Docket No. 60137.0034USP2
`
`NUCLEOSIDE PHOSPHORAMIDATE PRODRUGS
`
`The essential material for this application, including the background of the
`
`invention, the disclosure of the invention, including Preparations and Examples, is
`
`incorporated by reference from pending and commonly owned US. Provisional
`
`application No. 60/909,315, filed March 30, 2007, as well as references cited therein,
`
`under the provisions of MPEP 608.0l(p).
`
`EXAMPLES
`
`Example numbers 13-55 are prepared using similar procedures described for examples 5-
`8, as disclosed in US. Provisional application No. 60/909,315. The identification and
`NMIVMS details are shown below:
`
`
`
`Exam le R1
`R2
`R32
`R3b R“
`
`13
`Ph
`H
`H
`Vle Et
`
`14
`15
`
`16
`17
`18
`19
`20
`21
`22
`
`23
`24
`25
`26
`27
`28
`29
`30
`31
`
`32
`33
`34
`
`35
`36
`37
`38
`
`H
`H
`
`H
`H
`H
`H
`H
`H
`H
`
`H
`H
`H
`H
`H
`H
`H
`H
`H
`
`H
`H
`H
`
`H
`H
`H
`H
`
`l-Napth
`Ph
`
`2,4-Cl-Ph
`l-Napth
`Ph
`Ph
`Ph
`4-F-Ph
`4-Cl-Ph
`
`3,4-Cl-Ph
`Ph
`Ph
`4-MeO-Ph
`4-F-Ph
`4-F-Ph
`4-F-Ph
`4-MeO-Ph
`2-Cl-Ph
`
`2,4-Cl-Ph
`4-Me-Ph
`4-F-Ph
`
`H
`H
`
`H
`H
`*
`H
`H
`H
`H
`
`H
`H
`H
`H
`H
`H
`H
`H
`H
`
`H
`H
`H
`
`3,4-diCl-Ph H
`2-Cl-Ph
`H
`4-MeO-Ph
`H
`Ph
`H
`
`_ 1 _
`
`Vle Bn
`H
`Me
`
`Vle Me
`Vle Me
`*
`Me
`Vle
`n-Bu
`Vle Bn
`Vle Me
`Vle Me
`
`Vle Me
`Vle
`2-Bu
`Vle
`i-Pr
`Vle
`n-Bu
`Vle Et
`Vle
`1-Pr
`Vle Bn
`Vle
`1-Pr
`Vle Bn
`
`
`
`Vle
`Vle
`Vle
`
`n-Bu
`i-Pr
`n-Bu
`
`Vle Et
`Vle
`1-Pr
`Vle Bn
`Vle
`n—Pen
`
`G|L2014
`I-MAK, INC. V GILEAD PHARMASSET LLC
`|PR2018-00121
`
`GIL2014
`I-MAK, INC. V GILEAD PHARMASSET LLC
`IPR2018-00121
`
`

