Docket No. 60137.0034USP2
`
`NUCLEOSIDE PHOSPHORAMIDATE PRODRUGS
`
`The essential material for this application, including the background ofthe
`
`invention, the disclosure of the invention, including Preparations and Examples,is
`
`incorporated by reference from pending and commonly owned U.S. Provisional
`
`application No. 60/909,315, filed March 30, 2007, as well as references cited therein,
`
`under the provisions of MPEP 608.01(p).
`
`EXAMPLES
`
`Example numbers 13-55 are prepared using similar procedures described for examples 5-
`8, as disclosed in U.S. Provisional application No. 60/909,315. The identification and
`NMR/MS details are shown below:
`a
`3b
`
`OR!
`
`wo SOM
`
`nN ~N
`|
`R?
`
`O
`
`oO
`
`“A
`
`ion
`
`
`Example R’
`R? R® R® R'
`
`13
`Ph
`H
`4H
`Me Et
`14
`1-Napth
`H
`H
`Me Bn
`15
`Ph
`H
`4H
`H
`Me
`16
`2,4-Cl-Ph
`H
`4H
`Me Me
`17
`1-Napth
`H
`H
`Me Me
`18
`Ph
`*
`H
`*
`Me
`19
`Ph
`H
`4H
`Me
`n-Bu
`20
`Ph
`H
`4H
`Me Bn
`21
`4-F-Ph
`H
`4H
`Me Me
`22
`4-Cl-Ph
`H
`4H
`Me Me
`23
`3,4-Cl-Ph
`H
`4H
`Me Me
`24
`Ph
`H
`4H
`Me
`2-Bu
`
`25 Me_i-PrPh H 4H
`
`
`
`26
`4-MeO-Ph
`H
`H
`Me
`n-Bu
`27
`4-F-Ph
`H
`4H
`Me Et
`
`28 Me_i-Pr4-F-Ph H 4H
`
`
`
`29
`4-F-Ph
`H
`4H
`Me Bn
`
`30 Me_i-Pr4-MeO-Ph H H
`
`
`
`31
`2-Cl-Ph
`H
`4H
`Me Bn
`
`32 Me_n-Bu2,4-Cl-Ph H 4H
`
`
`
`
`33 Me_i-Pr4-Me-Ph H 4H
`
`
`
`
`34 Me_n-Bu4-F-Ph H 4H
`
`
`
`35
`3,4-dicl-Ph H
`H
`Me Et
`
`36 Me_i-Pr2-Cl-Ph H 4H
`
`
`
`37
`4-MeO-Ph
`H
`H
`Me Bn
`38
`Ph
`H
`4H
`Me
`n-Pen
`
`
`
`-l-
`
`GIL2014
`I-MAK,INC. V GILEAD PHARMASSETLLC
`IPR2018-00121
`
`GIL2014
`I-MAK, INC. V GILEAD PHARMASSET LLC
`IPR2018-00121
`
`

`

`Docket No. 60137.0034USP2
`
`
`
`Example
`_R’
`R’_ R* R” R'
`
`39 Me_i-Pr4-Cl-Ph H 4H
`
`
`
`40
`4-Cl-Ph
`H
`4H
`Me
`n-Bu
`41
`4-Cl-Ph
`H
`4H
`Me Et
`42
`4-Me-Ph
`H
`4H
`Me
`n-Bu
`43
`4-Me-Phe
`H
`4H
`Me Bn
`44
`Ph
`H
`4H
`Et Me
`45
`Ph
`H
`4H
`Me
`4-F-Bn
`
`46 Me_n-Bu4-Cl-Ph H 4H
`
`
`
`47
`Ph
`H
`4H
`Me
`3-Me-1-Bu
`48
`3,4-dicl-Ph H
`H
`Me Bn
`49
`Ph
`H
`4H
`Me
`_c-Hex
`50
`Ph
`H Me H
`n-Bu
`51
`Ph
`H Me H
`1-Pr
`52
`Ph
`H Me H
`Bn
`53
`2-Cl-Ph
`H
`4H
`Me
`n-Bu
`54
`4-Br-Ph
`H
`4H
`Me_
`i-Pr
`
`2————eetSFTFSoTTT"G
`*R’ and R”® together are -(CH>);— as derived from L-
`proline
`
`
`
`Example
`
`NMR/MS
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`1H NMR (DMSO-d6) 8 1.12-1.16 (m, 3H), 1.20-1.28(m,6H), 3.70-3.90 (m, 2H), 4.00-
`4.08 (m, 3H), 4.18-4.45 (m, 2H), 5.52-5.58 (m, 1H), 5.85-5.98 (m, 1H), 6.00-6.20 (m,
`2H), 7.16-7.23 (m, 3H), 7.37-7.40 (m, 2H) , 7.54-7.60 (m, 1H), 11.54 (s.1H) ; MS, m/e
`516.1 (M+1)+
`
`1H NMR (DMSO-d6) 5 1.18-1.30 (m, 6H), 3.78-4.10 (m, 3H), 4.38-4.49 (m, 2H),
`4.99-5.11 (m, 2H), 5.28-5.40 (m, 1H), 5.85-6.10 (m, 2H), 6.30-6.41 (m, 1H), 7.28-7.32
`(m, 5H), 7.41-7.60 (m, 5H), 7.73-7.76(m, 1H) , 7.94-8.11(m, 1H) , 8.13-8.15(m,
`
`1H) , 11.50 (s.1H) ; MS, m/e 628.4 (M+1)+
`
`1H NMR (DMSO-d6)5 1.22 (d, J=22.4 Hz, 3H), 3.59(s, 3H), 3.63-3.69 (m, 2H), 3.74-
`3.8(m, 1H), 4.02(d, J=11.2 Hz, 1H), 4.23-4.28(m, 1H), 4.40-4.43 (m, 1H), 5.57-5.60
`(m, 1H), 5.89(d, J=6.8 Hz, 1H), 6.00-6.06(m, 2H), 7.15-7.23 (m, 3H), 7.35-7.39 (m,
`2H),7.52(d, J=8 Hz, 1H), 11.52(s, 1H) ; MS, m/e 487.97 (M+1)+
`
`1H NMR (DMSO-d6) 5 1.22-1.28 (m, 6H), 3.57-3.60 (m, 3H), 3.84-3.92 (m, 2H),
`4.00-4.04 (m, 1H), 4.31-4.44 (m, 2H), 5.54-5.61 (m, 1H), 5.85-6.10 (m, 2H), 6.32-6.43
`(m, 1H), 7.44-7.54 (m, 3H), 7.72-7.75 (m, 1H), 11.54 (s.1H) ; MS, m/e 570.2 (M+1)+
`
`1H NMR (DMSO-d6) 8 1.15-1.27 (m, 6H), 3.51-3.55 (d, 3H), 3.85-3.96 (m, 2H), 4.00-
`4.10(m, 1H), 4.30-4.46 (m, 2H), 5.31-5.39 (m, 1H), 5.89-6.05 (m, 2H), 6.22-6.34 (m,
`1H), 7.44-7.60 (m, SH), 7.73-7.77 (m, 1H), 7.93-7.96 (m, 1H), 8.12-8.14 (m,
`1H),11.50(s.1H) ; MS, m/e 552.1 (M+1)+
`
`1H NMR (DMSO-d6) 5 1.19 (d, J=22.8 Hz, 3H), 1.69-1.84 (m, 3H), 1.99-2.04 (m, 1H),
`3.16-3.21 (m, 2H), 3.58 (s, 3H), 3.68-3.8 (m, 1H), 4.00 (m, 1H), 4.01-4.13 (m, 1H),
`4.22-4.25 (m, | H), 4.5 (d, J= 11.2 Hz, 1H), 5.54 (d, J = 8.0 Hz, 1H), 5.86 (s, 1H), 5.6
`(d, J = 19.6 Hz, 1H), 7.15-7.2 (m, 3H), 7.34 (t, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz,
`1H), 11.38 (s, 1H) ; MS, m/e 527.93(M+1)+
`
`

