996). 44, Carroll, S.S., ef al, ., International Patent Application

Publication No. WO 02057287, published 25 July 2002 45. Carroll, S.S., er al., ., International Patent Application

Publication No. WO 02057425, published 25 July 2002

All of the above publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

State of the Art

Hepatitis C virus (HCV) causes a liver damaging infection that can lead to cirrhosis, liver failure or liver cancer, and eventually death. HCV is an enveloped virus containing a positive-sense single-stranded RNA genome of approximately 9.4 kb, and has a virion size of 30-60 nm.’

HCV is a major causative agent for post-transfusion and for sporadic non-A, non-B hepatitis. Infection by HCV is insidious in a high proportion of chronically infected (and infectious) carriers who may not experience clinical symptoms for many years.

HCV is difficult to treat and it is estimated that there are 500 million 4

Amended sheet 27/02/2007 f people infected with it worldwide. No effective immunization is currently ® available, and hepatitis C can only be controlled by other preventive measures such as improvement in hygiene and sanitary conditions and interrupting the route of transmission.

At present, the only acceptable treatment for chronic hepatitis C is interferon (IFN-alpha) and this requires at least six (6) months of treatment and/or ribavarin, which can inhibit viral replication in infected cells and also improve liver function in some people.

IFN-alpha belongs to a family of naturally occurring small proteins with characteristic biological effects such as antiviral, immunoregulatory and antitumoral activities which are produced and secreted by most animal nucleated cells in response to several diseases, in particular viral infections.

IFN-alpha is an important regulator of growth and differentiation affecting cellular communication and immunological control. Treatment of HCV with interferon, however, has limited long term efficacy with a response rate about 25%. In addition, treatment of HCV with interferon has frequently been associated with adverse side effects such as fatigue, fever, chills, headache, myalgias, arthralgias, mild alopecia, psychiatric effects and associated disorders, autoimmune phenomena and associated disorders and thyroid dysfunction.

Ribavirin (1-p-D-ribofuranosyl-1 H-1,2,-4-triazole-3-carboxamide), an inhibitor of inosine 5'-monophosphate dehydrogenase (IMPDH), enhances the efficacy of IFN-alpha in the treatment of HCV. Despite the introduction of ribavirin, more than 50% of the patients do not eliminate the virus with the current standard therapy of interferon-alpha (IFN) and ribavirin. By now, standard therapy of chronic hepatitis C has been changed to the combination of PEG-IFN plus ribavirin. However, a number of patients still have significant side effects, primarily related to ribaviran. Ribavirin causes significant hemolysis in 10-20% of patients treated at currently recommended doses, and the drug is both teratogenic and embryotoxic.

Other approaches are being taken to combat the virus. They include, for example, application of antisense oligonucleotides or ribozymes for > Amended sheet 27/02/2007 inhibiting HCV replication. Furthermore, low-molecular weight compounds ® that directly inhibit HCV proteins and interfere with viral replication are considered as attractive strategies to control HCV infection. NS3/4A serine protease, ribonucleic acid (RNA) helicase, RNA-dependent RNA polymerase are considered as potential targets for new drugs.”

Devos, ef al.* describes purine and pyrimidine nucleoside derivatives and their use as inhibitors of HCV RNA replication. Sommadossi, ef al.’ describes 1', 2' or 3'-modified nucleosides and their use for treating a host infected with HCV. Carroll, ef al* 4 both of which published after the filing of the present application, describe nucleosides as inhibitors of RNA- dependent RNA viral polymerase. Applicants do not intend to cover any compounds specifically disclosed in these applications.

Given the fact of the worldwide epidemic level of HCV, there is a strong need for new effective drugs for HCV treatment. The present invention provides nucleoside derivatives for treating HCV infections.

SUMMARY OF THE INVENTION

This invention is directed to novel compounds that are useful in the treatment of HCV in mammals. Specifically, the compounds of this invention are represented by formula Ia, Ib and Ic below:

R2 R?

SIL, xy

NTOONT TY oy T

R R? R R! R R?

OHOH OH OH OHOH la Ib Ic wherein R and R' are independently selected from the group consisting of: hydrogen, alkyl, 6 Amended sheet 27/02/2007

® substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl provided that R and R' are not both hydrogen;

R? is selected from the group consisting of: alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acylamino guanidino amidino thioacylamino, hydroxy, alkoxy, substituted alkoxy, halo, nitro, thioalkyl aryl, substituted aryl, heteroaryl, substituted heteroaryl, -NR’R* where R* and R* are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, 7 Amended sheet 27/02/2007

® substituted heteroaryl, heterocyclic, substituted heterocyclic and where R* and

R* are joined to form, together with the nitrogen atom bond thereto, a heterocyclic, substituted heterocyclic, heteroaryl, or substituted heteroaryl , -NR’NR’R* where R® and R* are as defined above and R® is selected from the group consisting of hydrogen and alkyl,

W is selected from the group consisting of: hydrogen, phosphate (including monophosphate, diphosphate, triphosphate or a stablilized phosphate prodrug), phosphonate, acyl, alkyl, sulfonate ester selected from the group consisting of alkyl esters, substituted alkyl esters, alkenyl esters, substituted alkenyl esters, aryl esters, substituted aryl esters, heteroaryl esters, substituted heteroaryl esters, heterocyclic esters and substituted heterocyclic esters, a lipid, an amino acid, a carbohydrate, a peptide, and cholesterol;

X is selected from the group consisting of: hydrogen, halo, alkyl, substituted alkyl, and -NR?R* where R? and R? are as identified above;

Y is selected from the group consisting of: hydrogen, halo, hydroxy, 8 Amended sheet 27/02/2007

® alkylthio -NR®R* where R® and R* are as identified above;

Z is selected from the group consisting of: hydrogen, halo, hydroxy, alkyl, azido, and -NR’R* where R® and R* are as identified above

NR’NR3R* where R® , R* and R® are as identified above; and wherein T is selected from the group consisting of a) 1- and 3- deazapurines of the formula below: 7 20) 7 20)

N—{ N— °N « N= or & — b) purine nucleosides of the formula below:

M

N R10

Wd « v={

Y kd ¢) benzimidazole nucleosides of the formula below:

N

“~~ 2 « (R?), d) 5-pyrrolopyridine nucleosides of the formula below:

N

J \ a SN y R20) N ) or ¥ (R20), e) 4-pyrimidopyridone sangivamycin analogs of the formula below: 9

Amended sheet 27/02/2007

® 2 9 I oy

NSN

¢ : f) 2-pyrimidopyridone sangivamycin analogs of the formula below: z (R29),

ZN o

OO” N Ny $ : g) 4-pyrimidopyridone sangivamycin analogs of the formula below: 0 a

ART), (R21), ON

N Ny $ : h) pyrimidopyridine analogs of the formulae below:

Q Q

JL) | (rm x ww ’ x Nd i

SENS LAA

N $ 0 N N° "0 or < ; i) pyrimido-tetrahydropyridines of the formula below:

Q

CF

~ N

NSN

« .

J) Furanopyrimidines (& tetrahydro furanopyrimidines) of the formulae below:

R12 R12 / RY 10 "0 R10

R ~~

BB 0

N Ay Sw or ;

Amended sheet 27/02/2007

® k) pyrazolopyrimidines of the formula below:

R20 7 N ee

N™ SN 1) pyrolopyrimidines of the formula below:

R20 7/1 N

A

NN

£0 m) triazolopyrimidines of the formula below:

Oo

N-<

N

¢ 9

NS

= : n) pteridines of the formula below:

Q

0 { Ny 0) pyridine C-nucleosides of the formula below:

I

(R)

Si = p) pyrazolotriazine C-nucleosides of the formula below: 11

Amended sheet 27/02/2007

®

Aw

Non xn” — —

Foy q) Indole nucleosides of the formula below:

R20 0) o r) a base of the formula below:

Y R20) n 2 . z—

N SN

$ : s) a base of the formula below:

Q

Y

{ Rto z oT N~

N No t) a base of the formula below:

R20

NAA

N R22 u) a base of the formula below: 12

Amended sheet 27/02/2007 o TQ

N rd

J

N : v) a base of the formula below:

R20 (R19)

N 1 N rd P

Xx s ~

Na w) a base of the formula below:

Q

N. N A, : x) a base of the formula below:

Q

“Cr =

N A, $ y) a base of the formula below:

M N

REA

& =I TR ) n* 13

Amended sheet 27/02/2007

® and further wherein one of bonds characterized by --- is a double bond and the other is a single bond provided that, when the --- between the N and a ring carbon is a double bond, then p is 0 and when the --- between Q and a ring carbon is a double bond, then pis 1; each p is independently 0 or 1; each n is independently 0 or an integer from 1 to 4; each n* is independently 0 or an integer from 1 to 2;

L is selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, amino, substituted amino, azido, and nitro;

Q is selected from the group consisting of hydrogen, halo, =O, -OR'"! =N-R'!, -NHR'! =S, -SR"", aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic;

M is selected from the group consisting of =O, =N-R'!, and =S;

Y is as defined above;

R'is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, alkylthioether, substituted alkylthioether, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, with the proviso that when T is b), s), v), w) or x), then R'® is not hydrogen; each R'' and R'is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, amino, substituted amino, alkylthioether, substituted alkylthioether, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; each R? is independently selected from the group consisting of? hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, alkenyl, 1 Amended sheet 27/02/2007

[ substituted alkenyl, alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl, acylamino guanidino amidino thioacylamino, alkoxy, substituted alkoxy, alkylthio, nitro, halo, hydroxy -NR’R* where R? and R* are as defined above,

NR°NR’R? where R® , R* and R® are as defined above; each R?' and R* are independently selected from the group consisting of: -NR3R* where R? and R* are as defined above, and -NR°NR’R* where R® , R* and R’ are as defined above -C(ONR’R? where R® and R* are as defined above, and -C(O)NR’NR? R* where R?, R* and R® are as defined above; and pharmaceutically acceptable salts thereof; with the provisos that 1) for a compound of formula Ia, when Z is hydrogen, halo, hydroxy, azido, or NR’R*, where R? and R* are independently H, or alkyl; Y is hydrogen or -NR’R* where R? and R* are independently hydrogen or alkyl; then R? is not alkyl, alkoxy, halo, hydroxy, CFs, or -NR’R* where R® and R* are independently hydrogen or alkyl; 2) for a compound of formula Ia, when Z is hydrogen, halo, hydroxy, azido, or NR’R*, where R? and R* are independently H, or alkyl; Y is hydrogen, halo, hydroxy, or alkylthio; then R? is not alkyl, 1 Amended sheet 27/02/2007

® substituted alkyl, wherein the substituted alkyl is substituted with hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected or protected, halo, hydroxy, alkoxy, thioalkyl, or -NR’R*, where R® and R* are independently hydrogen, alkyl or alkyl substituted with hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected or protected); 3) for a compound of formula Ib, when X is hydrogen, halo, alkyl, CF; or -NR’R* where R® is hydrogen and R* is alkyl, then R? is not alkyl, alkoxy, halo, hydroxy, CFs, or -NR’R* where R? and R* are independently hydrogen or alkyl;and 4) for a compound of formula Ib, RZis not, halo, alkoxy, hydroxy, thioalkyl, or -NR*R* (where R® and R* are independently hydrogen, alkyl or alkyl substituted with hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected or protected)

And further provided that the compound of Formual Ia, Ib or Ic is not a) 2-Hydroxymethyl-5-(6-phenyl-purin-9-yl)-tetrahydro-furan-3,4-diol; or b) b) 2-Hydroxymethyl-5-(6-thiophen-3-yl-purin-9-yl)-tetrahydro-furan-3,4- diol.

In a preferred embodiment R' is selected from the group consisting of -CH3, -CF3, -CH=CH,, and -C=CH, more preferrably CHs.

In another preferred embodiment when T is a base of formula a) then

T is a 3-deazapurine.

This invention is further directed to a compound of Formula II: 16 Amended sheet 27/02/2007

® VAR

C(Hb Y? ~ 7

N

B oS E

AD |]

N =F

WO

0)

R R!

OH OH

I wherein R and R' are independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, azido, amino, and substituted amino; provided that R and R' are not both hydrogen;

Y? is CH,, N, S, SO, or SO;

N together with -C(H)y, and Y? forms a heterocyclic, substituted heterocyclic, heteroaryl or substituted heteroaryl group wherein each of said heterocyclic, substituted heterocyclic, heteroaryl or substituted heteroaryl group is optionally fused to form a bi- or multi-fused ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in turn, each of such ring structures is optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkyl, substituted thioalkyl, aryl, heteroaryl, heterocyclic, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, 17

Amended sheet 27/02/2007

® and substituted amino; b is an integer equal to 0 or 1;

A, B, D, and E are independently selected from the group consisting of >N, >CH, >C-CN, >C-NO,, >C-alkyl, >C-substituted alkyl, >C-NHCONH3,, >C-CONR"R'¢, >C-COOR"?, >C-hydroxy, >C-alkoxy, >C-amino, >C- alkylamino, >C-dialkylamino, >C-halogen, >C-(1,3-oxazol-2-yl), >C-(1,3- thiazol-2-yl) and >C-(imidazol-2-yl);

F is selected from >N, >C-CN, >C-NQO,, >C-alkyl, >C-substituted alkyl, >C-NHCONH,, >C-CONR'’R'S, >C-COOR", >C-alkoxy, >C-(1,3-oxazol-2-yl), >C-(1,3-thiazol-2-yl), >C-(imidazol-2-yl), and >C-Y, where Y is selected from the group consisting of hydrogen, halo, hydroxy, alkylthioether, and -NR’R* where R? and R? are independently selected from the group consisting of hydrogen, hydroxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where R* and R* are joined to form, together with the nitrogen atom bond thereto, a heterocyclic group, provided that only one of R? and R* are hydroxy, alkoxy, or substituted alkoxy;

R' and R'® are independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and

R" and R'® together with the atom to which they are attached may form a cycloalkyl, substituted cycloalkyl, hetercycloalkyl, substituted heterocylcoalkyl, heteroaryl, or substituted heteroaryl,

W is selected from the group consisting of’: 18 Amended sheet 27/02/2007

C hydrogen, phosphate (including monophosphate, diphosphate, triphosphate or a stablilized phosphate prodrug), phosphonate, acyl, alkyl, sulfonate ester selected from the group consisting of alkyl esters, substituted alkyl esters, alkenyl esters, substituted alkenyl esters, aryl esters, substituted aryl esters, heteroaryl esters, substituted heteroaryl esters, heterocyclic esters and substituted heterocyclic esters, a lipid, an amino acid, a carbohydrate, a peptide, and cholesterol; and pharmaceutically acceptable salts thereof.

In a preferred embodiment, the compounds of formula 11 are represented by formula IIA:

Ny = Tr

WO

(0)

OHOH

HA wherein R and R' are independently selected from the group consisting of: hydrogen, alkyl, 19 Amended sheet 27/02/2007

® substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, azido, amino, and substituted amino; provided that R and R' are not both hydrogen;

Y? is CHa, N, S, SO, or SO;

N together with -C(H), and Y* forms a heterocyclic, substituted heterocyclic, heteroaryl or substituted heteroaryl group wherein each of said heterocyclic, substituted heterocyclic, heteroaryl or substituted heteroaryl group is optionally fused to form a bi- or multi-fused ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in turn, each of such ring structures is optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkyl, substituted thioalkyl, aryl, heteroaryl, heterocyclic, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, and substituted amino; b is an integer equal to 0 or 1;

W is selected from the group consisting of? hydrogen, phosphate (including monophosphate, diphosphate, triphosphate or a stablilized phosphate prodrug), phosphonate, acyl, alkyl, sulfonate ester selected from the group consisting of alkyl esters, substituted alkyl esters, alkenyl esters, substituted alkenyl esters, aryl

Amended sheet 27/02/2007

® esters, substituted aryl esters, heteroaryl esters, substituted heteroaryl esters, heterocyclic esters and substituted heterocyclic esters, a lipid, an amino acid, a carbohydrate, a peptide, and cholesterol;

Y is selected from the group consisting of Y is selected from the group consisting of: hydrogen, halo, hydroxy, alkylthioether -NR’R* where R? and R* are independently selected from the group consisting of hydrogen, hydroxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where R® and R? are joined to form, together with the nitrogen atom bond thereto, a heterocyclic group, provided that only one of R® and R* are hydroxy, alkoxy, or substituted alkoxy;

Z is selected from the group consisting of: hydrogen, halo, hydroxy, alkyl, azido, and -NR’R* where R® and R* are independently selected from the group consisting of hydrogen, hydroxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where R? and R* are joined to form, together with the nitrogen atom bond thereto, a heterocyclic group, provided that only one of R? and R* are hydroxy, alkoxy, or 21 Amended sheet 27/02/2007 substituted alkoxy; ® and pharmaceutically acceptable salts thereof.