`

`Docket No. 60137.0034USP2
`
`
`
`Example R1
`R2
`R32
`R3b R“
`39
`4-C1-Ph
`H
`H
`We
`i-Pr
`40
`4-C1—Ph
`H
`H
`We
`n-Bu
`41
`4-C1-Ph
`H
`H
`We Et
`42
`4-Me-Ph
`H
`H
`We
`n-Bu
`43
`4-Me-Phe
`H
`H
`We Bn
`44
`Ph
`H
`H
`Et Me
`45
`Ph
`H
`H
`We
`4-F-Bn
`46
`4-C1-Ph
`H
`H
`We
`n-Bu
`47
`Ph
`H
`H
`We
`3-Me-1-Bu
`
`We Bn
`H
`3,4-diCl-Ph H
`48
`We
`c-Hex
`H
`Ph
`H
`49
`Ph
`H Me H
`n-Bu
`50
`Ph
`H Me H
`i-Pr
`51
`Ph
`H Me H
`Bn
`52
`2-C1—Ph
`H
`H
`Me
`n-Bu
`53
`4-Br-Ph
`H
`H
`Me
`i-Pr
`54
`—1j—
`*R2 and R3 together are 7(CH2)37 as derlved from L-
`proline
`
`
`
`Example
`
`NMR/MS
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`1H NMR (DMSO—d6) 5 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) 5 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, 5H), 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, 1 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 (m, 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 519.94(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 (d, 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) 5 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, J : 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): 5 :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),
`5.84—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, J :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 (DMSO—d6) 5 1.10—1.23 (m, 6H), 3.65—3.89(m,3H) ,4.10_4.30 (m,2H), 4.96—
`5.00(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): 5:1.15_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),
`5.91—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) 5 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 (DMSO—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 584.1 (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)+
`
`lHNMR (400MHz, DMSO): 5 :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, J1:16.0Hz, 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, J: 16.0Hz, 1H), 7.48—7.55 (m, 3H), 11.55 (s, 1H)
`
`1HNMR(400MHz,DMSO): 5:1.19_1.26 (m, 6H), 369—370 (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, J : 16.0Hz, 1H),
`5.85—5.92 (m, 1H), 6.04—6.10 (m, 2H), 6.86 (d, J: 8.0Hz, 2H), 7.09 (dd, J1:16.0Hz,
`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/eS77.95(M+1)+
`
`1H NMR (DMSO—d6) 5 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 557.99(M+1)+; 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, 5H), 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)+
`
`1HNMR (400MHz, DMSO): 5 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)
`
`1HNMR (400MHz, DMSO): 5 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)
`
`1H NMR (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)+
`
`1H NMR (DMSO—ds) 5 1.05—1.37 (m, 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),
`1H NMR (DMSO—ds) 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/6529.96 (M+1)+
`
`1H NMR (DMSO—ds) 5 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/eS77.99 (M+1)+
`
`1HNMR (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 (m, 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)
`
`1HNMR (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-y1)-4-flu0r0-3-hydr0xy-4-
`
`methyl-tetrahydro-fi.1ran-2-y1methoxy]-phenoxy-phosphory1amino} -pr0pi0nic acid
`
`methyl ester), 55.
`
`Scheme
`
`CI
`
`{I \>
`N
`H
`ammo (-t)3H/THFLiA|OBu BzO —> o
`
`BZO
`a
`
`BZO
`
`b
`
`\ N
`
`0
`
`OH
`
`c
`
`__-
`F
`
`DEAD, PPh3
`THF, rt, overnight
`
`BzO
`
`5
`BzO
`
`;
`F
`
`d
`
`//_N
`
`\
`N
`N /N
`
`—
`
`V
`
`Cl
`
`NHa/THF
`—’ BzO
`90 °C, overnight
`
`0
`
`5 :-
`320
`F
`
`e
`
`r“
`NH2
`N
`\
`/ —>
`N
`N
`NH3/MeOH
`V
`
`r,t, overnight
`
`N
`NF \
`
`NH2
`
`NVN
`
`HO
`
`g
`Ho‘
`
`o
`
`__
`F
`
`f
`
`O H
`CIHHN/Rf \
`O
`G Fl” —»0“ (jFr“*0/
`
`o\u CI
`CI
`
`o
`
`2
`
`Et3N/DCM
`
`on
`
`
`
`HO\
`
`i
`F
`
`NMI/THF
`
`~‘
`
`HO
`
`Preparation of compound (b)
`
`To a solution of compound a (l g, 2.69 mmol) in anhydrous THF (30 mL) was
`
`added dropwise l M solution of LiA1(OBu-t)3H in THF (2.69 mL, 2. 69 mol) at -20 0C.
`
`The reaction mixture was stirred for 2—3 h at the same temperature. EtOAc (100 mL) was
`
`added followed by saturated NH4C1 solution (10 mL) and reaction mixture was slowly
`
`brought to room temperature. Reaction mixture was extracted with EtOAc and washed
`
`with 1N HCl and water. Combined organic phase was evaporated to give 0.8 g of crude
`
`compound b as transparent oil, which was used directly for next reaction.
`
`