`

`Docket No. 60137.0034USP2
`
`Example
`
`NMR/MS
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`26
`
`27
`
`28
`
`29
`
`1H NMR (DMSO-d6) 5 0.80-0.90 (m, 3H), 1.20-1.35 (m, 8H), 1.48-1.55 (m, 2H),
`3.78-3.88 (m, 2H), 3.95-4.08 (m, 3H), 4.22-4.45 (m, 2H), 5.55-5.57(t, 1H), 5.85-6.18
`(m, 3H), 7.14-7.23 (m, 3H), 7.35-7.40 (1m, 2H), 7.51-7.60 (d, 1H), 11.50 (s.1H) ; MS,
`m/e 544.2 (M+1)+
`
`1H NMR (DMSO-d6) 5 1.20-1.30 (m, 6H), 3.72-4.05 (m, 3H), 4.23-4.27 (m, 1H),
`4.32-4.45 (m, 1H), 5.07-5.10(t, 2H), 5.52-5.56(t , 1H), 5.86-6.10 (m, 2H), 6.13-
`6.21(m, 1H), 7.15-7.21 (m, 3H), 7.29-7.40 (m, 7H), 7.51-7.56 (d, 1H), 11.50 (s.1H) ;
`MS, m/e 578.2 (M+1)+
`
`1H NMR (DMSO-d6)5 1.28-1.34 (m, 6H), 3.65(d, J= 4 Hz, 3H), 3.85-3.96 (m, 2H),
`4.06-4.12 (m, 1H), 4.30-4.34 (m,1H), 4.40-4.47 (m, 1H), 5.62-5.67 (m, 1H), 5.94-
`6.01(m, 1H), 6.09 (d, J=18.8 Hz, 1H), 6.17-6.26 (m, 1H), 7.27-7.33(m, 4H), 7.62 (d, J
`= 7.6 Hz, 1H), 11.61 (s, 1H) ; MS, m/e $19.94(M+1)+
`
`1H NMR (DMSO-d6) 5 1.22-1.28 (m, 6H), 3.58 (d, 2H), 3.70-3.95(m,2H), 3.95-4.08
`(m,1H), 4.23-4.45 (m, 2H), 5.55-5.61(t , 1H), 5.85-6.10 (m, 2H), 6.15-6.23(m,1H),
`7.20-7.26 (m, 2H), 7.43-7.46 (m, 2H), 7.54-7.57 (d, 1H), 11.50 (s.1H) ; MS, m/e 536.1
`(M+1)+
`
`1H NMR (DMSO-d6) 5 1.13 (m, 6H), 3.49 (s, 3H), 3.61-3.85 (m, 2H), 3.90-3.93 (m,
`1H), 4.16-4.22 (m, 1H), 4.27-4.31 (m, 1H), 5.47-5.52 (m, 1H), 5.82 (d, J = 11.6 Hz,
`1H), 5.93(d, J = 19.2 Hz, 1H), 6.15-6.25 (m, 1H), 7.13 (t, J= 9.6 Hz, 1H), 7.43 (4, J=
`12Hz, 2H), 7.57 (d, J = 6.0 Hz, 1H), 11.43(s, 1H) ; MS, m/e 569.85 (M+1)+
`
`1H NMR (DMSO-d6)6 0.83 (d, J = 6.8 Hz, 6H), 1.20-1.26 (m, 6H), 1.79-1.86 (m, 1H),
`3.73-3.90 (m, 4H), 4.01 (t, J= 11.2 Hz, 1H), 4.21-4.28 (m, 1H), 4.33-4.42 (m,1H),
`5.54 (t, ]=7.6 Hz, 1H), 5.85-5.92 (m, 1H), 5.99-6.13 (m, 2H), 7.19 (t, J = 8 Hz, 3H),
`7.36 (t, J = 7.6 Hz, 2H), 7.53 (d, J = 7.6 Hz, 1H), 11.52 (s, 1H) ; MS, m/e 544.00
`(M+1)+
`
`1H NMR (DMSO-d6) 5 1.13-1.28 (m, 12H), 3.74-3.81 (m, 2H), 3.95-4.08 (m,1H),
`4.20-4.45 (m, 2H), 4.83-4.87 (m, 1H), 5.52-5.58 (m, 1H), 5.84-6.15 (m, 3H), 7.17-7.23
`(m, 3H), 7.35-7.39 (m, 2H), 7.54-7.57 (m, 1H), 11.50 (s.1H) ; MS, m/e 530.2 (M+1)+
`
`LHNMR(400MHz, DMSO): 8 =0.78-0.82 (m, 3H), 1.29-1.47 (m, 8H), 1.49-1.54 (m,
`2H), 3.66-3.87 (m, 5H), 3.96-4.02 (m, 3H), 4.21-4.39 (m, 2H), 5.57 (t, J= 12.0Hz, 1H),
`§.84-6.05 (m, 3H), 6.90 (dd,J1 =8.0Hz, J2=4.0Hz, 2H), 7.09-7.14 (dd, J1=16.0Hz,
`J2=4.0Hz, 2H), 7.55 (d, ]=8.0Hz, 1H), 11.48-11.62 (s, 1H)
`
`1H NMR (DMSO-d6) 5 1.12-1.28 (m, 9H), 3.72-3.94(m,2H),3.98-4.10 (m,3H), 4.21-
`4.42(m,2H), 5.55-5.61 (t, 1H), 5.85-6.20 (m, 3H), 7.18-7.25 (m,4H), 7.55-7.58 (d, 1H),
`11.50 (s.1H) ; MS, m/e 533.90 (M+1)+
`
`1H NMR (DMSO-d6) 5 1.13-1.30 (m, 12H), 3.74-3.85(m,2H),3.98-4.06 (m,1H), 4.23-
`4.41(m,2H), 4.83-4.87 (m, 1H), 5.55-5.61 (t, 1H), 5.85-6.12 (m, 3H), 7.18-7.24
`(m,4H), 7.55-7.58 (d, 1H), 11.50 (s.1H) ; MS, m/e 547.91 (M+1)+
`
`1H NMR (DMS0-d6) 5 1.10-1.23 (m, 6H), 3.65-3.89(m,3H),4.10-4.30 (m,2H), 4.96-
`§.00(m,2H), 5.46-5.50 (t, 1H), 5.75-5.96 (m, 2H), 6.04-6.12(m,1H), 7.05-7.11 (m,4H),
`7.20-7.24 (d, 5H), 7.42-7.45(d,1H), 11.50 (s.1H) ; MS, m/e 595.94 (M+1)+
`
`