Compounds included within the scope of this invention include, for example, those set forth below (including pharmaceutically acceptable salts thereof):

Smee we @ ¢ SN 9-(2’-C-methyl-B-D-ribofuranosyl)-

Thy N 6-(thiophen-3-yl)-purine

HO OH

US

) & SN 9-(2°-C-methyl-B-D-ribofuranosyl)- ly NN, 6-(thiophen-2-yl)-2-aminopurine

HO OH

H

[) 3 SN 9-(2’-C-methyl-B-D-ribofuranosyl)- “1 N° 6-(pyrrol-3-yl)-purine

HO OH

>» : N 9-(2’-C-methyl-B-D-ribofuranosyl)- “19 NZ, 2-amino-6-phenyl-purine

HO OH

CN

Y N 9-(2’-C-methyl-B-D-ribofuranosyl)-

Thy ND 6-(3-cyanophenyl)-purine

HO OH

22

Amended sheet 27/02/2007 oy ® _ el oN 9-(2’-C-methyl-B-D-ribofuranosyl)- “1 nN 6-(pyridin-3-yl)-puring

HO OH s 4 9-(2’-C-methyl-B-D-ribofuranosyl)- 7 OT "t 6-(benzo[b]thiophen-3-yl)-2-

HO oN Nk, + aminopurine

HO OH

HN—

N 9-(2’-C-methyl-B-D-ribofuranosyl)-

SSN

1) LA 6-(1H-indol-5-yl)-purine

HO OH y C 9-(2’-C-methyl-B-D-ribofuranosyl)-

Ho < SN J) 6-(naphthalen-2-yl)-purine

BY)

HO OH

0 ) 9-(2’-C-methyl-f-D-ribofuranosyl)-

OT 6-(dibenzofuran-4-yl)-2- “1 NT NH . . 2 aminopurine

HO OH x,

S

1 J; a 9-(2’-C-methyl-B-D-ribofuranosyl)- : BL nN 6-(thianthren-1-yl)-purine

HO OH

23

Amended sheet 27/02/2007 a - oh 9-(2’-C-methyl-B-D-ribofuranosyl)- 1) N" NH, 6-cyclopropyl-2-aminopurine

HO OH é | oN 9-(2’-C-methyl-B-D-ribofuranosyl)-

EY N 6-(ethynyl)-purine

HO OH s [}

I 7-(2’-C-methyl-B-D-ribofuranosyl)- wo Si , PB) 4-thiophen-3-yl-7H-pyrrolo[2,3- 9 d]pyrimidine

HO OH

7-(2’-C-methyl-B-D-ribofuranosyl)- 4 ~N - TH. -

HO oN | \ A 4-phenyl-7H-pyrrolo|2,3

IK) : d]pyrimidin-2-ylamine

HO OH

S

/ ZZ 17 | Be 1-(2’-C-methyl-B-D-ribofuranosyl)-

Thy ° 4-thiophen-3-yl-1H-pyrimidin-2-one

HO OH e 1-(2°-C-methyl-B-D-ribofuranosyl)-

HO I) Ao 4-phenyl-1H-pyrimidin-2-one

HO OH

24

Amended sheet 27/02/2007

NS 1-(2°-C-Methyl-f-D-ribofuranosyl)-

SN 4-benzo[b]thiophen-2-yl-1H-

HO No imidin-2- ie) pyrimidin-2-one

HO OH

SN 1-(2’-C-methyl-B-D-ribofuranosyl)- 21 be ( yl-p yh)

HO iS} 0 4-cyclopentyl-1H-pyrimidin-2-one

HO OH

)

NNN oY y 9-(2’-C-methyl-B-D-ribofuranosyl)- 22 HO oN NZ 6 iE N”-(2-dimethylaminoethyl)-adenine

HO OH

HN ~~ NH:

N oN b he - Ho 4X 9-(2’-C-methyl-B-D-ribofuranosyl)- iE N° —(2-aminoethyl)adenine

HO OH

N

~~ 9-(2’-C-methyl-B-D-ribofuranosyl)- 24 oo a; N° —[2-(1H-indol-3-yl)- iu ethyl]adenine

HO OH

N » 9-(2’-C-methyl-B-D-ribofuranosyl)- no Si? 6 —[2-aminocarbonyl-(pyrrolidine-1- he yD)]-purine

HO OH

25

Amended sheet 27/02/2007 o HN NH, x 6) o C x, 1-(2’-C-methyl--D-ribofuranosyl)-

[6]

Re N*-(aminocarbonylmethyl)cytidine

HO OH

® y - & } 1-(2°-C-methyl-B-D-ribofuranosyl)-

HO Ty +o N*-[(pyridin-1 -yl)-methyl]cytidine

HO OH

NH,

TN N BS

HN 4 N ; ; A CT 9-(2’-C-methyl-B-D-ribofuranosyl)-

HO o NN Ne | (adenin-8-yi)-aminoethyl]

As adenine

HO OH

H

[SE 9-(2°-C-methyl-p-D-ribofuranosyl)- 31 Ne, N® —[(benzene-3,4,5- le " triol)methyl]adenine

HO OH

0 } NHN 9-(2’-C-methyl-p-D-ribofuranosyl)-

SN

32 wo ST) N° —[1-aminocarbonyl-2-(3H-indol- ie 3-yl)-ethyl]adenine

HO OH

26

Amended sheet 27/02/2007

HN

J 9-(2’-C-methyl-B-D-ribofuranosyl)- 33 ¢ Tr b 6-(1,3,4,9-tetrahydro-beta-carbolin- by N” 2-yl)purine

HO OH

No

ON 1-(2’-C-methyl-B-D-ribofuranosyl)- 34 Oy ° N* —[1-aminocarbonyl-2-(3H-indol-

HO N70 is 3-yl)-ethyl]cytosine

HO OH

F

" : d

Tl 1-(2’-C-methyl-B-D-ribofuranosyl)-

NH

® 4-(pentafluorophenyl-hydrazino)-

HO no «eq. is pyrimidin-2-one

HO OH

OH

OH orl 1-(2’-C-methyl-B-D-ribofuranosy!)-

HO N 4-[4-(3,4-dihydroxy-benzyl)-6,7- 37 Oy

HO— “NTO dihydroxy-3,4-dihydro-1H-

Is isoquinolin-2-yl]-pyrimidin-2-one

HO OH

=N es 1-(2’-C-methyl-B-D-ribofuranosyl)-

SN

38 Ho [3 N* -[ 2-(3H-indol-3-y1)-

Re ethyl]cytosine

HO OH

27

Amended sheet 27/02/2007

NH,

C WN

C he 1-(2’-C-methyl-B-D-ribofuranosyl)- 39 HO oN © 4

Rs N" —(2-aminoethyl)cytosine

HO OH

0. NH, wi 1-(2’-C-methyl-B-D-ribofuranosyl)- “N

HO 0, N*-(aminocarbonyl-isopropyl-

I€ methyl)cytidine

HO OH hae

OT 9-(2’-C-methyl-B-D-ribofuranosyl)- 53 Ty NO _{[(3H-indol-3-yl)-acetic acid]- le N hydrazide}adenine

HO OH oN

Os

HN 9-(2’-C-methyl-B-D-ribofuranosyl)-

N ES o Ae N® —[2-(5-fluoro-benzimidazol-1-

Ay yl)-ethyl]adenine

HO QOH

NH,

NH

T wo ¢ 7 9-(2’-C-methyl-p-D-ribofuranosyl)- he 6 —hydrazino-purine

HO OH un Cs

NSN 9-(2’-C-methyl-p-D-ribofuranosyl)- ¢ I

HO o NN N® (2,2,3,3,3,- pentafluoropropyl)adenine

HO OH

28

Amended sheet 27/02/2007

® CJ a, 9-(2’-C-methyl-B-D-ribofuranosyl)- 57 HO NN” ea. . ie 6-(piperidin-1-yl)purine

HO OH

N ae

Ho— ON 1-(2’-C-methyl-B-D-ribofuranosyl)- hey 1 H-benzimidazole

HO OH

NH

N AN

4 | _ 3-(2’-C-methyl-B-D-ribofuranosyl)- 61 HO o N N oy 3 H-imidazo[4,5-b]pyridin-7-ylamine

HO OH

HN NH,

N—SN 9-(2’-C-trifluoromethyl-B-D-

HO Ln? of N ribofuranosyl)-N°-(2-

Fs aminoethyl)adenine

HO OH

N s . oe 9-(2’-C-trifluoromethyl-f-D- 63 vo. CN ribofuranosyl)-N°®-[2-(3H-indol-3- [o] jo yl)-ethyl]adenine

HO OH lo 2 1 9-(2’-C-trifluoromethyl-B-D-

HO— JN nN? ribofuranosyl)-6-[2-aminocarbonyl- es (pyrrolidinc-1-yl)]-purine

HO OH

29

Amended sheet 27/02/2007

[e] ° D 9-(2’-C-trifl hyl-B-D -(2’-C-trifluoromethyl-B-D-

HO o N Po ( . 4 b hci ribofuranosyl)guanine

HO OH

N

(12 pe. Ho— ON 1-(2’-C-trifluoromethyl-B-D- hoy ribofuranosyl)-1H-benzimidazole

HO OH

Hn NH, ae

HO Sy [7 9-(2’-C-ethenyl-f-D-ribofuranosyl)- jos N®—(2-aminoethyl)adenine

HO OH

> _N poy 9-(2’-C-ethenyl-p-D-ribofuranosyl)- ¢ I

HO [A N®_[2-(3H-indol-3-yl)-ethyl]adenine

HO OH

0 2 Ty 9-(2’-C-ethenyl-B-D-ribofuranosyl)- 70 Ho— NW 6—[2-aminocarbonyl-(pyrrolidine-1- joZ yD}-purine

HO OH

N a2 3 HO oN 1-(2’-C-ethenyl-B-D-ribofuranosyl)- - 1 H-benzimidazole

HO OH

HN SNH; ae 4 HO SN LZ 9-(2’-C-ethynyl-B-D-ribofuranosyl)- jos N®—(2-aminoethyl)adenine

HO OH

Amended sheet 27/02/2007

® &, +s ry 9-(2’-C-ethynyl-B-D-nibofuranosyl)- gy NS_[2-(3H-indol-3-yl)-ethyl adenine we OH 0

N Ty 9-(2’-C-ethynyl-B-D-ribofuranosyl)- ¢ 76 HO a nN? 6—[2-aminocarbonyl-(pyrrolidine-1- 1 y1))-purine

HO OH

N ag - Ho— ON 1-(2’-C-ethynyl-B-D-ribofuranosyl)-

Ros 1 H-benzimidazole ud OH

Yr

N” NH, 5-(2’-C-methyl-p-D-ribofuranosyl)- “IY SH-pyrrolo[3,2-c]pyridin-4-ylamine

HO OH

0 0 NH, 4-Amino-8-(2’-C-methyl-B-D-

H,N ; ZY \ PNY J ribofuranosyl)-5-oxo-5,8-dihydro-

HO ie pyrido[2,3-d]pyrimidine-6- carboxylic acid amide

HO OH

0 O Nm, 2,4-Diamino-8-(2’-C-methyl-f-D-

TL ibof 1)-5-0%0-5,8-dihyd i o Ny - ribofuranosyl)-5-oxo-5,8-dihydro- oy pyrido[2,3-d]pyrimidine-6- carboxylic acid amide

HO OH

31

Amended sheet 27/02/2007

HN_ _O NH, ® LL 4-Amino-8-(2’-C-methyl-B-D- - oP Np ribofuranosyl)-7-0x0-7,8-dihydro-

HO— o pyrido[2,3-d]pyrimidine-5- carboxylic acid amide

HO OH

HNN__O NH

A 2,4-Diamino-8-(2’-C-methyl--D- ~ J ribofuranosyl)-7-oxo-7,8-dihydro- 07 “N7 NT NH,

HO— pyrido[2,3-d}pyrimidine-5- carboxylic acid amide

HO OH oO 0 oOo wp 8-(2’-C-methyl-B-D-ribofuranosyl)- . ENN 2-methylsulfanyl-4,5-dioxo-3,4,5,8-

HO o tetrahydro-pyrido[2,3-d]pyrimidine- 6-carboxylic acid amide

HO OH

) ~~ Tr 8-(2’-C-methyl-B-D-ribofuranosyl)- ~~ x

Ho. a NO 8H-pyrido[2,3-d]pyrimidine-2,4- 0 dione

HO OH

[0]

ST NH 1-(2’-C-methyl-B-D-ribofuranosyl)-

Cor, (Comey Dotan) 87 HO | 1H-pyrido[2,3-d]pyrimidine-2,4-

Tv dione

HO OH s oe } 8-(2’-C-methyl-B-D-ribofuranosyl)- 88 HO N SN 4-methylsulfanyl-5,6,7,8-tetrahydro- {0} 1 pyrido[2,3-d]pyrimidine

HO OH

32

Amended sheet 27/02/2007

® [3 3-(2’-C-methyl-f-D-ribofuranosyl)- o N"So 6-methyl-3,7a-dihydro-1H-furo[2,3-

K) d]pyrimidin-2-one

HO OH

0 oe NH 3-(2’-C-methyl-B-D-ribofuranosyl)-

Ho No 3,5,6,7a-tetrahydro-1H-furo[2,3- 8} d]pyrimidin-2-one

HO OH

Ss” 7 7-(2’-C-methyl-B-D-ribofuranosyl)- 92 HO— NSN” 4-methylsulfanyl-7H-pyrrolo[2,3- + d]pyrimidine

HO OH ss” fr N 1-(2’-C-methyl-B-D-ribofuranosyl)-

N= 93 HO o 4-methylsulfanyl-1H-pyrrolo[2,3- { \ d]pyrimidine

HO OH

O

MY 3-(2’-C-methyl-B-D-ribofuranosyl)-

Ho— o NON 3H-[1,2,4]triazolo[1,5-a)pyrimidin-

Hy 7-one

HO OH

0)

N ~

I + 3-methyl-8-(2’-C-methyl-B-D-

ONIN

HO 4 ribofuranosyl)-2-methylsulfanyl- he y 3H,8H-pteridine-4,7-dione

HO OH

33

Amended sheet 27/02/2007

SN

® > 5-(2’-C-methyl-3-D-ribofuranosyl)-

HO pyridin-2-ylamine

HO OH

0]

NH

5-(2’-C-methyl-B-D-ribofuranosyl)- 97 HO = 4 i 1 (5 V 1H-pyridin-2-one /

HO OH ig

N NSN 8-(2’-C-methyl-B-D-ribofuranosyl)-

HO— ow pyrazolo[1,5-a][1,3,5]triazin-4-

WV ylamine

HO OH

[e)

Noy 8-(2’-C-methyl-f3-D-ribofuranosyl)-

HO— 4 nN 3H-pyrazolo{1,5-a][1,3,5]triazin-4- he A one

HO OH

0)

Nov 2-Amino-8-(2’-C-methyl-B-D-

HO— Ne N” NH, ribofuranosyl)-3H-pyrazolo[1,5- { Al a][1,3,5]triazin-4-one

HO OH

NO, 7) 1-(2’-C-methyl-B-D-ribofuranosyl)-

HO—y 5 N tof 4-nitroindole

HO OH

NH,

J . (1) 1-(2°-C-methyl-B-D-ribofuranosyl)- 105 HO oN }

A$ 4-aminoindole

HO OH

34

Amended sheet 27/02/2007

® i 9-(2’-C-methyl-B-D-ribofuranosyl)-

Wl N®-[2-(1H-imidazol-4-yl)-

HN ethyl]purine

N ae ch

HO OH

107 OS 9-(2’-C-methyl-B-D-ribofuranosyl)-

N i 6-(azetidin-1-yl)purine an

WT

HO OH

) 9-(2’-C-methyl-p-D-ribofuranosyl)- \ L, 6-(pyrrolidin-1-yl)purine

J

WT

HO OH y a (2’-C-mcthyl-B-D-ribofuranosyl)- $y .

Ho W > hypoxanthine

HO OH

112 N— 9-(2’-C-methyl-B-D-ribofuranosyl)-

HN

OLY 6- N-methylhydrazinopurine

Bi

HO OH

113 Q 9-(2°-C-methyl-B-D-ribofuranosyl)-

N 6-(1,2,3,4-tctrahydropyridin-1-

N ~N ¢ Ts yl)purine

WT

HO OH

Amended sheet 27/02/2007

PS 9-(2’-C-methyl-B-D-ribofuranosyl)- 6-(1,2,3,4-tetrahydroisoquinolin-2- ~~ yl)purine yf ON

I =

HO OH

150 SCH, 9-(2’-C-methyl-B-D-ribofuranosyl)- % Tr N 6-methythio-purine 4

J of N =

HO OH

151 0 2’-C-methyl-B-D-ribofuranosyl-

Chiral

N uracil a 0)

HO OH

152 Chiral 0 2’-C-methyl-B-D-ribofuranosyl-

H,C 8 \ thymine

Vo

O

AY

HO OH

155 9-(2’-C-methyl-B-D-ribofuranosyl)-

Chiral 6-phenyladenine

NH

N ANY a8 oY 7

SY

HO OH

36

Amended sheet 27/02/2007

® 156 Chiral I j 9-(2’-C-methyl-B-D-ribofuranosyl)-

HN N 6-(2-(1H-imidazol-4-yl)-

N XN ethylamino)purine

CA)

Ho “oH 157 () 9-(2’-C-methyl-B-D-ribofuranosyl)-

Chiral 6-(2-piperidin-1-yl-

NGL (2-pip y ethylamino)purine

N NN

SP

Ho “oH 158 | Chiral 9-(2’-C-methyl-B-D-ribofuranosyl)- pe 6-(cyclopropylamino) purine

HN

N NN

1

BC

HO OH

159 1 9-(2’-C-methyl-B-D-ribofuranosyl)-

Chiral HN 6-(cyclopentylamino)purine

N NN ag

BT N

Ho on 37

Amended sheet 27/02/2007

® 160 0) 9-(2’-C-methyl-B-D-ribofuranosyl)-

Chiral 6-(cyclohexylamino)purine

N NN ay

Bol wo om 161 oc oo Oo 8-(2’-C-methyl-B-D-ribofuranosyl)-

N Nr NH, 4,5-dioxo-3,4,5,8-tetrahydro-

Ny SN pyrido[2,3-d]pyrimidine-6- oY carboxylic acid amide

OH OH

162 ci 7-(2’-C-methyl-B-D-ribofuranosyl)- ne Ji 4-chloro-pyrrolo[2,3-d]pyrimidine

WW

Ho on 163 F 9-(2’-C-methyl-B-D-ribofuranosyl)- 6-(6-fluoro-1,3,4,9-tetrahydro-f3-

A carbolin-2-yl)purine

N

N N ae

Bel : Ho OH 164 7) 9-(2’-C-methyl-B-D-ribofuranosyl)-

N 6-(3,6-dihydro-2H-pyridin-1- yl)purine

N ~ N

CA)

Bol

Ho OH 38

Amended sheet 27/02/2007

® 165 NH, 4-amino-8-(2’-C-methyl-f-D-

N “YL ribofuranosyl)-2-methylsulfanyl-8H-

NPN No pyrido[2,3-d]pyrimidin-7-one 0

HO oH oH 166 ] N 6-(2°-C-methyl-B-D-ribofuranosyl)- \ 1,3a,5,6-tetraaza-as-indacene

N | AN

LAL

®)