`

`Docket No. 60137.0034USP2
`
`Preparation of compound (d)
`
`To a solution of compound b (0.8 g, 2.1mrnol), compound 0 (0.45 g, 2.5 mmol) and
`
`Pth (0.56 g, 2.1 mmol) in anhydrous THF (20 mL) under nitrogen atmosphere was
`
`added DEAD (1.8 mL). The reaction mixture was stirred 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 fiarther purification.
`
`Preparation of compound (e)
`
`Compound d (0.8 g, 1.57 mmol) was dissolved in THF (2 mL) and THF saturated
`
`with ammonia (5 mL) was then added to this solution. The reaction mixture was heated to
`
`90 0C 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 was purified
`
`by column to give compound e (0.75 g) for the next step.
`
`Preparation of compound (1)
`
`Compound e (0.5 g, 1.01 mmol) was dissolved in methanol (2 mL) and methanol
`
`was saturated with ammonia (5 mL) was then added to this solution. The reaction mixture
`
`was stirred 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 of triethylamine (1.07 g, 10.6 mmol) in anhydrous dichloromethane (15
`
`mL) was added dropwise to 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 vigorous stirring at -78 0C over a
`
`period of 2 hours. After completion of addition, the reaction temperature was allowed to
`
`warm to room temperature gradually and stirred over night. Then the solvent was
`
`removed under vacuum and anhydrous ether 20 mL was added and the precipitated salt
`
`was filtered 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 compound j (0.1 g, 0.35 mmol) dissolved in 10 mL of anhydrous
`
`THF, stirred and added 0.4g NMI till the solution became clear, added compound i (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: 1H NMR (DMSO-d6) 5 1.08 (d, J: 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), 62-627 (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 volumes of these 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 25 ><30><2 mm column was used. The mobile phase was HPLC grade
`
`water (A), and HPLC grade acetonitrile (B). Fractions were collected into 100* 15mm
`
`glass tubes.
`
`HPLC gradient 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 MS test to collect the desired
`
`compounds. The fractions with target MS were combined in a well-weighted flask. Most
`
`of acetonitrile was removed under reduce pressure and the remaining solution was freeze-
`
`dried to give desired compound.
`
`Table 1:
`
`Preparative HPLC gradient
`
`
`
`

`

`Docket No. 60137.0034USP2
`
`All the references disclosed in US. 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 not lost.
`
`Anti-HCV activity for certain exemplified compounds (28, 36, 39, 53, and 54)
`
`was determined in a manner as disclosed in Example 13 of US. Provisional application
`
`No. 60/909,315, filed March 30, 2007, which is incorporated by reference in its entirety,
`
`as evidenced by the following Table
`
`
`
`Log10
`Reduction at
`Com ound
`Ex. #
`
`
`1’
`
`28
`
`3 do;
`
`O
`
`fL/Ng
`
`WM
`
`EC90
`
`(HM)
`
`-2.16
`
`0.75
`
`
`
`
`
`O'NAO
`HO
`F
`
`
`36
`
`04$
`
`<5
`
`O
`
`0
`
`6,,
`
`39
`
`CI
`
`©
`0
`
`/F',\
`
`=
`
`E
`
`o
`
`o
`
`0
`f8”:
`
`N
`
`o
`
`-1.64
`
`21.9
`
`-1.78
`
`0.47
`
`
`
`-10-
`
`

`

`Docket No. 60137.0034USP2
`
`
`
`Ex. #
`
`Compound
`
`Log10
`Reduction at
`
`
`
`
`54
`
`g
`:
`
`9
`P
`
`| E:
`
`—1.55
`
`0.57
`
`-11-
`
`

`

`Docket No. 60137.0034USP2
`
`We claim:
`
`1.
`
`A compound its stereoisomer, salt, hydrate, solvate, or crystalline form
`
`thereof selected from among
`
`5 2-D eoxy-2'-fluoro-2'-C—methyluridine 5'-(phenyl methoxy-alanyl phosphate
`((S)-2- {[(2R,3R,4R,5R)-5-(2,4-Dioxo-3 ,4-dihydro-2H-pyrimidin- l -yl)-4-fluoro-3-
`hydroxy-4-methyl-tetrahydro-fi1ran-2-ylmethoxy] -phenoxy-phosphorylamino} -propionic
`acid methyl ester);
`6 2-D eoxy-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- l -yl)-4-fluoro-3-
`hydroxy-4-methyl-tetrahydro-fi1ran-2-ylmethoxy] -phenoxy-pho sphorylamino} -3 -methyl-
`butyric acid methyl ester;
`7 2-D eoxy-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- l -yl)-4-fluoro-3 -hydroxy-4-methyl-tetrahydro-fi1ran-2-ylmethoxy]-
`phosphorylamino} -3 -methyl-butyric acid methyl ester);
`8 2-D eoxy-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- l -yl)-4-fluoro-3 -hydroxy-4-methyl-tetrahydro-fi1ran-2-ylmethoxy]-
`phosphorylamino} -propionic acid methyl ester);
`9 N4-(N,N-dimethylformamidinyl)-2'-deoxy-2'-fluoro-2'-C—methylcytidine;
`10 2-D eoxy-2'-fluoro-2'-C-methylcytidine 5'-(phenyl methoxy-alanyl phosphate
`(((S)-2- {[(2R,3R,4R,5R)-5-(2-oxo-4-amino-pyrimidin- l -yl)-4-fluoro-3-hydroxy-4-
`methyl-tetrahydro-fi1ran-2-ylmethoxy]-phenoxy-phosphorylamino} -propionic acid
`methyl ester);
`1 1 2-D eoxy-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- l -
`yl)-4-fluoro-3 -hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy] -phosphorylamino} -3 -
`methyl-butyric acid methyl ester);
`12 2'-deoxy-2'-fluoro-2'-C-methylcytidine 5'-(phenyl methoxy-valyl phosphate
`((S)-2- {[(2R,3R,4R,5R)-5-(2-oxo-4-amino-pyrimidin- l -yl)-4-fluoro-3-hydroxy-4-
`methyl-tetrahydro-fi1ran-2-ylmethoxy]-phenoxy-phosphorylamino} -3 -methyl-butyric
`acid methyl ester;
`13 (S)-2- { [(2R,3R,4R,5R)—5-(2,4-Dioxo-3 ,4-dihydro-2H-pyrimidin- l -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- l -yl)-4-
`fluoro-3 -hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen- l -yloxy)-
`phosphorylamino]-propionic acid benzyl ester;
`15 {[(2R,3R,4R,5R)-5-(2,4-Dioxo-3 ,4-dihydro-2H-pyrimidin- l -yl)-4-fluoro-3-
`hydroxy-4-methyl-tetrahydro-fi1ran-2-ylmethoxy] -phenoxy-phosphorylamino} -acetic
`acid methyl ester;
`
`-12-
`
`