`

`Docket No. 60137.0034USP2
`
`Example
`
`NMR/MS
`
`30
`
`31
`
`32
`
`33
`
`34
`
`35
`
`36
`
`37
`
`38
`
`39
`
`LHNMR(400MHz, DMSO): 8=1.15-1.27 (m, 12H), 3.71-3.89 (m, 5H), 3.98-4.02 (m,
`1H), 4.22-4.25 (m, 1H), 4.33-4.39 (m, 1H), 4.84-4.87 (m, 1H), 5.57 (t, J= 12.0Hz, 1H),
`§.91-6.03 (m, 3H), 6.90 (d, J= 8.0Hz, 2H), 7.09-7.14 (m, 2H), 7.55 (d, J= 8.0Hz, 1H),
`11.51 (s, 1H)
`
`1H NMR (DMSO-d6)5 1.23 (m, 6 H), 3.93-4.00 (m, 3 H), 4.27-4.40 (m, 2H), 5.0(t, J=
`7.2 Hz, 2 H), 5.53 (m 1 H), 5.80-6.0(m , 2 H), 6.30(m, 1H), 7.15 (d, J= 2.4 Hz, 1 H),
`7.27 (m, 6 H), 7.51 (m, 3 H), 11.5 (s, 1 H) ; MS, m/e 579.87(M+1)+ / 596.78 (M+18)+
`
`1H NMR (DMSO-d6) 5=0.82 (m, 3 H),1.23 (m, 8 H) , 1.47 (m, 2 H), 3.86 (m, 2 H),
`3.84 (m, 3 H),4.27-4.43 (m, 2H), 5.5 (m, 1 H), 6.02 (m ,2 H), 6.35(m, 1H), 7.44 (m, 3
`H), 7.77 (m, 1 H), 11.5 (s, 1 H) ; MS, m/e 611.87(M+1)+
`
`1H NMR (DMSO-d6) 8 1.14-1.27 (m, 12H), 2.17-2.26 (m, 3H), 3.73-3.82 (m, 1H),
`3.99-4.02 (m, 1H), 4.23-4.26 (m, 1H), 4.37-4.40 (m, 1H), 4.82-4.88 (m, 1H), 5.52-5.58
`(m, 1H), 5.85-6.07 (m, 3H), 7.01-7.20 (m, 4H), 7.55 (d, J= 16Hz, 1H), 11.51 (s, 1H);
`MS, m/e 543.98 (M+1)+; 1108.86 (2M+23)+
`
`1H NMR (DMS0-d6) 5 0.82-0.89 (m,3H), 1.20-1.31 (m, 8H), 1.48-1.53 (m,2H), 3.77-
`3.90 (m,2H),3.95-4.10 (m,3H), 4.21-4.45(m,2H), 5.56-5.61 (t, 1H), 5.83-6.20 (m, 3H),
`7.18-7.25 (m,4H), 7.55-7.58 (d, 1H), 11.50 (s.1H) ; MS, m/e $84.1 (M+23)+
`
`1H NMR (DMSO-d6) 51.12-1.31 (m, 9H), 3.77-3.92 (m,2H), 3.95-4.08 (m,3H), 4.21-
`4.45(m,2H), 5.56-5.62 (t, 1H), 5.80-6.11 (m, 2H), 6.18-6.33(m,1H), 7.18-7.25 (m,1H),
`7.49-7.56 (d, 2H), 7.62-7.67(m,1H), 11.50 (s.1H) ; MS, m/e 606.1 (M+23)+
`
`1HNMR(400MHz, DMSO): 8 =1.12-1.16 (m, 6H), 1.21-1.27 (m, 6H), 3.79-3.85 (m,
`2H), 4.00-4.07 (m, 1H), 4.28-4.32 (m, 1H), 4.38-4.43 (m, 1H), 4.83-4.87 (m, 1H), 5.56
`(dd, JI=16.0Hz, J2=8.0Hz, 1H), 5.85-6.12 (m, 2H), 6.20-6.33 (m, 1H), 7.19-7.22 (m,
`1H), 7.33 (t, JE 16.0Hz, 1H), 7.48-7.55 (m, 3H), 11.55 (s, 1H)
`
`1HNMR(400MHz,DMSO): 8=1.19-1.26 (m, 6H), 3.69-3.70(s, 3H), 3.87 (m, 2H), 3.99
`(m, 1H), 4.20-4.21 (m, 1H), 4.35 (m, 1H), 5.07-5.09 (m, 2H), 5.54 (t, ]= 16.0Hz, 1H),
`§.85-5.92 (m, 1H), 6.04-6.10 (m, 2H), 6.86 (d, J= 8.0Hz, 2H), 7.09 (dd, JI=16.0Hz,
`J2=4.0Hz, 2H), 7.30-7.34 (m, 5H), 7.53 (s, 1H), 11.52 (s, 1H)
`
`1H NMR (DMSO-d6) 5 0.79-0.81 (m, 3H), 1.17-1.23 (m, 10H), 3.74-3.81 (m, 2H),
`3.94-3.96 (m, 3H), 4.19-4.36 (m, 2H), 5.49-5.54 (m, 1H), 5.87-6.08 (m,3H), 7.14-7.33
`(m, 3H), 7.31-7.35 (m, 2H), 7.51 (d, J = 8Hz, 1H), 11.51 (s, 1H) ; MS, m/e 557.9
`(M+1)+; 1136.88 (2M+23)+
`
`1H NMR (DMSO-d6) 5 1.04-1.19 (m, 12H), 3.76-3.80 (m , 2H), 3.98-4.08 (m, 1H),
`4.42-4.42 (m, 2H), 4.82-4.85 (m, 1H), 5.55-5.60 (m, 1H), 5.80-6.20 (m,3H),7.20-7.2
`5(m, 2H), 7.43 (d, J = 8.8Hz, 1H), 7.54 (d, J= 8Hz, 1H), 11.51 (s, 1H) ; MS, m/e
`563.88 (M+1)+; 1148.73 (2M+23)+
`
`