HO on "OH 168 NO, 3-(2’-C-methyl-B-D-ribofuranosyl)-

N

& 0 7-nitro-imidazo[4,5-b]pyridine

N —

HO N o}

H H

OH OH

0 2-(2’-C-methyl-p-D-ribofuranosyl)-

A N 2H-[1,2,4]triazine-3,5-dione

PN

OH OH

170 9-(2’-C-methyl-B-D-ribofuranosyl)- 6-phenyl-purine - N AN N <1

HO ey N

OH OH

39

Amended sheet 27/02/2007

® 171 Chiral ~~ NH, 4-amino-7-(2’-C-methyl-p-D- ae N ribofuranosyl)-pyrrolo[2,3-

HO A > d]pyrimidine

HO OH

172 NH, 5-amino-2-(2’-C-methyl-B-D-

A N ribofuranosyl)-4,5-dihydro-2H-

HO 03 N As [1,2,4]triazine-3-thione

OH OH

173 NH, 6-amino-9-(B-D-ribofuranosyi)-7,9-

NT XN dihydro-purin-8-one

CY

N= TN

HO “oH 174 NH, 5-amino-2-(2’-C-methyl-f-D-

A N ribofuranosyl)-2H-[1,2,4]triazin-3-

HO Ty A, one

OH OH

175 NO, 1-(2’-C-methyl-B-D-ribofuranosyl)-

A 4-nitro-benzoimidazole

HO ¢ ) N

OH OH

40

Amended sheet 27/02/2007

® 176 NH, 4-amino-1-(2’-C-methyl-f-D- ) ribofuranosyl)-benzimidazole wo ¢

N

:

OH OH

177 OH 1-(2’-C-methyl-B-D-ribofuranosyl)-

OL 4-hydroxy-1H-pyridin-2-one

OH OH

178 [ 9-(2’-C-methyl-f-D-ribofuranosyl)- —N NN hi 6-(tetramethylguanidino)purine

N

N AY

CT

WO

Ho om 179 NH, 4-amino-1-(2’-C-methyl-B-D-

J AN ribofuranosyl)pyrrolo[2,3-b]

Ho »

N N pyridine lo]

OH OH

182 NH, 4-Amino-8-(2’-C-methyl-B-D-

OL ribofuranosyl)-8H-pyrido[2,3-

NT No d]pyrimidin-7-one *\ "on

OH

41

Amended sheet 27/02/2007

® 183 Cl 1-(2’-C-methyl-B-D-ribofuranosyl)- ¢ 10] 4,6-dichloro-1H-imidazo[4,5-

HO 6) ZN c]pyridine

OH OH

184a ; DN \ 1-(2’-C-methyl-B-D-ribofuranosyl)- 4 184b 0) aa, 5-aminobenzimidazole at) “a0

HO OH a b 1-(2’-C-methyl-p-D-ribofuranosyl)- 6-aminobenzimidazole 185 NH, H 6-amino-8-(N'-methyl-hydrazino)-9-

NT Ns NT (B-D-ribofuranosyl)-purine

Py

N N bea OH

HO ’ OH

I \ 6-(B-D-ribofuranosyl)-1,3a,5,6-

N ry tetraaza-as-indacene

NE

>

HO ; “OH

OH

188 Q 7-(2’-C-methyl-B-D-ribofuranosyl)-

OR 3,7-dihydro-pyrrolo[2,3-

Sn TN d]pyrimidin-4-one “

HO 1 “on ‘OH 42

Amended sheet 27/02/2007

® 189 Va \ 4-amino-5-(B-D-ribofuranosyl)-2-

N

N J ([1,2,4]triazolyl)-pyrimidine

N Ay :

NN

HO 2%8 NH,

HO OH

FN 4-methylamino-5-(B-D-

NJ ribofuranosyl)-2-([1,2,4]riazolyl)-

N A pyrimidine

NS ve eB

HO OH

200 4-methylamino-5-(B-D- _NH " ribofuranosyl)-2-(N'-methyl-

NT hydrazino)-pyrimidine

Xn ~

HO NT N

HO OH

201 NH, 1-(2’-C-methyl-B-D-ribofuranosyl)- ¢ po 6-amino-1H-imidazo[4,5-c]pyridine

Ww ]

OH OH

203 A 7-(2’-C-methyl-B-D-ribofuranosyl)-

H, . " ee 4-0x0-4,7-dihydro-3H-pyrrolo[2,3- “Tay | > d]pyrimidine-5-carboxamidine

HO OH

43

Amended sheet 27/02/2007

® 204 “0 4-amino-5-(furan-2-yl)-7-(B-D- — z ribofuranosyl)-pyrrolo[2,3- 717 N Ca “oy SN J d]pyrimidine

HO OH

205 Ao 4-amino-5-(oxazol-2-yl)-7-(B-D- rr ribofuranosyl)-pyrrolo[2,3- 7/17 N a “oy SN© d]pyrimidine

HO OH

206 4-cyclopropylamino-1-(2’-C- a= yclopropy (

Oo methyl-B-D-ribofuranosyl)-1H- oe pyrimidin-2-one

HO OH

207 an 1-(2’-C-methyl-B-D-ribofuranosyl)- ® N 4-hydrazino-1H-pyrimidin-2-one

HO OH

208 HNO 9-(2°-C-methyl-B-D-ribofuranosyl)- vo ga purine-6-carboxamide

HO OH

209 HN 8 9-(2’-C-methyl-B-D-ribofuranosyl)- oy 9H-purine-6-carbothioic acid amide “Kr SN

Ho oH 44

Amended sheet 27/02/2007

® 210 cl 1-(2’-C-methyl-B-D-ribofuranosyl)- ap 4.6-dichloro-pyrrolo[3,2-c]pyridine “hy Ze)

OHOH

211 NH; 1-(2°-C-methyl-B-D-ribofuranosyl)-

TE

Thy “al c]pyridine

OHOH

212 NH, 1-(2’-C-methyl-B-D-ribofuranosyl)- a 4-amino-pyrrolo[3,2-c]pyridine

OHOH

213 Ci 4-Chloro-7-fluoro-1-(2’-C-methyl-f3- ae D-ribofuranosyl)imidazo[4,5-

Cl = c]pyridine

F

OHOH

214 NH, 4-Amino-7-fluoro-1-(2’-C-methyl-f3- "vo < OJ D-ribofuranosyl)imidazo © F [4,5-c]pyridine

OHOH

215 yo NH 4-amino-7-(2’-C-methyl-p-D-

Ho ribofuranosyl)-5H-pyrrolo[3,2- oj MN d]pyrimidine

OHOH

3 Amended sheet 27/02/2007

® 216 NH, 4-Amino -1-(B-D-

N ES

¢ yg; ribofuranosyl)imidazo[4,5- ey ‘1 c]pyridine

OHOH

217 cl 4-Chloro-7-fluoro-1-(B-D-

N EN

¢ 70 ribofuranosyl)imidazo([4,5-

HO o NT ys ke F c]pyridine

OHOH

218 NH, 4-Amino-7-fluoro-1-(p-D- l | SN ribofuranosyl)imidazo[4,5-

HO— NT c]pyridine ie ]

OHOH

219 NH, 4-amino-6-methyl-7-(B-D-

De, ribofuranosyl)-pyrrolo[2,3-

N Ng d]pyrimidine

Oo

HO . “on

OH

220 NH, 4-amino-6-methyl-7-(2’-C-methyl-

Nee, B-D-ribofuranosyl)-pyrrolo[2,3-

N Ng d]pyrimidine

[0]

HO . “on

OH

221 NH, 0 4-Amino-8-(B-D-ribofuranosyl)-7-

N

“OY a 0x0-7,8-dihydro-pteridine-6-

N o “oo carboxylic acid amide oO “oH

OH

46

Amended sheet 27/02/2007

® 222 NH, 0 4-Amino-8-(2’-C-methyl-B-D-

AN oY Sw ribofuranosyl)-7-oxo-7,8-dihydro-

NY

NS vO pteridine-6-carboxylic acid amide oC “oH 223 NH, 0 O 4-Amino-8-(B-D-ribofuranosyl)-5-

YY 0x0-5,8-dihydro-pyrido[2,3-

S \ d]pyrimidine-6-carboxylic acid w{, amide “OH 224 NH, OO 4-Amino-8-(2’-C-methyl-B-D-

SOR ribofuranosyl)-5-0xo-5,8-dihydro-

NA pyrido[2,3-d]pyrimidine-6- {> “oH carboxylic acid amide “oH 225 NH, O 4-Amino-8-(B-D-ribofuranosyl)-5- 0 0x0-5,8-dihydro-pyrido[2,3-

SNTON ig oe d]pyrimidine

HO ) L oH 226 NH, 0 4-Amino-8-(2’-C-methyl-B-D- 90 ribofuranosyl)-8H-pyrido[2,3-

N. \ d]pyrimidin-5-one

L

“OH 227 NH, 4-Amino-8-(B-D-ribofuranosyl)-8H-

N

OY 1 pteridin-7-one

STON No o

HO ; oH “OH 47

Amended sheet 27/02/2007

® 228 NH, 4- Amino-8-(f-D-ribofuranosyl)-8H-

QO! pyrido[2,3-d]pyrimidin-7-one

SNOT No [o]

HO ’ “oH “OH 229 NH, 4-Amino-8-(3-D-ribofuranosyl)-2-

PIL methylsulfanyl-8H-pyrido[2,3-

I Fe dlovrimidin-7 o ]pyrimidin-7-one

HO . “oH “oH 230 NH, a 4-Amino-8-(B-D-ribofuranosyl)-2-

N rr Som methylsulfanyl-7-oxo-7,8-dihydro-

Ng Ny N [e] . . . . . pteridine-6-carboxylic acid amide [o} > “oH “OH

This invention is also directed to pharmaceutical compositions comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound of Formula Ia, Ib, Ic, II, IIA, III, or IV or mixtures of one or more of such compounds.

This invention is still further directed to methods for treating HCV in mammals which methods comprise administering to a mammal diagnosed with HCV or at risk of developing HCV a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound of Formula Ia, Ib, Ic, II, IIA, III, or IV or mixtures of one or more of such compounds.

In still another of its method aspects, this invention is directed to a method for preparing the compounds of formula III: 48

Amended sheet 27/02/2007

® NR3R4

N XN

= Fy

WO

0)

R R?

OH OH i where R, R', R3 R RY, W, X,Y and Z are as defined above which method comprises: (a) oxidizing a compound of formula IV

SRé

N XN

TS

N Py

WO

0]

R R1

OH OH

Vv where R® is selected from the group consisting of alkyl and aryl; (b) oxidizing the thio group to a sulfoxide or sulfone; and (©) contacting the oxidized compound prepared in (b) above with at least a stoichiometric equivalent of HNR*R* under conditions which result in formation of a compound of formula II wherein R? and R* are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where R? and R* are joined to form, together with the nitrogen atom bond thereto, a heterocyclic group. 49

Amended sheet 27/02/2007

® DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to compounds, compositions and methods for treating hepatitis C virus infections. However, prior to describing this invention in detail, the following terms will first be defined:

Definitions

As used herein, "alkyl" refers to alkyl groups having from 1 to 10 carbon atoms, preferably from 1 to 5 carbon atoms and more preferably 1 to 3 carbon atoms.

This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n- butyl, t-butyl, n-pentyl and the like. "Substituted alkyl" refers to an alkyl group having from 1 to 3, and preferably 1 to 2, substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl esters, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic. "Alkoxy" refers to the group "alkyl-O-" which includes, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, -butoxy, sec-butoxy, n-pentoxy and the like. "Substituted alkoxy" refers to the group "substituted alkyl-O-". "Acyl" refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)- cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O), heterocyclic-C(O)-, and substituted heterocyclic-C(O)- wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as 50

Amended sheet 27/02/2007

® defined herein. "Acylamino" refers to the group -C(O)NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where each R is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. "Acyloxy" refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, alkynyl-C(O)O-, substituted alkynyl-

C(0)O-, aryl-C(0O)0O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocyclic-

C(0O)O-, and substituted heterocyclic-C(O)O- wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. "Alkenyl" refers to alkenyl group preferably having from 2 to 6 carbon atoms and more preferably 2 to 4 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl unsaturation. "Substituted alkenyl" refers to alkenyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl esters, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic. 1 Amended sheet 27/02/2007

® "Alkynyl" refers to alkynyl group preferably having from 2 to 6 carbon atoms and more preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1- 2 sites of alkynyl unsaturation.

"Substituted alkynyl" refers to alkynyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl esters, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.

“Amino” refers to the group —-NH,.

“Substituted amino” refers to the group -NR'R"” where R' and R" are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where R’ and R" are joined, together with the nitrogen bound thereto to form a heterocyclic or substituted heterocylic group provided that R’ and R” are both not hydrogen.

When R' is hydrogen and R” is alkyl, the substituted amino group is sometimes referred to herein as alkylamino.

When R' and R" are alkyl, the substituted amino group is sometimes referred to herein as dialkylamino.

"Amidino" refers to groups with the formula -C(=NR")NR'R" where R', R" and R" are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where R' and R" are joined, together with the nitrogen bound thereto to form a heterocyclic, substituted heterocyclic, heteroaryl or substituted heteroaryl group.

The term amidino also refers to reverse amidino structures of the formula:

> Amended sheet 27/02/2007

NR' ° _-

NR"): where R"" is an alkyl or substituted alkyl group as defined above and R" and R' are as defined above. "Guanidino" refers to groups with the formula -NHC(=NR"')NR'R" where R’,

R" and R™ are as defined above for amidino. "Aminoacyl" refers to the groups -NRC(O)alkyl, -NRC(O)substituted alkyl, -NRC(O)cycloalkyl, -NRC(O)substituted cycloalkyl, -NRC(O)alkenyl, -NRC(O)substituted alkenyl, -NRC(O)alkynyl, -NRC(O)substituted alkynyl, -NRC(O)aryl, -NRC(O)substituted aryl, -NRC(O)heteroaryl, -NRC(O)substituted heteroaryl, -NRC(O)heterocyclic, and -NRC(O)substituted heterocyclic where R is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2- benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, and the like). Preferred aryls include phenyl and naphthyl. “Substituted aryl” refers to aryl groups which are substituted with from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of hydroxy, acyl, acylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, carboxyl, carboxyl esters, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, > Amended sheet 27/02/2007 thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted ® thioheterocyclic, cycloalkyl, substituted cycloalkyl, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, and substituted heterocyclyloxy. "Aryloxy" refers to the group aryl-O- that includes, by way of example, phenoxy, naphthoxy, and the like. "Substituted aryloxy" refers to substituted aryl-O- groups. "Aryloxyaryl" refers to the group -aryl-O-aryl. "Substituted aryloxyaryl" refers to aryloxyaryl groups substituted with from 1 to 3 substituents on either or both aryl rings as defined above for substituted aryl. “Carboxyl” refers to COOH or salts therof. “Carboxyl esters” refers to the groups —C(0)O-alkyl, ~C(0)O-substituted alkyl, -C(O)Oaryl, and —-C(O)O-substituted aryl wherein alkyl, substituted alkyl, aryl and substituted aryl are as defined herein. "Cycloalkyl" refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including, by way of example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like. "Cycloalkenyl" refers to cyclic alkeny! groups of from 4 to 10 carbon atoms having single or multiple cyclic rings and further having at least 1 and preferably from 1 to 2 internal sites of ethylenic (C=C) unsaturation. "Substituted cycloalkyl" and "substituted cycloalkenyl" refers to an cycloalkyl or cycloalkenyl group, having from 1 to 5 substituents selected from the group 54

Amended sheet 27/02/2007

PY consisting of oxo (=0), thioxo (=S), alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl esters, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic. "Cycloalkoxy" refers to -O-cycloalkyl groups. "Substituted cycloalkoxy" refers to -O-substituted cycloalkyl groups. "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo and preferably is fluoro or chloro. "Heteroaryl" refers to an aromatic group of from 1 to 15 carbon atoms, preferably from 1 to 10 carbon atoms, and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl, indolyl, thiophenyl, and furyl. "Substituted heteroaryl" refers to heteroaryl groups that are substituted with from 1 to 3 substituents selected from the same group of substituents defined for substituted aryl. " "Heteroaryloxy" refers to the group -O-heteroaryl and "substituted heteroaryloxy" refers to the group -O-substituted heteroaryl. "Heterocycle" or "heterocyclic" refers to a saturated or unsaturated group having a single ring or multiple condensed rings, from 1 to 10 carbon atoms and from 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur or oxygen within the ring wherein, in fused ring systems, onc or more the rings can be aryl or heteroaryl. 55

Amended sheet 27/02/2007

"Substituted heterocyclic" refers to heterocycle groups that are substituted ® with from 1 to 3 of the same substituents as defined for substituted cycloalkyl.

Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydro- isoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholiny! (also referred to as thiamorpholinyl), piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like. "Heterocyclyloxy" refers to the group -O-heterocyclic and "substituted heterocyclyloxy" refers to the group -O-substituted heterocyclic. “Phosphate” refers to the groups —OP(O)(OH), (monophosphate), -OP(O)(OH)OP(O)(OH), (diphosphate) and -OP(O)(OH)OP(O)(OH)OP(O)(OH), (triphosphate) or salts thereof including partial salts thereof. “Phosphonate” refers to the groups —OP(OR)(OH) or -OP(OR)(OR) or salts thereof including partial salts thereof. "Thiol" refers to the group -SH. "Thioalkyl" or “alkylthioether” or “thioalkoxy” refers to the group -S-alkyl. "Substituted thioalkyl" or “substituted alkylthiocther” or “substituted thioalkoxy” refers to the group -S-substituted alkyl. "Thiocycloalkyl" refers to the groups -S-cycloalkyl and "substituted 56

Amended sheet 27/02/2007

PY thiocycloalkyl" refers to the group -S-substituted cycloalkyl. "Thioaryl" refers to the group -S-aryl and "substituted thioaryl" refers to the group -S-substituted aryl. "Thioheteroaryl" refers to the group -S-heteroaryl and "substituted thioheteroaryl"” refers to the group -S-substituted heteroaryl. "Thioheterocyclic" refers to the group -S-heterocyclic and "substituted thioheterocyclic" refers to the group -S-substituted heterocyclic.

The term “amino acid” refers to a-amino acids of the formula

H,NCH(RYCOOH where R is alkyl, substituted alkyl or aryl. Preferably, the a-amino acid is one of the twenty naturally occurring L amino acids.

The term “carbohydrate” refers to oligosaccharides comprising from 2 to saccharide units. The particular saccharide units employed are not critical and include, by way of example, all natural and synthetic derivatives of glucose, galactose, N-acetylglucosamine, N-acetylgalactosamine, fucose, sialic acid, and the like. In addition to being in their pyranose form, all saccharide units described herein are in their D form except for fucose which is in its L form.

The term “lipid” is an art recognized term defined, for example, by

Lehninger, Biochemistry, 1970, at pages 189 et seq. which is incorporated herein by reference in its entirety.

The term “peptide” refers to polymers of a-amino acids comprising from about 2 to about 20 amino acid units, preferably from about 2 to about 10, more preferably from about 2 to about 5.

The term “stablilized phosphate prodrug” refers to mono-, di- and 57

Amended sheet 27/02/2007 tri-phosphate groups having one or more of the hydroxyl groups pendent ® thereto converted to an alkoxy, a substituted alkoxy group, an aryloxy or a substituted aryloxy group. "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

It is understood that in all substituted groups defined above, polymers arrived at by defining substituents with further substituents to themselves (e.g., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, etc.) are not intended for inclusion herein. In such cases, the maximum number of such substituents is three. That is to say that each of the above definitions is constrained by a limitation that, for example, substituted aryl groups are limted to —substituted aryl-(substituted aryl)-substituted aryl.

Similarly, it is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with fluoro groups or a hydroxyl group alpha to ethenylic or acetylenic unsaturation). Such impermissible substitution patterns are well known to the skilled artisan.

General Synthetic Methods

The compounds of this invention may be prepared by various methods known in the art of organic chemistry in general and nucleoside and nucleotide analogue synthesis in particular. The starting materials for the syntheses are either readily available from commercial sources or are known or may be prepared by techniques 58

Amended sheet 27/02/2007

® known in the art. General reviews of the preparation of nucleoside and nucleotide analogues are included in the following:

Michelson A.M. “The Chemistry of Nucleosides and Nucleotides,” Academic Press,

New York, 1963.

Goodman L. “Basic Principles in Nucleic Acid Chemistry,” Academic Press, New

York, 1974, vol. 1, Ch. 2. “Synthetic Procedures in Nucleic Acid Chemistry,” Eds. Zorbach W. & Tipson R.,

Wiley, New York, 1973, vol. 1 & 2.

The synthesis of carbocyclic nucleosides has been reviewed by Agrofoglio et al. (Tetrahedron, 1994, 50, 10611).

The compounds of the present invention may be prepared using methods outlined in U.S. Provisional Application Serial Number 60/378,624, incorporated herein by referenence in its entirety.

The strategies available for synthesis of compounds of this invention include:

A. General Synthesis of 2°-C-Branched Nucleosides 2’-C-Branched ribonucleosides of the following structures: 59

Amended sheet 27/02/2007

® { [

N XN X

N NT Y oA

WO WO N

O 0

R! Ri

OHOH OHOH la Ib where R', R%, W, X,Y and Z are as defined above, can be prepared by one of the following general methods. 1 Convergent approach: Glycosylation of Nucleobase with Appropriately

Modified Sugar

The key starting material of this process is an appropriately substituted sugar with 2°-OH and 2’-H with the appropriate leaving group, for example an acyl group or a chloro, bromo, fluoro or iodo. The sugar can be purchased or can be prepared by any known means including standard epimerization, substitution, oxidation and reduction techniques. For example, commercially available 1,3,5- tri-O-benzoyl-a-

D-ribofuranose (Pfanstiel Laboratories, Inc.) can be used. The substituted sugar can then be oxidized with the appropriate oxidizing agent in a compatible solvent at a suitable temperature to yield the 2’-modified sugar. Possible oxidizing agents are, for example, Dess-Martin periodine reagent, Ac,O+ DCC in DMSO, Swern oxidation (DMSO, oxalyl chloride, triethylamine), Jones reagent (a mixture of chromic acid and sulfuric acid), Collins’s reagent (dipyridine Cr(VI) oxide, Corey’s reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate, MnO,, ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymer, Cly-pyridine, H,O-ammonium molybdate, NaBrO,-CAN, NaOC1 in HOAc, copper chromite, copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (aluminum #-butoxide with another ketone) and N-bromosuccinimide. 60

Amended sheet 27/02/2007

Coupling of an organometallic carbon nucleophile, such as a Grignard ® reagent, an organolithium, lithium dialkylcopper or R'-SiMe; in TBAF with the ketone with the appropriate non-protic solvent at a suitable temperature, yields the 2’- alkylated sugar. For example, R'"MgBr/TiCl, or R'MgBr/CeCl; can be used as described in Wolfe et al. 1997. J. Org. Chem. 62: 1754-1759. The alkylated sugar can be optionally protected with a suitable protecting group, preferably with an acyl, substituted alkyl or silyl group, by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and

Sons, Second Edition, 1991.

The optionally protected sugar can then be coupled to the purine or pyrimidine base by methods well known to those skilled in the art, as taught by

Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994. For example, an acylated sugar can be coupled to a silylated base with a Lewis acid, such as tin tetrachloride, titanium tetrachloride or trimethylsilyltriflate in the appropriate solvent at a suitable temperature. Alternatively, a halo-sugar can be coupled to a silylated base with the presence of trimethylsilyltriflate.

Scheme 1 below describes the alternative synthesis of a protected sugar that is useful for coupling to bases where the connection to the base is on a carbon atom instead of a nitrogen atom.

Scheme 1: Alternative Sugar Synthesis and Coupling ol Amended sheet 27/02/2007

Ph Ph

HO \ : \ 0 4

HO of Ph._ 0 0 Ph._O OH a b c

Ph— Ph

R Ph A [i LUE 7x he re

Ph. _O O___Ph Ph._0 OH Ph._O © f . q

Formation of sugar a in Scheme 1, above, is accomplished as described by

Mandal, S.B., et al., Synth. Commun., 1993, 9, page 1239, starting from commercial

D-ribose. Protection of the hydroxy! groups to form sugar b is described in Witty,

D.R, etal, Tet. Lett, 1990, 31, page 4787. Sugar ¢ and d are prepared using the method of Ning, J. et al., Carbohydr. Res., 2001, 330, page 165, and methods described herein. R, in Sugar e can be hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl. Particularly preferred R groups are methyl, trifluoromethyl, alkenyl and alkynyl. Sugar e is prepared by using a modification of the Grignard reaction withn RMgBr or other appropriate organometallic as described herein (with no Titanium/cerium needed). Finally the halogenated sugar used in the subsequent coupling reaction is prepared using the same protection method as used in to make sugar b above. The halogenation is described in Seela.'’

Subsequently, any of the described nucleosides can be deprotected by methods well known to those skilled in the art, as taught by Greene ef al. Protective

Groups in Organic Synthesis, Jon Wiley and Sons, Second Edition, 1991.

In a particular embodiment, the 2’-C-branched ribonucleoside is desired. 2. Linear Approach: Modification of a pre-formed nucleoside 62

Amended sheet 27/02/2007

The key starting material for this process is an appropriately substituted ® nucleoside with a 2’-OH and 2°-H. The nucleoside can be purchased or can be prepared by any known means including standard coupling techniques. The nucleoside can be optionally protected with suitable protecting groups, preferably with acyl, substituted alkyl or silyl groups, by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John

Wiley and Sons, Second Edition, 1991.

The appropriately protected nucleoside can then be oxidized with the appropriate oxidizing agent in a compatible solvent at a suitable temperature to yield the 2°-modified sugar. Possible oxidizing agents are, for example, Dess-Martin periodine reagent, Ac;O+ DCC in DMSO, Swern oxidation (DMSO, oxaly! chloride, triethylamine), Jones reagent (a mixture of chromic acid and sulfuric acid), Collins’s reagent (dipyridine Cr(VI) oxide, Corey’s reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate, MnO, ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymer, C1,-pyridine, H,Oz-ammonium molybdate, NaBrO,-CAN, NaOCl in

HOAc, copper chromite, copper oxide, Raney nickel, palladium acetate, Meerwin-

Pondorf-Verley reagent (aluminum #-butoxide with another ketone) and N- bromosuccinimide. Coupling of an organometallic carbon nucleophile, such as a

Grignard reagent, an organolithium, lithium dialkylcopper or R'-SiMe; in TBAF with the ketone with the appropriate non-protic solvent at a suitable temperature, yields the appropriate substituted nucleoside.

Subsequently, the nucleoside can be deprotected by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic

Synthesis, John Wiley and Sons, Second Edition, 1991.

In a particular embodiment, the 2°-C-branched ribonucleoside is desired.

In another embodiment of the invention, the L-enantiomers are desired. Therefore, the L-enantiomers can be corresponding to the compounds of the invention can be prepared following the same foregoing general methods, beginning with the 63 Amended sheet 27/02/2007 corresponding L-sugar or nucleoside L-enantiomer as starting material.

B. General Synthesis of 3°-C-Branched Nucleosides 3’-C-Branched ribonucleosides of the following structure:

R2 R2

N AN X

N =

WO WO N

0 0)

R R

OHOH OH OH la lb where R, R?, W, X, Y and Z are as defined above, can be prepared by one of the following general methods. 1. Convergent approach: Glycosylation of the nucleobase with an appropriately modified sugar

The starting material for this process is an appropriately substituted sugar with a 3’-OH and 3’-H, with the appropriate leaving group, for example an acyl group, methoxy group or a chloro, bromo, fluoro, iodo. The sugar can be purchased or can be prepared by any known means including standard epimerization, substitution, oxidation and reduction techniques. The substituted sugar can then be purchased or can be prepared by any known means including standard epimerization, substitution, oxidation and reduction techniques. The substituted sugar can then be oxidized with the appropriate oxidizing agent in a compatible solvent at a suitable temperature to yield the 3’-modified sugar. Possible oxidizing agents are, for example, Dess-Martin periodine reagent, Jones reagent (a mixture of chromic acid and sulfuric acid),

Collins’s reagent (dipyridine Cr(V1) oxide, Corey’s reagent (pyridinium 64

Amended sheet 27/02/2007 chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate, ® MnQO,, ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymer, C1;-pyridine, H,O,-ammonium molybdate,

NaBrO,-CAN, NaOCl in HOAc, copper chromite, copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (aluminum ¢-butoxide with another ketone) and N-bromosuccinimide.

Then coupling of an organometallic carbon nucleophile, such as a Grignard reagent, an organolithium, lithium dialkylcopper or R-SiMes in TBAF with the ketone with the appropriate non-protic solvent at a suitable temperature, yields the 3’-

C-branched sugar. For example, RMgBr/TiCls or RMgBr/CeCl; can be used as described in Wolfe et al. 1997. J. Org. Chem. 62: 1754-1759. The 3’-C-branched sugar can be optionally protected with a suitable protecting group, preferably with an acyl or silyl group, by methods well known to those skilled in the art, as taught by

Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second

Edition, 1991.

The optionally protected sugar can then be coupled to the base by methods well known to those skilled in the art, as taught by Townsend Chemistry of

Nucleosides and Nucleotides, Plenum Press, 1994. For example, an acylated sugar can be coupled to a silylated base with a Lewis acid, such as tin tetrachloride, titanium tetrachloride or trimethylsilyltriflate in the appropriate solvent at a suitable temperature. Alternatively, a halo-sugar can be coupled to a silylated base with the presence of trimethylsilyltriflate.

Subsequently, the nucleoside can be deprotected by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic

Synthesis, John Wiley and Sons, Second Edition, 1991.

In a particular embodiment, the 3’-C-branched ribonucleoside is desired.

Alternatively, deoxyribonucleoside is desired. To obtain these nucleosides, the formed ribonucleoside can optionally be protected by methods well known to those 05 Amended sheet 27/02/2007 skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, ® John Wiley and Sons, Second Edition, 1991, and then the 2°-OH can be reduced with a suitable reducing agent. Optionally, the 2’-hydroxyl can be activated to facilitate reduction; i.e. via the Barton reduction. 2. Linear Approach: Modification of a pre-formed nucleoside

The key starting material for this process is an appropriately substituted nucleoside with a 3°-OH and 3’-H. The nucleoside can be purchased or can be prepared by any known means including standard coupling techniques. The nucleoside can be optionally protected with suitable protecting groups, preferably with acyl or silyl groups, by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons,

Second Edition, 1991.

The appropriately protected nucleoside can then be oxidized with the appropriate oxidizing agent in a compatible solvent at a suitable temperature to yield the 3’-modified sugar. Possible oxidizing agents are, for example, Dess-Martin periodine reagent, Jones reagent (a mixture of chromic acid and sulfuric acid),

Collins’s reagent (dipyridine Cr(VI) oxide), Corey’s reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate,

MnO; ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymer, Cl,-pyridine, H,0,-ammonium molybdate,

NaBrO;-CAN, NaOCl] in HOAc, copper chromite, copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (aluminum ¢-butoxide with another ketone) and N-bromosuccinimide.

Subsequently, the nucleoside can be deprotected by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic

Synthesis, John Wiley and Sons, Second Edition, 1991.

In a particular embodiment, the 3’-C-branched ribonucleoside is desired. 66 Amended sheet 27/02/2007

Alternatively, deoxyribonucleoside is desired. To obtain these nucleosides, the ® formed ribonucleoside can optionally be protected by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis,

John Wiley and Sons, Second Edition, 1991, and then the 2’-OH can be reduced with a suitable reducing agent. Optionally, the 2’-hydroxyl can be activated to facilitate reduction; i.e. via the Barton reduction.

In another embodiment of the invention, the L-enantiomers are desired.

Therefore, the L-enantiomers can be corresponding to the compounds of the invention can be prepared following the same foregoing general methods, beginning with the corresponding L-sugar or nucleoside L-enantiomer as starting material.

C._ General Synthesis of Purine Bases of Formula Ja and Pyrimidines Bases of

Formula Ib

The purine bases of formula 1-IVa and pyrimidines bases of formula I-IVb for above condensation reactions can be obtained commercially or can be prepared by procedures known to the art.

The preparation of purine bases of formula [-IVa is reviewed by G. Shaw in “Comprehensive Heterocyclic Chemistry,” Pergamon Press, Vol. 5, chapter 4.09, p. 449 and “Comprehensive Heterocyclic Chemistry II” Pergamon Press, Vol. 7, chapter 7.11, p. 397.

The preparation of pyrimidines bases of formula I-IVb is reviewed by Brown

D. “The Chemistry of Heterocyclic Compounds — The Pyrimidines “ 1962 and

Supplement 1, 1970 John Wiley and Sons, New York, by Brown D. in “Comprehensive Heterocyclic Chemistry,” Pergamon Press Vol. 7, chapter 4.09, p. 499 and by K. Unheim and T. Benneche in “Comprehensive Heterocyclic Chemistry

II’ Pergamon Press Vol. 6 chapter 6.02, p. 93.

For example, the appropriate purine base of formula I-IVa may be prepared from the corresponding purine wherein the 2, 6 or 8 position of the purine base is 67 Amended sheet 27/02/2007 substituted with a suitable leaving group such as halogen or sulphonate. Such purine ® precursors bearing leaving groups are available commercially, e.g. 6-chloropurine (Aldrich Chemical Company), 2,6-dichloropurine (Aldrich Chemical Company), 2- chloro-6-aminopurine (Aldrich Chemical Company), 8-bromoadenine (Sigma-

Aldrich Company Limited) or obtained by procedures known in the art. For example 2- and 6-chloro substituted purines can be prepared by chlorination of the corresponding 2 and 6-hydroxypurines respectively by the use of chlorinating agents such as phosphorus oxychloride (Bakuni et al. Indian J. Chem., Sect B 1984, 23, 1286; LaMontagne et al. J. Heterocycl. Chem. 1983, 20, 295) while introduction of a bromine into the 8-position of purines can be accomplished by direct bromination using brominating agents such as, for example, bromine (Mano et al, Chem Pharm

Bull 1983, 31, 3454) or N-bromosuccinimide (Kelley et al. Heterocycl. Chem. 1990, 27, 1505). The purines where the 6-substituent is alkoxy, aryloxy, SH, alkylthio, arylthio, alkylamino, cycloalkylamino, saturated cyclic amino, nitrogen linked heteroaromatic, hydroxylamino, alkoxylamino, hydrazine, alkylhydrazino may be prepared by treatment of the corresponding 6-halopurine with the appropriate alkoxides, thiols, amines, nitrogen containing heterocycles, hydroxylamines and hydrazines, (for example, Chae et al. J Med 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; Estep et al J Med

Chem 1995, 38, 2582). Similarly, 2-substituted purines can be prepared from the corresponding 2-halopurine, for example, purines where the 2-substituent is alkoxy, aryloxy, SH, alkythio, arylthio or NR’R* can be prepared from the corresponding 2- halopurine by treatment with alkoxides, thiols or amines (e.g. Barlin and Fenn, dust J

Chem, 1983, 36, 633; Nugiel et al., J Org Chem, 1997, 62, 201). Similarly, 8- substitued purines can be prepared from the corresponding 8-halopurines. For example purines where the 8-substituent is alkoxy, aryloxy, SH, alkythio, arylthio or

NR’R’ can be prepared by treatment of the corresponding 8-bromopurine with the appropriate alkoxides, thiols or amines (Xing et al, Tetrahedron Lett, 1990, 31, 5849;

Mano et al, Chem Pharm Bull 1983, 31, 3454). Where the 2, 6 or 8 substituent is a cyclic amine moiety the purine can be prepared from the 6-aminopurine by reaction with an appropriate dialkylating agent such as dihaloalkane. In some cases where the 68 Amended sheet 27/02/2007

6-substituent is a nitrogen containing heteroaromatic linked through the nitrogen @ atom the purine may be prepared from the 6-aminopurine by reaction with a dicarbonyl compound or a reactive derivative of this such as an acetal. For example 6-(1H-pyrrol-1-yl)-1H-purine can be prepared from a 6-chloropurine by reaction with 2,5-dimethoxytetrahydrofuran as described by Estep et al J Med Chem 1995, 38, 2582.

D. General Synthesis of 6-aryl(heteroaryl)/alkyl-substituted purine and 4- aryl(heteroaryl)/alkyl-substituted pyrimidine

Synthesis of 6-aryl(heteroaryl)/alkyl-substituted purines and 4- aryl(heteroaryl)/alkyl-substituted pyrimidines is shown in Scheme 2.