`

`Docket No. 60137.0034USP2
`
`Example
`
`NMR/MS
`
`40
`
`41
`
`42
`
`43
`
`44
`
`45
`
`46
`
`47
`
`48
`
`1H NMR (DMSO-d6)5 0.85 (t, J = 7.2 Hz, 3H), 1.22-1.33 (m, 8H),1.45-1.53 (m, 2H),
`3.80-3.87 (m, 2H), 3.96-4.04 (m, 3H), 4.24-4.27 (m, 1H), 4.35-4.39 (m, 1H), 5.56-5.61
`(m, 1H), 5.82-6.11 (m, 2H), 6.15-6.18 (m, 1H), 7.20-7.56 (m, 4H), 7.51-7.57 (m.1H),
`11.54 (s, 1H); MS, m/e577.95(M+1)+
`
`1H NMR (DMSO-d6) 6 1.14 (t, J = 7.0Hz, 3H), 1.20-1.28 (m, 6H),3.77-3.88 (m, 2H),
`3.99-4.07 (m, 3H), 4.24-4.28 (m, 1H), 4.34-4.43 (m, 1H), 5.56-5.61 (m, 1H), 5.86-6.13
`(m, 2H), 6.15-6.24 (m, 1H), 7.20-7.26 (m, 2H), 7.44 (d, J = 7.6Hz, 2H) , 7.55 (d, J =
`7.6Hz, 1H), 11.55 (s, 1H); MS, m/e549.11(M+1)+
`
`1H NMR (DMSO-d6)5 0.79-0.83 (m, 3H), 1.17-1.28 (m, 8H), 1.45-1.47 (m, 2H), 2.22
`(d, J = 2.8Hz, 1H), 3.70-3.90 (m, 2H), 3.95-3.98 (m, 3H), 4.10-4.40 (m, 2H),5.51 (t,
`1H), 5.80-5.90 (m, 1H), 5.95-6.05 (m, 2H), 7.02-7.06 (m, 2H), 7.51 (t, J = 4.2Hz, 4H),
`7.51 (d, 1H), 11.51 (s, 1H) ; MS, m/e $57.99(M+1)4; 1136.84(2M+23)+
`
`1H NMR (DMSO-d6) 5 1.16-1.24 (m, 6H), 2.22 (s , 3H), 3.65-4.03 (m,3H), 4.11-4.38
`(m, 2H), 5.04-5.05 (m, 2H), 5.48-5.50 (m, 1H), 5.77-5.87 (m,1H),5.90-6.11 (m, 2H),
`6.98-7.10 (m, 4H), 7.28-7.32 (m, SH), 7.50 (t 1H), 11.48 (s, 1H) ; MS, m/e 592.00
`(M+1)+.
`
`1H NMR (DMSO-d6) 5 0.70-0.80 (m, 3H), 1.11-1.26 (m, 3H), 1.42-1.61 (m, 2H),
`3.50-3.54 (m, 3H), 3.58-3.80 (m, 2H), 3.91-4.02 (m, 1H), 4.12-4.38 (m, 2H), 5.47-5.52
`(m,1H),5.90-6.03 (m, 2H), 7.08-7.16 (m, 3H), 7.26-7.35 (m, 2H),7.48 (t,1H), 11.45 (s,
`1H) ; MS, m/e 515.95 (M+1)+; 1052.82 (2M+23)+
`
`‘HNMR (400MHz, DMSO): 8 1.20-1.26 (m, 6H), 3.80-3.93 (m, 2H), 3.98 (s, 1H),
`4.25-4.26 (m, 1H), 4.36-4.37 (m, 1H), 5.07 (s, 2H), 5.52-5.55 (m, 1H), 5.86-5.87(m,
`1H), 5.98-6.04 (m, 1H), 6.14-6.17 (m, 1H), 7.15-7.20 (m, 5H), 7.36 (dd, J = 20.0, 8.0
`Hz, 4H), 7.54 (s, 1H), 11.55 (s, 1H)
`
`‘HNMR (400MHz, DMSO): 8 1.21-1.28 (m, 6H), 3.71-3.88 (m, 1H), 3.91-3.98 (m,
`1H), 4.00-4.01 (m, 1H), 4.23-4.27 (m, 1H), 4.35-4.38 (m, 1H), 5.08 (d, J = 4.0Hz, 2H),
`5.57 (dd, J = 12.0, 8.0 Hz, 1H), 5.91 (d, J = 8.0 Hz, 1H), 6.01 (d, J = 8.0 Hz, 1H),
`6.22-6.24 (m, 1H), 7.17-7.23 (m, 2H), 7.31-7.40 (m, 7H), 7.53 (s, 1H), 11.50 (s, 1H)
`
`‘HNMR (DMSO-ds)5 0.80-0.82 (m, 6H), 1.18-1.40 (m, 8H), 1.50-1.58 (m, 1H), 3.71-
`3.82 (m, 3H), 3.97-3.4.01 (m, 3H), 4.21-4.40 (m, 2H), 5.30(t, J = 8.6 Hz, 1H), 5.81-
`6.10 (m, 3H), 7.15-7.20 (m, 3H), 7.32-7.36 (m, 2H), 7.48 (d, J= 8.4 Hz, 1H), 11.38 (s,
`1H) ; MS, m/e 557.98 (M+1)"; 1136.88 (2M+23)"
`
`‘HNMR (DMSO-ds)8 1.05-1.37 (1m, 6H), 3.71-3.82 (m, 1H), 3.87-4.02 (m, 2H), 4.28-
`4.29 (m, 1H),4.36-4.38 (m, 1H),5.04 (d, J = 5.2Hz, 2H), 5.55-5.64 (m, 1H), 5.85-5.94
`(m, 1H), 6.00-6.05 (m, 1H), 6.29-6.40 (m, 1H),7.17-7.24 (m, 1H), 7.30-7.41 (m, 5H),
`7.45-7.58 (m, 2H), 7.61 (d, J = 4.0Hz, 1H), 11.53 (s, 1H); MS, m/e545.80(M+1)";
`
`