Scheme 2. [o] onto o 0

PhO OH ph—4 ¢ Tow ap 7 °7 of Nn, Ho < A 341 h&) Rm ty NH,

Pn © OP Ho oH i i ° © 346 ore 345

Pn. 0 0.” o ° ° 342 0 t ph—< Cy ® or 07 0 No HO NS 0 ° ty R-M y an J i PhO 0. Ph HO OH 8 =

Ph © OP 347 348 0 fo} 343

I

R

N ~N og

HO OH

344 69

Amended sheet 27/02/2007

PS Commercial 341 is converted to the 2’methyl-ribose derivative 342 as described in Wolfe, et al., J. Org. Chem., 1997, 62, 1754. 6-Bromopurine 2’- methylriboside (343) is prepared using the procedure for the synthesis of 6- chloropurine described in Wolfe, ef al., J. Org. Chem., 1997, 62, 1754. 6-aromatic- substituted purine 2’-methylribosides 344 are synthesized using the protocols reported by Hocek ef al., J. Med. Chem., 2000, 43, 1817 with commercially available boronic acids (R-M in Scheme 2). 6-alkyl-substituted purine 2’-methylribosides 344 are synthesized using modifications of the protocol reported by Bergstrom and

Reday, Tet. Lett., 1982, 23,4191. 6-aromatic-substituted-2-amino-purine 2’- methylribosides 345 are synthesized using modification of the protocols reported by

Lakshman ef al., Org. Lett.., 2002, 4, 1479 with commercially available boronic acids (R-B(OH); in Scheme 2). 6-alkyl- substituted-2-amino-purine 2’-methylribosides 34S are synthesized using modifications of the protocol reported by Bergstrom and

Reday, Tet. Lett., 1982, 23,4191.

In similar manner, but using the appropriate pyrimidine bases, 4- aryl(heteroaryl)/alkyl-substituted pyrimidines 348 are synthesized.

According to this protocol, the following nucleosides are prepared. #] Swwetwe | Name (J

Pa SN 9-(2’-C-methyl-pB-D-ribofuranosyl)-6- yf 's (thiophen-3-yl)-purine

HO OH

US

Np 9-(2’-C-methyl-f3-D-ribofuranosyl)-6-

SY N" NH, (thiophen-2-yl)-2-aminopurine

HO OH

70

Amended sheet 27/02/2007

N

® [, 3 & SN 9-(2’-C-methyl-B-D-ribofuranosyl)-6- “1 N (pyrrol-3-yl)-purine

HO OH

& Y 9-(2’-C-methyl-B-D-ribofuranosyl)-2- iy NPN, amino-6-phenyl-purine

HO OH

CN

& Y 9-(2’-C-methyl-B-D-ribofuranosyi)-6-(3-

Thy N cyanophenyl)-purine

HO OH

SN

= oL 9-(2’-C-methyl-B-D-ribofuranosyl)-6-

Ty nN (pyridin-3-yl)-purine

HO OH

S y . > SN 9-(2’-C-methyl-B-D-ribofuranosyl)-6-

Tie NPN, (benzo[b]thiophen-3-yl)-2-aminopurine

HO OH

HN—)

N 9-(2’-C-methyl-B-D-ribofuranosyl)-6- 74 SN “1 7 (1H-indol-5-yl)-purine

HO OH

71

Amended sheet 27/02/2007

CC 9-(2’-C-methyl-B-D-ribofuranosyl)-6- : y N .

HO SN J (naphthalen-2-yl)-purine

HO OH or

N 9-(2’-C-methyl-B-D-ribofuranosyl)-6-

AY

“1g - (dibenzofuran-4-yl)-2-aminopurine

HO OH x s & oN 9-(2’-C-methyl-B-D-ribofuranosyl)-6- “1 7 (thianthren-1-yl)-purine

HO OH

3 . ¢ > “ 9-(2’-C-methyl-B-D-ribofuranosyl)-6-

Ky N° NH, cyclopropyl-2-aminopurine

HO OH

¢ a I 9-(2’-C-methyl-B-D-ribofuranosyl)-6- “iy N (ethynyl)-purine

HO OH

Ss @

In 7-(2°-C-methyl-B-D-ribofuranosyl)-4- 2 ~N .

HO oN LZ thiophen-3-yl-7H-pyrrolo|2,3- ty d]pyrimidine

HO OH

72

Amended sheet 27/02/2007

® 7-(2’-C-methyl-B-D-ribofuranosyl)-4- z “N UT

Ho i . Ln phenyl-7H-pyrrolo[2,3-d]pyrimidin-2- 9 ylamine

HO OH

Ss 4 Z 17 Bh he 1-(2’-C-methyl-B-D-ribofuranosyl)-4-

Thy © thiophen-3-yl-1H-pyrimidin-2-one

HO OH x 1-(2’-C-methyl-f3-D-ribofuranosyi)-4- at phenyl-1H-pyrimidin-2-one

HO OH

NS 1-(2’-C-Methyl-f3-D-ribofuranosyl)-4- (oN benzo[b]thiophen-2-yl-1H-pyrimidin-2- ati one

HO OH

SN 1-(2’-C-methyl-f-D-ribofuranosyl)- 21 & ie © 4-cyclopentyl-1H-pyrimidin-2-one

HO OH

E. General Synthesis of N6-substituted adenine and

N4-substituted cytosine

Synthesis of 6-aryl(heteroaryl)/alkyl-substituted purines and 4-aryl(heteroaryl)/alkyl-substituted pyrimidines is shown in Scheme 3. 73

Amended sheet 27/02/2007

Scheme 3 te oy

HO SS [7 — he 22

HO OH

HN NH2

A

HO Ss L/ / @ ie 323 3° HO OH

Re RCS,

HO NON HO— NTN ~

HN \ hy oe,

HO OH HO OH HO ° N N 349 351 ie 324

HO OH

HO 0 N N 80 Bz — ie 325

HO OH

BzO 0OBz TU 32 Cre

Be 0 326

HO OH

C) nN - i» oy Cy Cy

BzO No HO o No HO o No

BzO 0Bz 347 HO OH 352 HO OH

NHz NH NH2 on; os; op; 4 | - y | 4 “i ; 2° J “4 *

HO OH HO OH HO OH

350 328 329 74

Amended sheet 27/02/2007

® Synthesis of 9-(2’-C-methyl- p -D-ribofuranosyl)- 6-methylthio-purine 49, 9- (2’-C-methyl- B -D-ribofuranosyl)-uridine 347, and 9-(2’-C-methyl- 8 -D- ribofuranosyl)- 6-methylthio-adenine 350 are performed as described by R. Harry-

O’kury, J. Smith, and M. Wolf J. Org. Chem. 1997, 62, 1754-1759. Methylthio- purine is oxidized to methylsulfonyl-purine using the procedure described by Y-Z.

Xu Tetrahedron, 1996, 52, 10737-10750; Y-Z. Xu, Q. Zheng, and P. Swann

Nucleosides Nucleotides 1995, 14, 929-934. For substitution of methylsulfonyl and triazolyl groups for amine, protocols similar to the protocol reported for deoxynucleosides by P.Srivastava, G.Revankar, R.Robins, and R.Rousseau J. Med.

Chem, 1981, 24, 393-398, can be used. Synthesis of 4-triazolyl-uridine and it substitution with amines can be performed as described for 2’-deoxythymidine by

Y.-Z. Xu, Q. Zheng, and P. Swann J. Org. Chem.1992, 57, 3839-3845. Bromination of purine nucleosides can be performed as described by J.Gerster et al. .J. Org.

Chem.1968, 33, 1070-1073. # | Stewe | Name

NR

- o Ras: 9-(2’-C-methyl- p -D-ribofuranosyl)- ks N8-(2-dimethylaminoethyl)-adenine

HO OH

HN NH; i” o SX 9-(2’-C-methyl-B-D-ribofuranosyl)- N° he —(2-aminoethyl)adenine

HO OH

Ne 24 “1 3 7-(2"-Crmethyl-B-Dribofuranosyl)- N®

Be N —[2-(1H-indol-3-yl)-ethyl}adenine

HO OH

& Amended sheet 27/02/2007

0 @® { Vi NH, ; S 9-(2’-C-methyl-B-D-ribofuranosyl)- 6 —

HO— NM nN? [2-aminocarbonyl-(pyrrolidine-1-yl)]- purine

HO OH

Hn NN ® © , .

HO A nro 1-(2’-C-methyl- B -D-ribofuranosyl)- ks N*-(aminocarbonylmethyl)cytidine

HO OH

(2) 2 on . 7 Oo) 1-(2’-C-methyl- B -D-ribofuranosyl)- nel N*-[(pyridin-1-yl)-methyl]cytidine

HO OH

NH, ~~ NA yA yes

Noy HON nN? 6 eT J H 9-(2’-C-methyl-f-D-ribofuranosyl)- N | ro NN? ie —[ (adenin-8-yl)-aminoethyl]adenine

HO OH

OH

OH

OH

31 oo 9-(2’-C-methyl-B-D-ribofuranosyl)- N°

N yf NZ —[(benzene-3,4,5-triol)methyl]adenine

HO OH

76

Amended sheet 27/02/2007

0} @® wi ~

N NHN 9-(2°-C-methyl-B-D-ribofuranosyl)- N°

N

2, Ne —[1-aminocarbonyl-2-(3H-indol-3-y1)- oy ethyl]adenine

HO OH

HN __

L 9-(2’-C-methyl-B-D-ribofuranosyl)- 6- 33 NNN (1,3,4,9-tetrahydro-beta-carbolin-2- ¢ 1 J

Be N yl)purine

HO OH

New

On 1-(2°-C-methyl- -D-ribofuranosyl)- 34 Oy ° N* —[1-aminocarbonyl-2-(3H-indol-3-

HO o N" "0 ke yl)-ethyl]cytosine

HO OH

F

" ; d ] NH F 1-(2’-C-methyl-B-D-ribofuranosyl)- 4-

NH

Oy (pentafluorophenyl-hydrazino)-

HO vo EET

Re pyrimidin-2-one

HO OH

OH

OH

HO 1-(2’-C-methyl-B-D-ribofuranosyl)- 4-

HO N [4-(3,4-dihydroxy-benzyl)-6,7- 37 ion ( y-benzy

Ho— no dihydroxy-3,4-dihydro-1H-isoquinolin- o y y q

RE 2-yl]-pyrimidin-2-one

HO OH

77

Amended sheet 27/02/2007

=N ® wD

SN [-(2’-C-methyl- B -D-ribofuranosyl)- 18 ~ C 3 ; yl- B yl) he N* _[ 2-(3H-indol-3-yl)-ethyl]cytosine

HO OH

NH, 7 N {D°.C- _ Dori n 39 wo f, x, 1-(2’-C-methyl- -D-ribofuranosyl)

Re N* —(2-aminoethyl)cytosine

HO OH

04 NH, ot 1-(2°-C-methyl- -D-ribofuranosyl)- “N

HO Lube N*-(aminocarbonyl-isopropyl-

Re methyl)cytidine

HO OH

NC

H in o 9-(2°-C-methyl-p-D-ribofuranosyl)- N° 53 el Ty —{[(3H-indol-3-yl)-acetic acid]-

Be N hydrazide}adenine

HO OH ry w 2 0, 9-(2°-C-methyl-B-D-ribofuranosyl)- N°®

HO oN nN? —[2-(5-fluoro-benzimidazol-1-yl)- oy ethyl]adenine

HO OH

78

Amended sheet 27/02/2007

NH, °

AQ

Ho ¢ | 9-(2’-C-methyl-B-D-ribofuranosyl)- 6 — lo} N . . he hydrazino-purine

HO OH an” Fs ae ho JN nN? 9-(2’-C-methyl-B-D-ribofuranosyl)- N he —2,2,3,3,3,-pentafluoropropyl)adenine

HO OH

CJ

NX 9-(2’-C-methyl-f3-D-ribofuranosyl)- 6- 57 IT oo

Thy N (piperidin-1-yl)purine

HO OH

H

$ A

N

HN 9-(2’-C-methyl- PB -D-ribofuranosyl)-

N NN

¢ 9, NS-[2-(1H-imidazol-4-yl)-ethyl] purine

HO OH

107 O

N e, 9-(2°-C-methyl- p -D-ribofuranosyl)- 6- le 7 (azetidin-1-yl)purine

HO OH

» 50 9-(2’-C-methyl- B -D-ribofuranosyl)- 6- le (pyrrolidin-1-yl)purine

HO OH

79

Amended sheet 27/02/2007

PS 110 0

N

74 NH al R.Dor _ vo fee (2°-C-methyl-pB-D-ribofuranosyl)

WW hypoxanthine

HO OH

112 A

HN

CTY 9-(2’-C-methyl--D-ribofuranosyl)- 6- “1 N” N- methylhydrazinopurine

HO OH

113 @

N

0 9-(2°-C-methyl-B-D-ribofuranosyl)- 6- “1 (1,2,3,4-tetrahydropyridin- 1-yl)purine

HO OH

( y 9-(2°-C-methyl-B-D-ribofuranosyl)- 6- 0, (1,2,3,4-tetrahydroisoquinolin-2- “1 > yl)purine

HO OH

Following procedures set forth above and procedures well-known in the art, as well as those described by Li ef al, 2’-C-trifluoromethyl-p-D-ribofuranosyl derivatives can be prepared.

By following the procedures set forth above, as well as procedures well known in the art, including those procedures set forth by Devos’, ef al. and

Sommadossi’ ef al., the following compounds can be made. 1-Deazapurines can be prepared and coupled to ribofuranosyl derivatives as described in by Cristalli, ef al. in J. Med. Chem. 1987, 30(9) p. 1686 or Seela, F., ef al.in Nucleosides Nucleotides, 1998, 17(4), p. 729. 80

Amended sheet 27/02/2007

R20 ® A

N

N—/ of N=

Purine nucleosides can be prepared and coupled to ribofuranosyl derivatives using methods and materials described herein.

M

N R10

G4 7 ta

N

« n={

Y

Benzimidazole nucleosides can be prepared and coupled to ribofuranosyl derivatives as described in by Sagi, G., ef al., in J. Med. Chem. 1992, 35(24), 4549.

N

"~¢ 3 5-Pyrrolopyridine Nucleosides can be prepared and coupled to ribofuranosyl derivatives as described in Tetrahedron 1976, 32, 773.

Hi

NY

$ 4-Pyrimidopyridone Sangivamycin Analogs can be prepared and coupled to ribofuranosyl derivatives as described in J. Org. Chem., 1972, 37, 3980, and J. Org.

Chem., 1977, 42, 997. 81

Amended sheet 27/02/2007

° QP o

N Ny $ 2-Pyrimidopyridone Sangivamycin Analogs can be prepared and coupled to ribofuranosyl derivatives as described in J. Org. Chem., 1977, 42, 997.

R21 0 Rr» or )

HY Sy ¢ 4-Pyrimidopyridone Sangivamycin Analogs can be prepared and coupled to ribofuranosyl derivatives as described in J. Org. Chem., 1972, 37, 3975. oO 0 M “NO

N Ny $

Pyrimidopyridine Analogs can be prepared and coupled to the sugar as described in Chem. Pharm. Bull., 1968, 16, 1076, and J. Org. Chem., 1972, 37, 3975.

Q a (R10) (R')

Or | or

NTN Ko N” NS 0 $ $

Pyrimido-tetrahydropyridines can be prepared and coupled to ribofuranosyl derivatives as described in Biorog. Khim., 1979, 5, 1369. 82

Amended sheet 27/02/2007

Q

° Ce ~ N

NSN

<

Furanopyrimidines (& tetrahydro furanopyrimidines) can be prepared and coupled to ribofuranosyl derivatives as described in J. Med. Chem., 1983, 26, 661; J.

Org. Chem., 1983, 48, 1854; and J. Med. Chem., 1985, 28, 1679.

R12 R12 0) / ? _ Rw Pa [0 2S hy Ay

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

Q R20 (R19) an oe

N » NT J

N N N

& H

Pyrolopyrimidines can be prepared and coupled to ribofuranosyl derivatives as described in Liebigs Ann. Chem., 1983, 1576.

Q R20

ARM), ZN

Ty = > NTN

NTN g

Triazolopyrimidines can be prepared and coupled to ribofuranosyl derivatives as described in J. Heterocycl. Chem., 1971, 8, 237, and J. Carbohydr. Nucleosides

Nucleotides, 1976, 3,281. 83

Amended sheet 27/02/2007

0

N-

N

¢ g

NTS

<

Pteridines can be prepared and coupled to ribofuranosyl derivatives as described in Nucleosides Nucleotides, 1989, 8, 1345, and Chem. Berich., 1974, 107, 3377.

Oo 0 J Ny

Pyridine C-nucleosides can be prepared by coupling ribofuranosyl derivatives to a variety of bases as described in Angew. Chem. Int. Ed. Engl., 1996, 35, 1968, and

Helv. Chim. Acta, 1996, 79, 702-709.

I

(R19)

Sn >

Pyrazolotriazine C-nucleosides can be prepared by coupling ribofuranosyl derivatives to a variety of bases as described in J. Heterocycl. Chem., 1976, 13, 175;

J. Heterocycl. Chem., 1976, 13, 1305; J. Heterocycl. Chem., 1980, 17, 1435; J. Org.

Chem., 1977, 42, 109.

Q

Nonny” — = —. 9-Deazapurine C-nucleosides can be prepared by coupling ribofuranosyl 84

Amended sheet 27/02/2007 derivatives to a variety of bases as described in J. Org. Chem., 1977, 42, 109; Chem. ® Ber., 1968, 101, 41; Tet. Lett., 1981, 21, 1013; J. Org. Chem., 1967, 32, 1825; J.

Heterocycl. Chem., 1978, 15, 353; Tet. Lett., 1981, 22, 25; Tet. Lett., 1986, 27, 815; and J. Med. Chem., 1990, 33, 2750.

Q

: (R10)

A Sw —

Py

Indole nucleosides can be prepared by coupling ribofuranosyl derivatives to a variety of indole bases as described in Yokoyama, M., et al., J. Chem. Soc. Perkin

Trans. I, 1996, 2145.

R20 0

N

&

Utility, Testing, and Administration

Utility

The present invention provides novel compounds possessing antiviral activity, including hepatitis C virus. The compounds of this invention inhibit HCV replication by inhibiting the enzymes involved in replication, including RNA dependent RNA polymerase. They may also inhibit other enzymes utilized in the activity or proliferation of HCV.

The compounds of the present invention can also be used as prodrug nucleosides. As such they are taken up into the cells and can be intracellularly phosphorylated by kinases to the triphosphate and are then inhibitors of the polymerase (NS5b) and/or act as chain-terminators.

Compounds of this invention maybe used alone or in combination with other compounds to treat viruses. 85

Amended sheet 27/02/2007

Administration and Pharmaceutical Composition ® In general, the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of the compound of this invention, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors. The drug can be administered more than once a day, preferably once or twice a day.

Therapeutically effective amounts of compounds of Formula Ia, Ib, Ic, II, IIA,

I1I, or IV may range from approximately 0.05 to 50 mg per kilogram body weight of the recipient per day; preferably about 0.01-25 mg/kg/day, more preferably from about 0.5 to 10 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range would most preferably be about 35-70 mg per day.

In general, compounds of this invention will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen that can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions. Another preferred manner for administering compounds of this invention is inhalation. This is an effective method for delivering a therapeutic agent directly to the respiratory tract, in particular for the treatment of diseases such as asthma and similar or related respiratory tract disorders (see U. S. Patent 5,607,915).

The choice of formulation depends on various factors such as the mode of drug administration and bioavailability of the drug substance. For delivery via inhalation the compound can be formulated as liquid solution, suspensions, aerosol 86 Amended sheet 27/02/2007 propellants or dry powder and loaded into a suitable dispenser for administration. ® There are several types of pharmaceutical inhalation devices-nebulizer inhalers, metered dose inhalers (MDI) and dry powder inhalers (DPI). Nebulizer devices produce a stream of high velocity air that causes the therapeutic agents (which are formulated in a liquid form) to spray as a mist that is carried into the patient’s respiratory tract. MDI’s typically are formulation packaged with a compressed gas.

Upon actuation, the device discharges a measured amount of therapeutic agent by compressed gas, thus affording a reliable method of administering a set amount of agent. DPI dispenses therapeutic agents in the form of a free flowing powder that can be dispersed in the patient’s inspiratory air-stream during breathing by the device. In order to achieve a free flowing powder, the therapeutic agent is formulated with an excipient such as lactose. A measured amount of the therapeutic agent is stored in a capsule form and is dispensed with each actuation.

Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example,

U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.

The compositions are comprised of in general, a compound of Formula Ia, Ib,

Ic, 11, IIA, III, or IV in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula Ia, Ib, Ic, II, TTA,

III, or IV. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art. 87 Amended sheet 27/02/2007

Solid pharmaceutical excipients include starch, cellulose, talc, glucose, ® lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.

Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.

Other suitable pharmaceutical excipients and their formulations are described in

Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing

Company, 18th ed., 1990).

The amount of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (Wt%) basis, from about 0.01-99.99 wt% of a compound of Formula

Ia, Ib, Ic, II, ITA, 111, or IV based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80 wt%. Representative pharmaceutical formulations containing a compound of Formula Ia, Ib, Ic, II, TIA, III, or IV are described below.

EXAMPLES

In the examples below, the following abbreviations have the following meanings. lf an abbreviation is not defined, it has its generally accepted meaning.

DS

EC SA

= CT 88 Amended sheet 27/02/2007

Boc Py N-Boc-4-amino-1-methyl pyrrole-2-carboxylic o [| [e—

EE

BeTin |=[Nes Anno eT Ao

Boc-5-Ain-HBA-AMPS N-Boc-5-Amino-Indole-2-Carboxylic Acid (p-

I i og

Boc-Py-HBA-AMPS N-Boc-4-Amino-1-Methyl Pyrrole-2-Carboxylic

Acid (p-Hydroxy benzamide methyl polystyrene)ester

BOP Benzotriazol-1-yloxy- tris(dimethylamino)phosphonium mmm—

CL

I Li i

IC LL

IC LE

EE So SR

EC

EE So

Eo Co

Fo LL

Eo

Ee GO LC

EC Ec

Ee Po

EL Lr

Ec rr

ES SO

Ea

Ee eC

Amended sheet 27/02/2007 o [FT [ [owes

Eo SO

Ec

EO ero SR

CC

EE

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EE GC = RE

EE LE

Fee [Terman pins

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CL

AAS |= phan ees

HBTU O-Benzotriazol-1yl-N,N,N’,N’-

IR onion

WE | omar Ts sry

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= Amended sheet 27/02/2007

® MMT monomethoxytrytil (p-anisyldiphenylmethyl)

I Hl Fe

EE OL

EE a

EL Le

ER LE

EL Te

EC iL

Npc(Et) 4-nitro-1-ethyl-1H-pyrrole-2-carboxylic acid em

Npc(Me) 4-nitro-1-methyl-1H-pyrrole-2-carboxylic acid

RA

Npc(Pr) 4-nitro-1-propyl-1H-pyrrole-2-carboxylic acid

RR I

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Py 4-amino-1-methyl-1H-pyrrole-2-carboxylic acid

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Pzl-Gu-(Boc), N,N ’-Bis(tert-butoxycarbonyl)-1 H-pyrazole-1- i

EE i

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TE fee

ELC SN Lr

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In reporting NMR data, chemical shifts are given in ppm and coupling constants (J) given in Hertz (Hz). All melting points are uncorrected.

In the following examples and procedures, the starting materials and reagents are commercially available from any one of Aldrich, Lancaster, Sigma, Specs, TCI,

Maybridge Frontier Scientific and Bachem. The term "Aldrich" indicates that the compound or reagent used in the procedure is commercially available from Aldrich

Chemical Company, Inc., Milwaukee, WI 53233 USA; the term "Lancaster" indicates that the compound or reagent is commercially available from Lancaster Synthesis,

Inc., NH 03087 USA; the term "Sigma" indicates that the compound or reagent is commercially available from Sigma, St. Louis MO 63178 USA; the term "Maybridge" indicates that the compound or reagent is commercially available from

Maybridge Chemical Co. Trevillett, Tintagel, Cornwall PL34 OHW United 72 Amended sheet 27/02/2007

Kingdom; and the term "TCI" indicates that the compound or reagent is commercially ® available from TCI America, Portland OR 97203; the term "Frontier Scientific" indicates that the compound or reagent is commercially available from Frontier

Scientific, Utah, USA; the term "Specs" indicates that the compound or reagent is commercially available from Netherlands; and "Bachem" indicates that the compound or reagent is commercially available from Bachem, Torrance, California,

USA.

Set forth in the examples below are compounds and intermiediates useful for making compounds of the present invention.

Example 1

Synthesis of 9-(2°-C-methyl- B -D-ribofuranosyl)- 6-bromopurine (41) 9-(2’-C-methyl- B -D-ribofuranosyl)- 6-bromopurine (41) can be synthesized utilizing the general procedure described in R. Harry-O’kuru, J. Smith, and M. Wolf

J. Org. Chem. 1997, 62, 1754-1759.

Example 2

Synthesis of 9-(2°-C-methyl--D-ribofuranosyl)-6-(thiophen-3-yl)-purine (1)

Toluene (10 mL) is added to an argon-purged flask containing 9-(2’-C- methyl- B -D-ribofuranosyl)- 6-bromopurine (41) (1 mmol), K,CO3 (200 mg, 1.5 mmol), 3-thiopheneboronic acid (1.5 mmol) and Pd(PPhs)s (59 mg, 0.05 mmol) and the mixture is stirred under argon at 100°C for 8 h. After cooling to ambient temperature the mixture is evaporated in vacuo and the residue is chromatographed on a silica gel column. The residue is then taken up into 10 mL NHj3 saturated MeOH and reacted at 55°C for 12 hours in a sealed tube. The reaction was cooled and concentrated in vacuo. The product was isolated by column chromatography on silica gel (chloroform/methanol/ammonia 9:1:0.5 v/v/v).

Example 3

Synthesis of 9-(2’-C-methyl- B -D-ribofuranosyl)- N*-isobutyryl-guanosine (42) 9-(2’-C-methyl- p -D-ribofuranosyl)- N’-isobutyryl-guanosine (42) is 7 Amended sheet 27/02/2007 synthesized utilizing the general procedure described in R. Harry-O’kuru, J. Smith, ® and M. Wolf J. Org. Chem. 1997, 62, 1754-1759 and is isolated by HPLC.

Example 4

Synthesis of 9-(2°-C-methyl- B -D-ribofuranosyl)-2-amino-6-phenylpurine (4) 9-(2’-C-methyl- B -D-ribofuranosyl)- N*-isobutyryl-guanosine (42) (1 mmol) is dissolved in dichloromethane (10 mL) under argon and 2,6-di-tert-butyl-4- methylpyridine (3 mmol) is added. The solution is cooled to 0°C and trifluoromethanesulfonic anhydride (3 mmol) is added and the reaction is allowed to warm to ambient temperature. After 12 hours the reaction is concentrated in vacuo and chromatographed on silica gel (ethyl acetate/dichoromethane). The product is dissolved in toluene (10 mL) and then K;COj3 (200 mg, 1.5 mmol), phenylboronic acid (1.5 mmol) and Pd(PPh3)4 (59 mg, 0.05 mmol) are added and the mixture is stirred under argon at 100°C for 8 h. After cooling to ambient temperature the mixture is evaporated in vacuo and the residue is chromatographed on a silica gel column. The residue is then taken up into 10 mL NHj3 saturated MeOH and reacted at 55°C for 12 hours in a sealed tube. The reaction is cooled and concentrated in vacuo.

The product is isolated by column chromatography on silica gel (chloroform/methanol/ammonia 9:1:0.5 v/v/v).

Example 5

Synthesis of 9-(2’-C-methyl- 3 -D-ribofuranosyl)-uracil (43) 9-(2’-C-methyl- -D-ribofuranosyl)-uracil (43) is synthesized as described in

R. Harry-O’kuru, J. Smith, and M. Wolf J. Org. Chem. 1997, 62, 1754-1759.

Example 6

Synthesis of 1-(2’-C-methyl-B-D-ribofuranosyl)-4-thiophen- 3-yl-1H-pyrimidin-2-one (17) 9-(2’-C-methyl- p -D-ribofuranosyl)-uracil (43) (1 mmol) is dissolved in dichloromethane (10 mL) under argon and 2,6-di-tert-butyl-4-methylpyridine (3 mmol) is added. The solution is cooled to 0°C and trifluoromethanecsulfonic 4 Amended sheet 27/02/2007 anhydride (3 mmol) is added and the reaction is allowed to warm to ambient ® temperature. After 12 hours the reaction is concentrated in vacuo and chromatographed on silica gel (ethyl acetate/dichoromethane). The product is dissolved in toluene (10 mL) and then K>CO5 (200 mg, 1.5 mmol), 3- thiopheneboronic acid (1.5 mmol) and Pd(PPh;)4 (59 mg, 0.05 mmol) are added and the mixture is stirred under argon at 100 °C for 8 h. After cooling to ambient temperature the mixture is evaporated in vacuo and the residue is chromatographed on a silica gel column. The residue is taken up into 10 mL NHj saturated MeOH and is reacted at 55°C for 12 hours in a sealed tube. The reaction is cooled and concentrated in vacuo. The product is isolated by column chromatography on silica gel (chloroform/methanol/ammonia 9:1:0.5 v/v/v).

Example 7

Synthesis of 1-(2’-C-methyl-B-D-ribofuranosyl)-4-cyclopentyl- 1 H-pyrimidin-2-one ( 21) 9-(2°-C-methyl- B -D-ribofuranosyl)-uracil (43) (1 mmol) is dissolved in dichloromethane (10 mL) under argon and 2,6-di-tert-butyl-4-methylpyridine (3 mmol) is added. The solution is cooled to 0°C and trifluoromethanesulfonic anhydride (3 mmol) is added and the reaction is allowed to warm to ambient temperature. After 12 hours the reaction is concentrated in vacuo and chromatographed on silica gel (ethyl acetate/dichoromethane). The product is dissolved in anhydrous THF (10 mL) and Pd(PPhs)4 (59 mg, 0.05 mmol) is added under Ar atmosphere. Cyclopentylzinc bromide (1.5 mmol, 0.5 M in THF) is then added and the reaction stirred at ambient temperature for 18 hours. The mixture is evaporated in vacuo and the residue is chromatographed on a silica gel column. The residue is taken up into 10 mL NH; saturated MeOH and reacted at 55°C for 12 hours in a sealed tube. The reaction is cooled and concentrated in vacuo. The product is isolated by column chromatography on silica gel (chloroform/methanol/ammonia 9:1:0.5 v/v/v).

Example 8

Synthesis of 9-(2°-C-methyl- B -D-ribofuranosyl)- 6-methylthio-purine (49) % Amended sheet 27/02/2007

® 9-(2’-C-methyl- B -D-ribofuranosyl)- 6-methylthio-purine (49) is synthesized as described in R. Harry-O’kuru, J. Smith, and M. Wolf J. Org. Chem. 1997, 62, 1754-1759.

Example 10

Synthesis of 9-(2°-C-methyl- $ -D-ribofuranosyl)- 6-[2-(1H-imidazol-4-yl)- ethyljpurine (106)

Compound 106 was synthesized as described herein from histamine.

MS 361.45 (M+H)

H'-NMR (DMSO0-d6): 0.80 (s, 3H, 2’-CH3), 3.25-3.45 (m, 4H, 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 11

Synthesis of 9-(2’-C-methyl-B-D-ribofuranosyl)-N® —(2-aminoethyl)adenine (23) 9-(2’-C-methyl-B-D-ribofuranosyl)-6 —(methylsulfonyl)purine (1 mmol) is dissolved in pyridine (5 mL), ethylenediamine (5 mM) is added and the reaction mixture is kept overnight at room temperature. The solvent is evaporated; the product (23) is isolated by column chromatography on silica gel (chloroform/methanol/ ammonia 9:1:0.5, v/v/v).

Example 12

Synthesis of 9-(2’-C-methyl-B-D-ribofuranosyl)-N°-[2-(1H-indol-3-yl)- ethylladenine (24)

Compound 24 was synthesized as described herein from tryptamine.

MS 410.38 (M+H)

H'-NMR (DMSO0-d6): 0.76 (s, 3H, 2°-CH3), 2.60-4.10 (m, sugar and methylene), 5.98 (s, 1H, 1’-H), 6.80 (d, 1H, indole), 7.18 (m, 4H, indole), 8.35 and 8.68 (s, 1H, purine), 9.02 (s, 1H, NH).

Example 13

Synthesis of 9-(2°-C-methyl- -D-ribofuranosyl)- 6-[2-aminocarbonyl- 26 Amended sheet 27/02/2007

(pyrrolidin-1-yl)}-purine (25) ® Compound 25 was synthesized as described herein from L-proline amide.

MS 380.35 (M+H)

H'-NMR (DMSO0-d6): 0.86 (s, 3H, 2°-CH3), 2.25-3.95 (m, 4H, pyrrolidine), 3.10-4.10 (m, sugar and pyrrolidine), 5.98 (s, 1H, 1°-H), 8.35 and 8.68 (s, 1H, purine), 9.25 (s, 1H, amide).

Example 14

Synthesis of 1-(2°,3°.5°-Tri-O-benzoyl -2°-C-methyl-B-D-ribofuranosyl)- uracil (47) 1-(2°,3°,5’-Tri-O-benzoyl-2’-C-methyl-B-D-ribofuranosyl)-uracil ( 47) is synthesized as described in R. Harry-O’kuru, J. Smith, and M. Wolf J. Org. Chem. 1997, 62, 1754-1759.

Example 15

Synthesis of 1-(2°.3°.5°-Tri-O-benzoyl-2’-C-methyl-B-D-ribofuranosyl)-4- (1.2.4-triazol-1-yl) uracil (52) 1,2,4-Triazo! (60 mmol) is suspended in dry acetonitrile (70 mL) at 0°C.

Phosphorous oxychloride (15 mM) is slowly added with rapid stirring followed by drop wise addition of triethylamine (50 mmol). The reaction mixture is stirred for 30 min at 0°C and than nucleoside (47) (15 mmol) is added. In 1 hour the reaction is quenched with 50 mL of saturated solution of sodium bicarbonate, The product is extracted with 50 mL of chloroform. Organic extract is washed with 5% sodium bicarbonate, water, dried over magnesium sulphate and evaporated. The product is isolated by column chromatography on silica gel (toluene/ethyl acetate).

Example 16

Synthesis of 1-(2°-C-methyl- B -D-ribofuranosyl)-N"- (aminocarbonylmethyl)cytidine (26)

Nucleoside (52) (1 mmol) is dissolved in 95% pyridine (5 mL), glycine amide (5 mM) is added and the reaction mixture is kept for 16 hours at 55°C. The solvent is evaporated. The product (26) is isolated by column chromatography on silica gel 77 Amended sheet 27/02/2007

® (chloroform/methanol/ammonia 9:1:0.5 v/v/v).

Example 17

Synthesis of 1-(2’-C-methyl- 8 -D-ribofuranosyl)- :

N*(pyridin-1-yl)methyl)cytidine (27)

Nucleoside (52) (1 mmol) is dissolved in 95% pyridine (5 mL), pyridin-1-yl- methylamine (5 mM) is added and the reaction mixture is kept for 16 hours at 55°C.

The solvent is evaporated. The product (27) is isolated by column chromatography on silica gel (chloroform/methanol/ammonia 9:1:0.5 v/v/v).

Example 18

Synthesis of 2°-C-methyladenosine (50) 2’-C-methyladenosine (50) is prepared 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-methyl-8-bromoadenosine (28)

Bromine (2 mL) is added to S50 mL of water and stirred vigorously at room temperature for 3 min. Nucleoside (50) (5g) is suspended in 30 mL of water and Br,- water is added by aliquots at such a rate that yellow color of the reaction mixture disappeared between each addition. The total amount of Br,-water is 45 mL. The solid is collected by filtration and washed carefully with iced water up to pH 5.5. The residue is recrystallized from hot water to yield 60% of the target product.

Example 21

Synthesis of 5-(2’-C-methyl-f3-D-ribofuranosyl)-S H- pyrrolo[3.2-c]pyridin-4-ylamine (80)

The title compound can be prepared by methods similar to those set forth by

Ducrocq® on page 779 to 780.