`

`Docket No. 60137.0034USP2
`
`Example
`
`NMR/MS
`
`49
`
`50
`
`51
`
`52
`
`53
`
`54
`
`12H), 1.59-1.67 (m, 4H), 3.74-13.80 (m, 1H),
`‘HNMR (DMSO-d) 5 1.18-1.41 (m,
`3.96-4.02 (m, 1H), 4.19-4.26 (m, 1H), 4.31-4.39 (m, 1H), 4.60 (s, 1H), 5.52 (t, J= 7.8
`Hz, 1H), 5.80-6.09 (m, 3H), 7.15-7.20 (m, 3H), 7.32-7.36 (m, 2H), 7.52 (d, J= 8 Hz,
`1H), 11.50 (s, 1H) ; MS, m/e 569.98 (M+1)*; 592.14 (M+23)*
`
`1H NMR (DMSO-d6)5 0.76 (t, J = 7.2Hz, 3H), 1.10-1.22 (m, 8H), 1.38-1.43 (m, 2H),
`3.72-3.75 (m, 2H), 3.87-3.93 (m, 3H), 4.14-4.21 (m, 1H), 4.23-4.33 (m, 1H), 5.46-5.54
`(m, 1H), 5.84-6.11 (m, 3H), 7.09-7.14 (m, 2H), 7.27-7.32 (m, 2H), 7.34-7.51 (m, 1H),
`11.47 (s, 1H); MS, m/e543.98(M+1)+
`
`1H NMR (DMSO-d6)5 1.39 (d, J = 7.2Hz, 6H), 1.19-1.29 (m, 6H), 3.65-3.75 (m, 2H),
`3.95-4.05 (m, 1H), 4.20-4.22 (m, 1H), 4.31-4.33 (m, 1H), 4.79-4.82 (m, 1H), 5.48-5.57
`(m, 1H), 5.84-5.91 (m, 1H), 5.96-6.07 (m, 2H), 7.12-7.35 (m, 5H), 7.44-7.54 (m.1H),
`11.49(s, 1H); MS, m/e529.96 (M+1)+
`
`‘HNMR (DMSO-ds)8 1.18-1.28 (m, 6H), 3.70-3.83 (m, 1H), 3.87-3.94 (m, 1H), 3.99-
`4.01 (m, 1H), 4.23-4.26 (m, 1H), 4.33-4.37 (m, 1H), 5.03-5.12 (m, 2H), 5.51-5.59 (m,
`1H), 5.87-5.90 (m, 1H), 5.95-6.07 (m, 1H), 6.10-6.27 (m, 1H), 7.15-7.23 (m, 3H), 7.31-
`7.38 (m, 7H), 7.47-7.56 (m, 1H), 11.50 (s, 1H); MS, m/e577.99 (M+1)+
`
`‘HNMR (400MHz, DMSO): 5 0.81-0.86 (m, 3H), 1.21-1.31 (m, 8H), 1.46-1.52 (m,
`2H), 3.84-3.90 (m, 2H), 3.97-4.04 (m, 3H), 4.27-4.41 (im, 2H), 5.53-5.58 (m, 1H), 5.82-
`5.95 (m, 1H), 5.96-6.10 (m, 1H), 6.27-6.31 (m, 1H), 7.19-7.22 (m, 1H), 7.34 (dd, J =
`8.0, 4.0 Hz, 1H), 7.47-7.55 (m, 3H), 11.55 (s, 1H)
`
`‘HNMR (400MHz, DMSO): 5 1.10-1.14 (m, 6H), 1.20-1.27 (m, 6H), 3.74-3.81 (m,
`2H), 3.99-4.01 (m, 1H), 4.21-4.25 (m, 1H), 4.37-4.38 (m, 1H), 4.81-4.85 (m, 1H), 5.58
`(dd, J = 8.0, 4.0 Hz, 1H), 5.82-5.95 (m, 1H), 5.96-6.09 (m, 1H), 6.10-6.13 (m, 1H),
`7.18 (dd, J = 12.0, 8.0 Hz, 2H), 7.53-7.57 (m, 3H), 11.52 (s, 1H)
`
`