Example 22

Synthesis of 4-amino-8-(2°-C-methyl-B-D-ribofuranosyl)-5-oxo- ’8 Amended sheet 27/02/2007

5.8-dihydro-pyrido[2.3-d]pyrimidine-6-carboxylic acid amide (81) ® The title compound can be prepared by methods similar to those set forth by

Rizkalla’ on page 3985.

Example 23

Synthesis of 2.4-diamino-8-(2’-C-methyl-B-D-ribofuranosyl)-5-0x0-5.8- dihydro-pyrido[2.3-d]pyrimidine-6-carboxylic acid amide (82)

The title compound can be prepared by methods similar to those set forth by

Anderson? page 999.

Example 24

Synthesis of 4-amino-8-(2°-C-methyl-B-D-ribofuranosyl)-7-oxo- 7.8-dihydro-pyrido[2.3-d]pyrimidine-5-carboxylic acid amide (83)

The title compound can be prepared by methods similar to those set forth by

Anderson® page 1000.

Example 25

Synthesis of 2.4-diamino-8-(2’-C-methyl-B-D-ribofuranosyl)-7- 0x0-7.8-dihydro-pyrido[2.3-d]pyrimidine-5-carboxylic acid amide (84)

The title compound can be prepared by methods similar to those set forth by

Anderson® page 1000.

Example 26

Synthesis of 8-(2°-C-methyl-B-D-ribofuranosyl)-2-methylsulfanyl- 4,5-diox0-3.4,5.8-tctrahydropyrido[2,3-d]pyrimidine-6-carboxylic acid amide (85)

Step 1. Synthesis of 2-methylsulfanyl-4.5-dioxo-3.4.5.8-tetrahydro-pyrido[2.3- d]pyrimidine-6-carboxylic acid ethyl ester 4,5-dioxo-3,4,5,8-tetrahydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was synthesized as described in B.H.Rizkalla and A.D.Broom, J Org.Chem. 1972, 37(25), 3980-3985.

Step 2. Synthesis of 8~(2°, 3°, 5°-tris-benzoyloxy-2’-C-methyl-8-D-ribofuranosyl)-2- » Amended sheet 27/02/2007 methylsulfanyl-4.5-dioxo-3.4.5.8-tetrahydro-pyrido[2.3-d]pyrimidine-6-carboxylic ® acid ethyl ester

To a suspension of the product from Step 1 above (0.2g, 0.71mmol) in dry acetonitrile (3.5 mL), BSA (0.385 mL, 1.56 mmol) was added and the mixture refluxed under argon for 30min. The resulting solution was cooled to room temperature and 1,2,3,5-tetra-O-benzoyl-2’-C-methyl B-D-ribofuranose (0.32g, 0.55mmol) in dry acetonitrile was added followed immediately by TMSOTT (0.513 mL, 2.84 mmol). The resulting reaction mixture was heated to reflux for 2 hours.

The reaction was allowed to cool to room temperature then was concentrated in vacuo to an oily residue. The oily residue was taken up in EtOAc and washed 1X with saturated NaHCO; and the aqueous layer was re-extracted 2X with EtOAc. The organic fractions were combined, washed with H,O, brine, and dried over Na;SO4 and concentrated in vacuo. The crude reaction was purified by column chromatography on silica gel using 10% methanol in methylene chloride for elution.

The appropriate fractions were pooled, evaporated, and foamed from methylene chloride to get 0.406g (100%) of the title compound.

Step 3. Synthesis of 8-(2°-C-methyl-B-D-ribofuranosyl)-2-methylsulfanyl-4,5-dioxo- 3.4.5.8-tetrahydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide.

The product from Step 2 above (0.2g, 0.270mmol) was dissolved in 40mLs liquid ammonia and stirred at room temperature for 48 hours. The liquid ammonia was allowed to evaporate and the resulting yellow oily residue was purified by HPLC 0-20% Buffer B over 30min at a flow rate of 10mLs/min. Buffer A — 0.1% triethylammonium acetate in water, Buffer B-0.1% triethylammonium acetate in

CH;3;CN. Pooled fractions containing nucleoside and evaporated in vacuo and dried by co-evaporation with absolute ethanol to yield 27mg (25%) of the desired nucleoside.

MS: 397.13 (M-H).

H'-NMR (DMSO-d6): 0.8 (s, 3H, 2’-CHs), 2.5 (s, 3H, -CH3), 3.0-4.0 (m, 4H, sugar), 5.0-5.5 (m, 3H, -OH), 6.7 (s, 1H, 1°-H), 7.4 (s, 1H, -Ar), 8.8 and 9.2 (s, 2H, -NHy). 100 Amended sheet 27/02/2007

® Example 27

Synthesis of 8-(2°-C-methyl-B-D-ribofuranosyl)-8 H- pyrido[2.3-d]pyrimidine-2.4-dione (86)

The title compound can be prepared by methods similar to those set forth by

Rizkalla’ on page 3979.

Example 28

Synthesis of 1-(2°-C-methyl-B-D-ribofuranosyl)-1H- pyrido[2.3-d]pyrimidine-2.4-dione (87)

The title compound can be prepared by methods similar to those set forth by

Rizkalla® on page 3979.

Example 29

Synthesis of 8-(2°-C-methyl-B-D-ribofuranosyl)-4- methylsulfanyl-5.6.7.8-tetrahydro-pyrido[2.3-d]pyrimidine (88)

The title compound can be prepared by methods similar to those set forth in

Biorog. Khim., 1979, 5, 1369.

Example 30

Synthesis of 3-(2’-C-methyl-B-D-ribofuranosyl)-6-methyl- 3.7a-dihydro-1H-furo[2,3-d]pyrimidin-2-one (89)

The title compound can be prepared by methods similar to those set forth in

De Clercq'? page 666.

Example 31

Synthesis of 3-(2°-C-methyl-8-D-ribofuranosyl)- 3.5,6.7a-tetrahydro-1H-furo[2.3-d]pyrimidin-2-one (90)

The title compound can be prepared by making appropriate modifications to the methods set forth by Grieng]" on page 1680.

Example 33

Synthesis of 7-(2’-C-methyl-B-D-ribofuranosyl)-4-methylsulfanyl-7 H- 101

Amended sheet 27/02/2007

Ie pyrrolo[2.3-d]pyrimidine (92) ® The title compound can be prepared by methods similar to those set forth by

Seela'” page 1585.

Example 34

Synthesis of 1-(2°-C-methyl-B-D-ribofuranosyl)-4-methylsulfanyl-1H- pyrrolo[2.3-d]pyrimidine (93)

The title compound can be prepared by methods similar to those set forth by

Seela'” page 1585.

Example 35

Synthesis of 3-(2’-C-methyl-B8-D-ribofuranosyl)-3H- [1,2.4]triazolo[1.5-a]pyrimidin-7-one (94)

The title compound can be prepared by methods similar to those set forth in

Winkley'® page 239.

Example 36

Synthesis of 3-methyl-8-(2’-C-methyl--D-ribofuranosyl)-2- methylsulfanyl-3H.8H-pteridine-4.7-dione (95)

The title compound can be prepared by methods similar to those set forth by

Hawkin®®, et al. page 2875.

Example 37

Synthesis of 5-(2’-C-methyl-B-D-ribofuranosyl)pyridin-2-ylamine (96)

The title compound can be prepared by coupling the alternative the sugar f, prepared as described in Scheme 1, to the base prepared by methods similar to those described previously 2

Example 38

Synthesis of 5-(2’-C-methyl-B-D-ribofuranosyl)-1 H-pyridin-2-one (97)

The title compound can be prepared by coupling the alternative sugar f, prepared as described in Scheme 1, to the base prepared by methods similar to those 102 Amended sheet 27/02/2007

® described previously.”>?

Example 39

Synthesis of 8-(2’-C-methyl-B-D-ribofuranosyl)-pyrazolo[1,5-a] [1.3.5]triazin-4-ylamine (98)

The title compound can be prepared by coupling the alternative sugar f, prepared as described in Scheme 1, to the base prepared by methods similar to those described by Tam’, ef al. on page 1307. Other pyrazolotrazine C-nucleosides, for example compounds 99 and 100, may be prepared using this sugar (f) and other techniques well known in the art.*?’

Example 41

Synthesis of 9-(2’-C-trifluoromethyl-B-D-ribofuranosyl)-

N°-(2-aminoethyl)adenine (62)

The title compound can be prepared by methods similar to those set forth by

Li*, ef al. and methods described herein. Trifluoromethylated ribofuranosyl derivates maybe coupled to a variety of bases, for example compounds 63, 64, 66 and 67, may be prepared by techniques described herein as well as methods well known in the art.

Example 42

Synthesis of 1-(2°-C-ethenyl-B-D-ribofuranosyl)-1H-benzimidazole (73)

The title compound can be prepared by methods similar to those set forth by

Sagi’ 8 et al. and methods described herein. Ethenylated ribofuranosyl derivates maybe coupled to a variety of bases, for example compounds 68-70, may be prepared by techniques described herein as well as methods well known in the art.

Examplc 43

Synthesis of 1-(2°-C-ethynyl-B-D-ribofuranosyl)-1 H-benzimidazole (79)

The title compound can be prepared by methods similar to those set forth by

Sagi’?, et al. and methods described herein. Ethynylated ribofuranosyl derivates maybe coupled to a variety of bases, for example compounds 74-76, may be prepared 103 Amended sheet 27/02/2007

® by techniques described herein as well as methods well known in the art.

Example 44

Synthesis of 1-(2°-C-methyl-B-D-ribofuranosyl)-4-nitroindole (104)

The title compound can be prepared by methods similar to those set forth in

Yokoyama®, ef al. Other Indole nucleosides can be prepared by coupling ribofuranosyl derivatives to a variety of indole, for example compounds 105, maybe prepared by techniques described herein as well as methods well known in the art.

Example 45

Synthesis of 9-(2’-C-methyl- B -D-ribofuranosyl)- 6-(azetidin-1-yl)purine (107)

Compound 107 was synthesized as described herein from azetidine.

MS 323.32 (M+H)

H'-NMR (DMSO-d6): 0.76 (s, 3H, 2°-CHs), 3.25-3.45 (m, 4H, methylene), 3.10-4.10 (m, sugar and azetidine), 5.98 (s, 1H, 1’-H), 8.35 and 8.68 (s, 1H, purine).

Example 46

Synthesis of 9-(2’-C-methyl- $ -D-ribofuranosyl)- 6-(pyrrolidin-1-yl)purine (108)

Compound 108 was synthesized as described herein from pyrrolidine.

MS 336.32 (M+H)

H'-NMR (DMSO0-d6): 0.77 (s, 3H, 2’-CH3), 2.00 (m, 4H, pyrrolidine), 3.43- 4.14 (m, sugar and pyrrolidine), 5.98 (s, 1H, 1°-H), 8.36 and 8.72 (s, 1H, purine).

Example 47

Synthesis of 9-(2’-C-methyl- B -D-ribofuranosyl)- 6-(piperidin-1-yl)purine (57)

Compound 57 was synthesized as described herein from pyrrolidine.

MS 350.37 (M+H)

H'-NMR (DMSO0-d6): 0.78 (s, 3H, 2°-CH3), 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, 1’-H), 8.28 and 8.58 (s, 1H, purine). 104 Amended sheet 27/02/2007

Example 48 ® Synthesis of 9-(2’-C-methyl-B-D-ribofuranosyl)- 6 —(hydroxylamino)purine (109) and 9-(2°-C-methyl-B-D-ribofuranosyl)- hypoxanthine (110) 9-(2'-C-methyl-B-D-ribofuranosyl)-6-(methylsulfonyl)purine (0.2 mmol) was dissolved in 3 mL of dry ethanol, solution of hydroxylamine (prepared as described by P.K.Chang, J. Med.Chem., 1965, 8, 884) was added (2 mM) and the mixture was refluxed for 1 h and than concentrated in vavuo. The residue was dissolved in DMF (5 mL) and purified by HPLC 20-100% B in 30 min, flow 10 mL/min. A-0.2% triethylammonium acetate in water, B-0.2% triethylammonium acetate in CH3CN.

The fractions contained the mixture of protected nucleosides 109 and 110 were evaporated, dissolved in MeOH, treated with HCl/MeOH for 5 min at 0°C and the mixture of nucleosides 109 and 110 (3:1) was precipitated with ether. The mixture was separated by HPLC, 0-20% B in 30 min, buffers as described above.

Corresponding fractions were combined, evaporated, co-evaporated with water (3 x 10 mL), dissolved in methanol (1 mL) and precipitated with ether (35 mL) to yield white solid. 9-(2’-C-methyl-B-D-ribofuranosyl)- N° —(hydroxylamino)purine (109)

MS: 283.19 (M+H),

Amax 261.5nm, )

H'-NMR (DMSO-d6): 0.68 (s, 3H, 2’-CH3), 3.81-4.04 (m, 2H, 5’-H) 4.07 (1, 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-(2°-C-methyl- -D-ribofuranosyl)- hypoxanthine (110).

MS: 298.38 (M+H),

Amax 249.5 nm,

H'-NMR (DMSO0-d6): 1.09 (s, 3H, 2°-CH3), 3.85-4.24 (m, 3H, sugar), 6.16 (s, 1H, 1’-H), 8.21 and 8.62 (s, 1H, hypoxanthine).

Example 49

Synthesis of 9-(2’-C-methyl- 3 -D-ribofuranosyl)- 6-methoxyaminopurine (111)

Compound 111 was synthesized as described herein from methoxyamine. 105 Amended sheet 27/02/2007

MS 312.41 (M+H); ® H'-NMR (DMSO0-d6): 0.91 (s, 3H, 2°-CHj), 3.82-4.04 (m, 7H, sugar), 3.95 (s,

O- CH3), 6.01 (s, 1H, 1°-H), 8.22 and 8.88 (s, 1H, adenine).

Example 50

Synthesis of 9-(2’-C-methyl-B-D-ribofuranosyl)- 6-hydrazinopurine (55)

Nucleoside 55 was synthesized as described herein from hydrazine.

MS 297.31 (M+H)

H'-NMR (DMSO0-d6): 0.80 (s, 3H, 2°-CHs), 3.80-4.00 (m, 7H, sugar), 6.02 (s, 1H, 1°-H), 8.47 and 8.77 (s, 1H, purine).

Example 51

Synthesis of 9-(2°-C-methyl-B-D-ribofuranosyl)- 6-N-methylhydrazinopurine (112)

Nucleoside 112 was synthesized as described herein from hydrazine.

MS 313.72 (M+H)

H'-NMR (DMSO-d6): 0.68 (s, 3H, 2°-CH3), 3.80-4.00 (m, 7H, sugar), 3.88 (s,

N- CH3), 5.90 (s, 1H, 1’-H), 7.68 and 8.21 (s, 1H, purine).

Example 52

Synthesis of 9-(2°-C-methyl- 8 -D-ribofuranosyl)- 6-(1.2.3.4-tetrahydropyridin-1-yl) purine (113)

Compound 113 was synthesized as described herein from 3,6- dihydropyridine.

MS 348.32 (M+H)

H'-NMR (DMSO-d6): 0.88 (s, 3H, 2°-CH3), 3.10-3.40 (m, 6H, CH2- tetrahydropyridine), 3.80-4.00 (m, 7H, sugar), 5.80-5.98 (m, 2H, CH- tetrahydropyridine), 6.01 (s, 1H, 1°-H), 8.23 and 8.48 (s, 1H, purine).

Example 53

Synthesis of 9-(2°-C-methyl- 8 -D-ribofuranosyl)- 6-(1.2.3.4-tetrahydroisoquinolin-2- yl)purine (114) 106 Amended sheet 27/02/2007

Compound 114 was synthesized as described herein from 3,4- ® dihydroisoquinoline.

MS 398.53 (M+H)

H'-NMR (DMSO0-d6): 0.88 (s, 3H, 2°-CH3), 2.25-2.31 and 2.90-3.00 (m, 2H, methylene), 3.10-3.40 (m, 6H, CH,-tetrahydropyridine), 3.80-4.00 (m, 4H, sugar), 5.20-5.35 (m, 3H, OH-sugar), 6.01 (s, 1H, 1°-H), 7.16-7.25 (m, 4H, benzene), 8.27 and 8.53 (s, 1H, purine).

Example 54

Preparation of 9-(2°-C-methyl- -D-ribofuranosyl)- 6-(1.3.4.9-tetrahydro-beta- carbolin-2-yl)purine (33)

Compound 33 was synthesized as described herein from 1,3,4,9-tetrahydro- beta-carboline.

MS 437.43 (M+H)

H'-NMR (DMSO-d6): 0.89 (s, 3H, 2’-CHs), 2.98 (m, 2H, methylene), 3.40- 4.00 (m, sugar and methylene of tetrahydopyridine), 4.05 (d, 3°-H), 6.05 (s, 1H, 1°-

H), 6.90-7.05 (m, 2H, aromatic), 7.29-7.40 (m, 2H, aromatic), 8.32 and 8.65 (s, 1H, purine), 10.99 (s, 1H, NH).

Example 55

Synthesis of 7-(2’-C-methyl-B-D-ribofuranosyl)- 4- hydroxylamino-pyrrolo[2,3- d]pyrimidine (117)

Step 1. Synthesis of 7-(2’-C-methyl-B-D-ribofuranosyl)- 4- chloro-pyrrolo[2,3- dlpyrimidine (141) was prepared as described in WO 02/057287, p 27-30.

Step 2. 7-(2’-C-methyl--D-ribofuranosyl)- 4- hydroxylamino-pyrrolo[2,3- d]pyrimidine (117).

Nucleoside 141 (300 mg, 1 mmol) was dissolved in dry ethanol (10 mL), solution of hydroxylamine (prepared as described by P.K.Chang, J. Med.Chem., 1965, 8, 884) was added (10 mM) and the mixture was refluxed for 1 h and than concentrated in vavuo. The residue was purified by HPLC 0-30% B in 30 min, flow 10 mL/min. A — 107 Amended sheet 27/02/2007

0.2% triethylammonium acetate in water, B-0.2% triethylammonium acetate in ® CH;3CN. Corresponding fractions were combined, evaporated, co-evaporated with water (3 x 10 mL), dissolved in methanol (1 mL) and precipitated with ether (35 mL) to yield 117 as white solid.

Example 56

Synthesis of 7-(2°-C-methyl-B-D-ribofuranosyl)- 4- methoxylamino-pyrrolo [2.3-d]pyrimidine (118)

Nucleoside 118 was prepared from the nucleoside 141 (example 55, step 1) substituting methoxylamine for hydroxylamine.

Example 57

Synthesis of 1-(2’-C-methyl-B8-D-ribofuranosyl)- 4- hydroxylamino-pyrazolo[3.4- d]pyrimidine (120)

Step 1. Synthesis of 2.3.5-tri-O-benzoyl-2’-methyl- 1.5-dihydro-pyrazolo[3.4-d] pyrimidin-4-one (142)

Nucleoside 142 was synthesized as described in example 1 by substitution of 6-bromopurine for 1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one.

Step 2. Synthesis of 2,3.5-tri-O-benzoyl-2’-methyl- 4-chloro-pyrazolo[3.4-d] pyrimidine (143)

Nucleoside 142 was dissolved in toluene, 10 equivalents of SOCI, was added and the mixture was heated at 50°C for 2 hours. The solvents were evaporated in vacuum, the residue was co-evapotated with toluene and purified by flash chromatography on silica gel (toluene-ethyl acetate, 9:1 v/v). Corresponding fractions were evaporated, dissolved in 10 mL of methanol and 5 mL NH4OH was added.

Reaction mixture was kept at room temperature overnight and evaporated. The titled nucleoside was isolated by HPLC as described in example 55, step2.

Step 3. 1-(2’-C-methyl-B-D-ribofuranosyl)- 4- hydroxylamino-pyrazolo[3.4-d] pyrimidine (120) 108 Amended sheet 27/02/2007

Nucleoside 143 was transformed to nucleoside 120 as it is described in ® example 55, step 2.

Example 58

Synthesis of 1-(2’-C-methyl-B-D-ribofuranosyl)- 4- methoxylamino-pyrazolo [3.4-d]pyrimidine (119)

Nucleoside 119 was prepared from the nucleoside 143 (example 57, step 3) substituting hydroxylamine for methoxylamine.

Example 59

Synthesis of 7-(2’-C-methyl-f-D-ribofuranosyl)- 5-chloro-4- hydroxylamino pyrrolof2.3-d]pyrimidine (123)

Nucleoside 117 (0.1 mmol) is dissolved in DMF (0.5 mL) and cooled to 0 °C.

N-chlorosuccinimide (NCS) (0.1 mmol) dissolved in DMF (0.5 mL) is then added dropwise and the reaction stirred for 30 min at 0°C and 30 min at room temperature.

The reaction is quenched with methanol (5 mL) and then concentrated. Column chromatography (SiO;) with MeOH/DCM affords 123.

Example 60

Synthesis of 7-(2°-C-methyl-B-D-ribofuranosyl)- 5-bromo-4- hydroxylamino pyrrolo[2.3-d]pyrimidine (124)

Nucleoside 124 is prepared in the same manner as for 123, substituting N- bromosuccinimide (NBS) for NCS.

Example 61

Synthesis of 7-(2°-C-methyl-B-D-ribofuranosyl)- S-methyl-4-hydroxylamino- pyrrolo[2.3-d]pyrimidine (125)

Step 1: Nucleoside 141 (1 mmol) is dissolved in DMF (5 mL) and cooled to 0°C.

NBS (1 mmol) dissolved in DMF (5 mL) is then added dropwise and the reaction stirred for 30 min at 0°C and 30 min at room temperature. The reaction is quenched with methanol (50 ml.) and then concentrated. Column chromatography (SiO,) with 109 Amended sheet 27/02/2007

® MeOH/DCM affording the 7-bromo-6-chloro-7-deazapurine riboside.

Step 2: The nucleoside from Step 1 (0.5 mmol) is dissolved in 10% aqueous dioxane (2.5 mL) and potassium carbonate (1.5 mmol) and palladium tetrakis(triphenylphosphine) are added followed by trimethylboroxine (0.5 mmol).

The reaction is refluxed for 18 hrs. then filtered through Celite and concentrated.

Column chromatography (SiO,) with MeOH/DCM affording the 7-methyl-6-chloro- 7-deazapurine riboside.

Step 3: Nucleoside 125 is synthesized as described in Example 55, step 2 using hydroxylamine.

Example 62

Synthesis of 7-(2°-C-methyl-B-D-ribofuranosyl)-5-ethyl-4- hydroxylamino- pyrrolo[2.3-d]pyrimidine (128)

Step 1: The nucleoside from Example 61, Step 1 (0.1 mmol) is dissolved in THF (1 mL) and then palladium tetrakis(triphenylphosphine) is added. To this reaction is then added diethyl zinc and the reaction heated to reflux for 6 hours. The reaction is quenched with aqueous NH4Cl and extractively worked up. Column chromatography (8107) with MeOH/DCM affording the 7-cthyl-6-chloro-7-deazapurine riboside.

Step 2: Nucleoside 128 is synthesized as described in Example 55, step 2 using hydroxylamine.

Example 63

Synthesis of 7-(2’-C-methyl-B-D-ribofuranosyl)- 5-cyano-4- hydroxylamino- pyrrolo[2.3-d]pyrimidine (126)

Step 1: To the nucleoside from Example 61, step 1 (0.5 mmol)) is dissolved in THF (5 mL) and then palladium tetrakis(triphenylphosphine) is added. To this reaction is then added zinc cyanide and the reaction heated to reflux for 6 hours. The reaction is quenched with aqueous NH4Cl and extractively worked up. Column chromatography (Si0,) with MeOH/DCM affording the 7-cyano-6-chloro-7-deazapurine riboside.

Ho Amended sheet 27/02/2007

Step 2: Nucleoside 126 is synthesized as described in Example 55, step 2 using ® hydroxylamine.

Example 64

Synthesis of 7-(2’-C-methyl-B-D-ribofuranosyl)-4- hydroxylamino-pyrrolo [2.3-d]pyrimidine S-carboxyl amide (127)

Step 1: The nucleoside from Example 63, step 1 (0.5 mmol) is dissolved in anhydrous ethanol (10 mL) and then saturated with anhydrous HCI. The reaction is stirred at room temperature overnight and then concentrated. The residue is redissolved in ethanol (5 mL) and then water (1 mL) is added and the reaction stirred for 2 hours. The solution is concentrated and purified by column chromatography (SiO) with MeOH/DCM affording the 7-carboxamide-6-chloro-7-deazapurine riboside.

Step 2: Nucleoside 127 is synthesized as described in Example 55, step 2 using hydroxylamine.

Example 65

Synthesis of 7-(2’-C-methyl-B-D-ribofuranosyl)- 5-bromo-4- methoxylamino- pyrrolo[2.3-d]pyrimidine (129)

Nucleoside 129 is synthesized from 118 as described in Example 60.

Example 66

Synthesis of 7-(2’-C-methyl-B-D-ribofuranosyl)- S-methyl-4- methoxylamino- pyrrolo[2.3-d]pyrimidine (130)

Nucleoside 130 is synthesized as described in Example 55, step 2, substituting methoxylamine for hydroxylamine.

Example 67

Synthesis of 7-(2’-C-methyl-B-D-ribofuranosyl)- 5-cyano-4- methoxylamino- pyrrolof[2.3-d]pyrimidine (131)

Hi Amended sheet 27/02/2007

® The nucleoside from example 61, step 2 is converted to 131 as described in

Example 66.

Example 69

Synthesis of 7-(2’-C-methyl-B-D-ribofuranosyl)-4- methoxylamino-pyrrolo [2.3-d]pyrimidine 5-carboxyl amide (132)

The nucleoside from example 63, step 1 is converted to 132 as described in

Example 66.

Example 70

Synthesis of 1-(2°-C-methyl-B-D-ribofuranosyl)-3-bromo- 4- hydroxylamino- pyrazolo[3.4-d]pyrimidine (133)

Nucleoside 120 is converted to 133 as described in Example 60.

Example 71

Synthesis of 1-(2’-C-methyl-B-D-ribofuranosyl)-3-methyl- 4- hydroxylamino- pyrazolo[3.4-d]pyrimidine (134)

Nucleoside 134 is synthesized from 143 using conditions described in

Example 61.

Example 72

Synthesis of 1-(2’-C-methyl-B-D-ribofuranosyl)-3-cyano- 4- hydroxylamino- pyrazolo[3.4-d]pyrimidine (135)

Nucleoside 135 is synthesized from 143 using conditions described in

Example 63.

Example 73

Synthesis of 1-(2’-C-methyl--D-ribofuranosyl) - 4- hydroxylamino-pyrazolo [3.4-d]pyrimidine- 3-carboxamide (136)

Nucleoside 136 is synthesized from 143 using conditions described in

Example 64. 112

Amended sheet 27/02/2007

® Example 74

Synthesis of 1-(2’-C-methyl-B-D-ribofuranosyl)-3-bromo- 4- methoxylamino- pyrazolo[3.4-d]pyrimidine (137)

Nucleoside 137 is synthesized from 119 using conditions described in

Example 61.

Example 75

Synthesis of 1-(2’-C-methyl-B-D-ribofuranosyl)-3-methyl- 4- methoxylamino- pyrazolo[3.4-d]pyrimidine (138)

Nucleoside 138 is synthesized from 143 using conditions described in

Example 61, substituting methoxylamine for hydroxylamine.

Example 76

Synthesis of 1-(2’-C-methyl-B-D-ribofuranosyl)-3-cyano- 4- methoxylamino- pyrazolo[3.4-d]pyrimidine (139)

Nucleoside 139 is synthesized from 143 using conditions described in

Example 63, substituting methoxylamine for hydroxylamine.

Example 77

Synthesis of 1-(2’-C-methyl-B-D-ribofuranosyl) - 4- methoxylamino-pyrazolo [3.4-d]pyrimidine- 3-carboxamide (140)

Nucleoside 140 is synthesized from 143 using conditions described in

Example 64, substituting methoxylamine for hydroxylamine.

Example 78

Synthesis of 9-(2°-C-methyl-B-D-ribofuranosyl)-6-methylthio-purine (150)

Step 1. Synthesis of 2°,3°.5°-Tri-O-benzoyl-2’-C-methyl-B-D-ribofuranosyl-6- methylthio-purine. 6-Mcthylthio-purine (1.43 g, 8.6 mmolol)) was suspended in 100 mL of dry

CH;CN, bis-trimethylsilylacetamide (BSA) was added (5 mL, 20 mmolol) and the 113

Amended sheet 27/02/2007

Claims (13)

® CLAIMS:

1. A compound of Formula la R2 N—"SN ST, wo Xe R R? OHOH la wherein R and R' are independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; provided that R and R! are not both hydrogen; R? is selected from the group consisting of: cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acylamino, guanidino, amidino, thioacylamino, aryl, substituted aryl, 161 Amended sheet 27/02/2008 heteroaryl, ® substituted heteroaryl,

-NR’R* where R? and R* are joined to form, together with the nitrogen atom bond thereto, a heterocyclic, substituted heterocyclic, heteroaryl, or substituted heteroaryl, and

-NR’NR?R* where R? and R* are independently selected from the group consisting of substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where R? and R* are joined to form, together with the nitrogen atom bond thereto, a heterocyclic, substituted heterocyclic, heteroaryl, or substituted heteroaryl, and R’ is selected from the group consisting of hydrogen and alkyl;

W is selected from the group consisting of:

hydrogen,

phosphate (including monophosphate, diphosphate, triphosphate or a stablilized phosphate prodrug),

phosphonate,

acyl,

alkyl,

sulfonate ester selected from the group consisting of alkyl esters, substituted alkyl esters, alkenyl esters, substituted alkenyl esters, aryl esters, substituted aryl esters, heteroaryl esters, substituted heteroaryl esters, heterocyclic esters and substituted heterocyclic esters,

a lipid,

an amino acid,

a carbohydrate,

a peptide, and cholesterol;

Y is selected from the group consisting of:

hydrogen,

halo,

hydroxy,

alkylthio, and

162 Amended sheet 27/02/2008

-NR’R* where R’ and R* are independently selected from the group ® consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where R® and R* are joined to form, together with the nitrogen atom bond thereto, a heterocyclic, substituted heterocyclic, heteroaryl, or substituted heteroaryl, Z is selected from the group consisting of: hydrogen, halo, hydroxy, alkyl, azido, -NR®R* where where R? and R* are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where R’ and R* are joined to form, together with the nitrogen atom bond thereto, a heterocyclic, substituted heterocyclic, heteroaryl, or substituted heteroaryl, and NR’NR’R* where R? and R* are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where R’ and R* are joined to form, together with the nitrogen atom bond thereto, a heterocyclic, substituted heterocyclic, heteroaryl, or substituted heteroaryl, and : R’ is selected from the group consisting of hydrogen and alkyl; and pharmaceutically acceptable salts thereof.

2. A compound according to Claim 1 wherein R is hydrogen and R'is methyl.

3. A compound according to Claim 1 wherein W is hydrogen.

4. A compound according to Claim 1 wherein Z is hydrogen. 163 Amended sheet 27/02/2008

® 5. A compound according to Claim 1 wherein Y is hydrogen or NH.

6. A compound according to Claim 1 wherein R'is methyl; R, W, and Z are hydrogen; and Y is hydrogen or NH,.

7. A compound of Claim 1 selected from the group consisting of: 9-(2’-C-methyl-B-D-ribofuranosyl)-6-(thiophen-3-yl)-purine (1); : 9-(2’-C-methyl-B-D-ribofuranosyl)-6-(thiophen-2-yl)-2-aminopurine (2), 9-(2’-C-methyl-B-D-ribofuranosyl)-6-(pyrrol-3-yl)-purine (3); 9-(2’-C-methyl-B-D-ribofuranosyl)-6-phenyl-2-aminopurine (4); 9-(2’-C-methyl-p-D-ribofuranosyl)-6-(3-cyanophenyl)-purine (5); 9-(2’-C-methyl-B-D-ribofuranosyl)-6-(pyridin-3-yl)-purine (6); 9-(2’-C-methyl-B-D-ribofuranosyl)-6-(benzo[b]thiophen-3-yl)-2-aminopurine (7); 9-(2’-C-methyl-B-D-ribofuranosyl)-6-(1H-indol-5-yl)-purine (8); 9-(2’-C-methyl-B-D-ribofuranosyl)-6-(naphthalen-2-yl)-purine (9); 9-(2’-C-methyl-B-D-ribofuranosyl)-6-(dibenzofuran-4-yl)-2-aminopurine (10); 9-(2’-C-methyl-p-D-ribofuranosyl)-6-(thianthren-1-yl)-purine (11); 9-(2’-C-methyl-B-D-ribofuranosyl)-6-cyclopropyl-2-aminopurine (13); 9-(2’-C-methyl-B-D-ribofuranosyl)-6-(ethynyl)-purine (14); 9-(2’-C-methyl-B-D-ribofuranosyl)-6-[2-aminocarbonyl-(pyrrolidine-1-yl)]- purine (25); 9-(2’-C-methyl-B-D-ribofuranosyl)- 6-(1,3,4,9-tetrahydro-beta-carbolin-2- yD)purine (33); 9-(2’-C-methyl-B-D-ribofuranosyl)- N° —{[(3H-indol-3-yl)-acetic acid]- hydrazide} adenine (53); 9-(2’-C-methyl-B-D-ribofuranosyl)-6-(piperidin-1-yl)purine (57); 9-(2’-C-trifluoromethyl-B-D-ribofuranosyl!)-6-[2-aminocarbonyl-(pyrrolidine- 1-yl)]-purine (64); 9-(2’-C-ethenyl-B-D-ribofuranosyl)-6—[2-aminocarbonyl-(pyrrolidine-1-yl)]- purine (70); 9-(2’-C-ethynyl-p-D-ribofuranosyl)-6-[2-aminocarbonyl-(pyrrolidine-1-yl)}- purine (76); 164 Amended sheet 27/02/2008

9-(2’-C-methyl-B-D-ribofuranosyl)- 6-(azetidin-1-yl)purine (107); ® 9-(2’-C-methyl-B-D-ribofuranosyl)- 6-(pyrrolidin-1-yl)purine (108); 9-(2’-C-methyl-B-D-ribofuranosyl)- 6-(1,2,3,4-tetrahydropyridin-1-yl)purine (113); 9-(2’-C-methyl- B -D-ribofuranosyl)-6-(1,2,3,4-tetrahydroisoquinolin-2- yl)purine (114); 9-(2’-C-methyl-B-D-ribofuranosyl)-6-(6-fluoro-1,3,4,9-tetrahydro-fB-carbolin- 2-yl)purine (163); 9-(2°-C-methyl-B-D-ribofuranosyl)-6-(3,6-dihydro-2H-pyridin-1-yl)purine (164); 9-(2’-C-methyl-B-D-ribofuranosyl)-6-phenyl-purine (170); 9-(2’-C-methyl-B-D-ribofuranosyl)-6-(tetramethylguanidino)purine (178); 9-(2’-C-methyl-B-D-ribofuranosyl)purine-6-carboxamide (208); and 9-(2’-C-methyl-B-D-ribofuranosyl)-9H-purine-6-carbothioic acid amide (209).

8. A pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound or mixture of any one of the compounds of Claims 1 to 7.

9. Use of a composition of Claim 8 for the treatment of hepatitis C virus in a mammal diagnosed with hepatitis C virus, or at risk of developing hepatitis C virus.

10. Use of any one of the compounds of any one of Claims 1 to 7, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of hepatitis C virus in a mammal diagnosed with hepatitis C virus, or at risk of developing hepatitis C virus.

11. A process of preparing 2’C and/or 3’C branched ribonucleosides of Formula Ia as defined in Claim 1, comprising coupling an optionally protected sugar to a purine base,

12. A process of preparing 2’C and/or 3’C branched ribonucleosides of Formula la as defined in Claim 1, comprising coupling an organometallic carbon nucleophile with a ketone, said ketone having been produced by oxidizing an optionally protected nucleoside. 165 Amended sheet 27/02/2008

13. A compound of Formula Ia as defined in claim 1, uses thereof, pharmaceutical ® composition thereof, methods and uses involving said pharmaceutical compositions and/or processes of preparing said compounds substantially as herein described with reference to the examples herein. 166 Amended sheet 27/02/2008