`

`Docket No. 60137.0034USP2
`
`Preparation of Example 55
`
`Preparation of (S)-2- {[(2R,3R,4R,5R)-5-(6-aminopurin-9-yl)-4-fluoro-3-hydroxy-4-
`
`methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino }-propionic acid
`
`methyl ester), 55.
`
`Scheme
`
`cl
`‘cl
`N
`‘on y
`Ty
`-N
`4N
`O.-OH ve
`O20
`-
`ao LiAKOBu-t)3H/THF—Bz0 rs Oe NN
`ot
`DEAD, PPh;
`ot
`~
`BzO
` F
`BzO-
`OF
`THF,rt, overnight
`
`B20
`
`Se
`BzO
`fF
`
`-
`
`a
`
`b
`
`q
`
`NH2/THF
`> 50
`90 °C,overnight
`
`oN
`N
`‘Y—nNH,
`g
`a—a—o—s—
`ON ON
`NH3/MeOH
`~~
`
`r,t, overnight
`
`se
`BzO
`£
`
`OV ILCI
`
`9
`i
`
`cl
`
`e
`
`canis
`oF
`
`_—_——
`
`Et,N/DCM
`
`N
`oN NH2
`
`NAN
`
`HO
`
`Oo.
`
`oar
`HO
`¢—
`
`f
`
`of HP
`Eon
`
`i
`
`
`
`HO
`F
`
`NMUTHF
`
`oe
`HOE
`
`Preparation of compound(b)
`
`To a solution of compound a (1 g, 2.69 mmol) in anhydrous THF (30 mL) was
`
`added dropwise | M solution of LiAl(OBu-t)3H in THF (2.69 mL, 2.69 mmol) at -20 °C.
`
`The reaction mixture wasstirred for 2-3 h at the same temperature. EtOAc (100 mL) was
`
`added followed by saturated NH4Cl solution (10 mL) and reaction mixture was slowly
`
`brought to room temperature. Reaction mixture was extracted with EtOAc and washed
`
`with IN HCl and water. Combined organic phase was evaporated to give 0.8 g of crude
`
`compound b as transparent oil, which wasused directly for next reaction.
`
`

`

`Docket No. 60137.0034USP2
`
`Preparation of compound(d)
`
`To a solution of compound b (0.8 g, 2.1mmol), compound ¢ (0.45 g, 2.5 mmol) and
`
`PhsP (0.56 g, 2.1 mmol) in anhydrous THF (20 mL) undernitrogen atmosphere was
`
`added DEAD (1.8 mL). The reaction mixture wasstirred at room temperature overnight.
`
`The reaction solution was concentrated under reduce pressure. The residue was separated
`
`by preparative layer chromatography (hexanes:EtOAc = 3:1) to give crude compound d
`
`(0.8 g). The crude compound d was used to the next step without further purification.
`
`Preparation of compound(e)
`
`Compoundd (0.8 g, 1.57 mmol) wasdissolved in THF (2 mL) and THF saturated
`
`with ammonia (5 mL) was then addedto this solution. The reaction mixture was heated to
`
`90°C overnight. After 18 hours, the solution was cooled to room temperature by ice
`
`water, then the solvent was removed under reduced pressure and the residue waspurified
`
`by column to give compounde (0.75 g) for the nextstep.
`
`Preparation of compound(f)
`
`Compound e (0.5 g, 1.01 mmol) was dissolved in methanol (2 mL) and methanol
`
`was saturated with ammonia (5 mL) was then addedto this solution. The reaction mixture
`
`wasstirred at room temperature overnight. After 18 hours, the solvent was removed
`
`under reduced pressure and the residue was purified by column to give crude compound f
`
`(0.15 g) for the next step.
`
`Preparation of compound(i)
`
`A solution oftriethylamine (1.07 g, 10.6 mmol) in anhydrous dichloromethane (15
`
`mL) was added dropwiseto a solution of compound g (1.16 g, 5.3 mmol) and compound
`
`h (1.31 g, 5.3 mmol) in dichloromethane (10 mL) with vigorousstirring at -78 °C over a
`
`period of 2 hours. After completion of addition, the reaction temperature was allowed to
`
`warm to room temperature gradually andstirred over night. Then the solvent was
`
`removed under vacuum and anhydrousether 20 mL was addedandthe precipitated salt
`
`wasfiltered and the precipitate was washed with ether. The combined organic phase was
`
`concentrated to give the colorless oil of compound i (1.0 g).
`
`Preparation of 55
`
`To a solution of compoundj (0.1 g, 0.35 mmol) dissolved in 10 mL of anhydrous
`
`THF, stirred and added 0.4g NMItill the solution becameclear, added compoundi (0.8 g,
`
`

`

`Docket No. 60137.0034USP2
`
`2.89 mmol) in 10 mL THF dropwise,stirred at r.t. overnight. Checked by LCMS it was
`
`ok, the solvent was evaporated and purified by Pre-HPLC to afford the 53. (25 mg, Yield:
`
`13.6%).
`55: 'H NMR (DMSO-ds) & 1.08 (d, / = 22.8 Hz, 3H), 1.17-1.24 (m, 3H), 3.50-3.52 (m,
`
`3H), 3.78-3.83 (m, 1H), 4.10-4.13 (m, 1H), 4.24-4.44 (m, 2H), 5.85-5.92 (m, 1H), 6.01-
`
`6.11 (m,1H), 6.2.-6.27 (m, 1H), 7.08-7.19 (m, 4H), 7.31-7.38 (m, 3H), 8.15 (s, 1H), 8.26
`(s, 1H); MS, m/e 525 (M+1)"
`
`The purification procedure by Pre-HPLC:
`
`Crude products were dissolved in methanol. Injection volumesofthese solutions
`
`were 5 mL.
`
`The preparative HPLC system including 2 sets of Gilson 306 pumps, a Gilson 156
`
`UV/Vis detector, a Gilson 215 injector & fraction collector, with Unipoint control
`
`software. A Ymc 25302 mm column was used. The mobile phase was HPLC grade
`
`water (A), and HPLCgrade acetonitrile (B). Fractions were collected into 100* 15mm
`
`glass tubes.
`
`HPLCgradient is shown in Table 1. Once the gradient was selected, acetonitrile
`
`solution was injected into HPLC system, and then fractions collected according to UV
`
`peaks. After the separation, each glass tubes were run MStest to collect the desired
`
`compounds. The fractions with target MS were combinedin a well-weighted flask. Most
`
`of acetonitrile was removed underreduce pressure and the remaining solution wasfreeze-
`
`dried to give desired compound.
`
`Table 1:
`
`Preparative HPLC gradient
`
` 0
`
`30
`
`15
`
`15
`
`90
`
`60
`
`10
`
`40
`
`

`

`Docket No. 60137.0034USP2
`
`All the references disclosed in U.S. Provisional application No. 60/909,315, filed
`
`March 30, 2007, are hereby incorporated by reference in the present application so far as
`
`needed to supplement the present disclosure. In the event that the incorporated reference
`
`contains a term that conflicts with a term disclosed herein, the meaning of the term
`
`contained herein controls provided that the overall meaning of the incorporated subject
`
`matter is notlost.
`
`Anti-HCVactivity for certain exemplified compounds(28, 36, 39, 53, and 54)
`
`was determined in a manneras disclosed in Example 13 of U.S. Provisional application
`
`No. 60/909,315, filed March 30, 2007, which is incorporated by referencein its entirety,
`
`as evidenced by the following Table
`
`
`
`Ex. #
`
`Compound
`
`Reduction at GM
`50uM
`B
`
`
`Log10
`
`2.16
`
`0.75
`
`
`
`~*o
`
`.G
`
`28
`
`Y
`4 Cyi
`O.>N*
`OO ob
`HOF
`>
`
`
`36
`
`oO
`
`Cy
`“I
`oA,
`of 2
`NTEHO
`
`OF
`
`-1.64
`
`21.9
`
`
`Cl
`
`39
`
`ot 9
`
`0
`
`NH
`
`Cr
`
`-1.78
`
`0.47
`
`-10-
`
`

`

`Docket No. 60137.0034USP2
`
`
`
`Ex. #
`
`Compound
`
`Log10
`Reduction at
`50uM
`
`EC90
`
`
`(uM)
`
`Og cr
`
`s4
`
`-1.55
`
`0.57
`
`
`
`-ll-
`
`

`

`Docket No. 60137.0034USP2
`
`Weclaim:
`
`1.
`
`A compoundits stereoisomer, salt, hydrate, solvate, or crystalline form
`
`thereof selected from among
`
`2'-Deoxy-2'-fluoro-2'-C-methyluridine 5'-(phenyl methoxy-alanyl phosphate
`5
`((S)-2- {[((2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-
`hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino} -propionic
`acid methylester);
`6
`2'-Deoxy-2'-fluoro-2'-C-methyluridine 5'-(phenyl methoxy-valyl phosphate
`((S)-2- {[((2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-
`hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino} -3-methyl-
`butyric acid methylester;
`7
`2'-Deoxy-2'-fluoro-2'-C-methyluridine 5'-(4-bromophenyl methoxy-valyl
`phosphate ((S)-2- {(4-bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-
`pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-
`phosphorylamino}-3-methyl-butyric acid methyl ester);
`8
` 2'-Deoxy-2'-fluoro-2'-C-methyluridine 5'-(4-bromophenyl methoxy-alanyl
`phosphate (((S)-2- {(4-bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-
`pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-
`phosphorylamino}-propionic acid methylester);
`9 N‘(N,N-dimethylformamidinyl)-2'-deoxy-2'-fluoro-2'-C-methylcytidine;
`10 2'-Deoxy-2'-fluoro-2'-C-methylcytidine 5'-(phenyl methoxy-alanyl phosphate
`(((S)-2- {[((2R,3R,4R,5R)-5-(2-oxo-4-amino-pyrimidin-1 -yl)-4-fluoro-3-hydroxy-4-
`methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino }-propionic acid
`methyl ester);
`11 2'-Deoxy-2'-fluoro-2'-C-methylcytidine 5'-(4-bromophenyl methoxy-valyl
`phosphate ((S)-2- {(4-bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2-oxo-4-amino-pyrimidin-1-
`yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino} -3-
`methyl-butyric acid methylester);
`12 2'-deoxy-2'-fluoro-2'-C-methylcytidine 5'-(phenyl methoxy-valyl phosphate
`((S)-2- {[((2R,3R,4R,5R)-5-(2-0xo-4-amino-pyrimidin- 1 -yl)-4-fluoro-3-hydroxy-4-
`methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-3-methyl-butyric
`acid methylester;
`13 (S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-
`fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino} -
`propionic acid ethyl ester;
`14 (S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-
`fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-
`phosphorylamino]-propionic acid benzyl ester;
`15 {[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-
`hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino} -acetic
`acid methylester;
`
`-12-
`
`

`

`Docket No. 60137.0034USP2
`
`16 (S)-2-{(2,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-
`pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-
`phosphorylamino}-propionic acid methyl ester;
`17 (S)-2-[[2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-
`fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-
`phosphorylamino]-propionic acid methylester;
`18 (S)-1-{[((@2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-
`fluoro-3-hydroxy-4-methy1-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphory]}-
`pytrolidine-2-carboxylic acid methyl ester;
`19 (S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-
`fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino} -
`propionic acid butylester;
`20 (S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-
`fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino} -
`propionic acid benzylester;
`21 (S)-2-[[(@R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-
`fluoro-3-hydroxy-4-methy1-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-
`phosphorylamino]-propionic acid methylester;
`22 (S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3 ,4-dihydro-2H-
`pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-
`phosphorylamino}-propionic acid methyl ester;
`23 (S)-2-{(3,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3 ,4-dihydro-2H-
`pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-
`phosphorylamino}-propionic acid methyl ester;
`24 (S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-
`fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino} -
`propionic acid sec-butylester;
`25 (S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-
`fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino} -
`propionic acid isopropylester;
`26 (S)-2-[[((2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-
`fluoro-3-hydroxy-4-methy1-tetrahydro-furan-2-ylmethoxy]-(4-methoxy-phenoxy)-
`phosphorylamino]-propionic acid butyl ester;
`27 (S)-2-[[@R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-
`fluoro-3-hydroxy-4-methy1-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-
`phosphorylamino]-propionic acid ethyl ester;
`28 (S)-2-[[((2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-
`fluoro-3-hydroxy-4-methy1-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-
`phosphorylamino]-propionic acid isopropylester;
`29 (S)-2-[[((2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-
`fluoro-3-hydroxy-4-methy1-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-
`phosphorylamino]-propionic acid benzyl ester;
`30 (S)-2-[[(@R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-
`fluoro-3-hydroxy-4-methy1-tetrahydro-furan-2-ylmethoxy]-(4-methoxy-phenoxy)-
`phosphorylamino]-propionic acid isopropylester;
`
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`Docket No. 60137.0034USP2
`
`31 (S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-
`pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-
`phosphorylamino}-propionic acid benzylester;
`32 (S)-2-{(2,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-
`pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-
`phosphorylamino}-propionic acid butyl ester;
`33 (S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-
`fluoro-3-hydroxy-4-methy|-tetrahydro-furan-2-ylmethoxy]-p-tolyloxy-
`phosphorylamino}-propionic acid isopropylester;
`34 (S)-2-[[((2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-
`fluoro-3-hydroxy-4-methy1-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-
`phosphorylamino]-propionic acid butyl ester;
`35 (S)-2-{(3,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-
`pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-
`phosphorylamino}-propionic acid ethyl ester;
`36 (S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-
`pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-
`phosphorylamino}-propionic acid isopropylester;
`37 (S)-2-[[(@2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-
`fluoro-3-hydroxy-4-methy1-tetrahydro-furan-2-ylmethoxy]-(4-methoxy-phenoxy)-
`phosphorylamino]-propionic acid benzylester;
`38 (S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-
`fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino} -
`propionic acid pentylester;
`39 (S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-
`pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-
`phosphorylamino}-propionic acid isopropylester;
`40 (S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-
`pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-
`phosphorylamino}-propionic acid butyl ester;
`41 (S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-
`pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-
`phosphorylamino}-propionic acid ethyl ester;
`42 (S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-
`fluoro-3-hydroxy-4-methy|-tetrahydro-furan-2-ylmethoxy]-p-tolyloxy-
`phosphorylamino}-propionic acid butyl ester;
`43 (S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo- 3,4-dihydro-2H-pyrimidin-1-yl)-4-
`fluoro-3-hydroxy-4-methy|-tetrahydro-furan-2-ylmethoxy]-p-tolyloxy-
`phosphorylamino}-propionic acid benzyl ester;
`44 (S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-
`fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino} -
`butyric acid methylester;
`45 (S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-
`fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino} -
`propionic acid 4-fluoro-benzy]lester;
`
`-14-
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`

`Docket No. 60137.0034USP2
`
`46 (S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-
`pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-
`phosphorylamino}-propionic acid butyl ester;
`47 (S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-
`fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino} -
`propionic acid 3-methyl-butylester;
`48 (S)-2-{(2,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-
`pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-
`phosphorylamino}-propionic acid ethyl ester;
`49 (S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-
`fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino} -
`propionic acid cyclohexyl ester;
`50 (R)-2- {[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-
`fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino} -
`propionic acid butylester;
`51 (R)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-
`fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino} -
`propionic acid isopropylester;
`52 (R)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-
`fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino} -
`propionic acid benzyl ester;
`53 (S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-
`pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-
`phosphorylamino}-propionic acid butyl ester;
`54 (S)-2-{(4-Bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-
`pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-
`phosphorylamino}-propionic acid isopropyl ester; and
`55 (S)-2-{[(2R,3R,4R,5R)-5-(6-aminopurin-9-y1)-4-fluoro-3-hydroxy-4-methyl-
`tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid methyl ester).
`
`2.
`
`A composition for the treatment and/or prophylaxis of any ofthe viral
`
`agents disclosed herein said composition comprising a pharmaceutically acceptable
`
`medium selected from among an excipient, carrier, diluent, or equivalent medium and a
`
`compound,its stereoisomer, salt, hydrate, solvate, or crystalline form thereof, selected
`
`from among
`
`2'-Deoxy-2'-fluoro-2'-C-methyluridine 5'-(phenyl methoxy-alanyl phosphate
`5
`((S)-2- {[((2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-
`hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino} -propionic
`acid methylester);
`6
`2'-Deoxy-2'-fluoro-2'-C-methyluridine 5'-(phenyl methoxy-valyl phosphate
`((S)-2- {[((2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-
`
`-15-
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`

`Docket No. 60137.0034USP2
`
`hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino} -3-methyl-
`butyric acid methylester;
`7
`2'-Deoxy-2'-fluoro-2'-C-methyluridine 5'-(4-bromophenyl methoxy-valyl
`phosphate ((S)-2- {(4-bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-
`pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-
`phosphorylamino}-3-methyl-butyric acid methyl ester);
`8
` 2'-Deoxy-2'-fluoro-2'-C-methyluridine 5'-(4-bromophenyl methoxy-alanyl
`phosphate (((S)-2- {(4-bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-
`pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-
`phosphorylamino}-propionic acid methylester);
`9 N’‘(N,N-dimethylformamidinyl)-2'-deoxy-2'-fluoro-2'-C-methylcytidine;
`10 2'-Deoxy-2'-fluoro-2'-C-methylcytidine 5'-(phenyl methoxy-alanyl phosphate
`(((S)-2- {[((2R,3R,4R,5R)-5-(2-oxo-4-amino-pyrimidin-1 -yl)-4-fluoro-3-hydroxy-4-
`methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino }-propionic acid
`methyl ester);
`11 2'-Deoxy-2'-fluoro-2'-C-methylcytidine 5'-(4-bromophenyl methoxy-valyl
`phosphate ((S)-2- {(4-bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2-oxo-4-amino-pyrimidin-1-
`yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino} -3-
`methyl-butyric acid methylester);
`12 2'