`

`Docket No. 60137.0034USP2
`
`1 6 (S)-2- {(2,4-Dichlor0-phenoxy)-[(2R,3R,4R,5R)-5 -(2,4-di0X0-3 ,4-dihydr0-2H-
`pyrimidin- l -yl)-4-flu0ro-3 -hydr0xy-4-methyl-tetrahydro-fi1ran-2-ylmethoxy]-
`phosphorylamino} -pr0pi0nic acid methyl ester;
`1 7 (S)-2-[[(2R,3R,4R,5R)-5 -(2,4-Di0x0-3 ,4-dihydr0-2H-pyrimidin- l -yl)-4-
`fluoro-3 -hydr0xy-4-methyl-tetrahydr0-furan-2-ylmeth0xy]-(naphthalen- l -yloxy)-
`phosphorylamino]-pr0pi0nic acid methyl ester;
`1 8 (S)- l - { [(2R,3R,4R,5R)—5 -(2,4-Di0x0-3 ,4-dihydr0-2H-pyrimidin- l -yl)-4-
`fluoro-3 -hydr0xy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phen0xy-ph0sphoryl} -
`pyrrolidine-2-carb0xylic acid methyl ester;
`1 9 (S)-2- { [(2R,3R,4R,5R)—5 -(2,4-Di0x0-3 ,4-dihydr0-2H-pyrimidin- l -yl)-4-
`fluoro-3 -hydr0xy-4-methyl-tetrahydro-furan-2-ylmeth0xy]-phenoxy-ph0sphorylamino} -
`propionic acid butyl ester;
`20 (S)-2- { [(2R,3R,4R,5R)—5 -(2,4-Di0x0-3 ,4-dihydr0-2H-pyrimidin- l -yl)-4-
`fluoro-3 -hydr0xy-4-methyl-tetrahydro-furan-2-ylmeth0xy]-phenoxy-ph0sphorylamino} -
`propionic acid benzyl ester;
`2 1 (S)-2-[[(2R,3R,4R,5R)-5 -(2,4-Di0x0-3 ,4-dihydr0-2H-pyrimidin- l -yl)-4-
`fluoro-3 -hydr0xy-4-methyl-tetrahydr0-furan-2-ylmeth0xy]-(4-fluoro-phenoxy)—
`phosphorylamino]-pr0pi0nic acid methyl ester;
`22 (S)-2- {(4-Chlor0-phenoxy)- [(2R,3R,4R,5R)-5 -(2,4-di0X0-3 ,4-dihydro-2H-
`pyrimidin- l -yl)-4-flu0ro-3 -hydr0xy-4-methyl-tetrahydro-fi1ran-2-ylmethoxy]-
`phosphorylamino} -pr0pi0nic acid methyl ester;
`23 (S)-2- {(3 ,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5 -(2,4-di0X0-3 ,4-dihydr0-2H-
`pyrimidin- l -yl)-4-flu0ro-3 -hydr0xy-4-methyl-tetrahydro-fi1ran-2-ylmethoxy]-
`phosphorylamino} -pr0pi0nic acid methyl ester;
`24 (S)-2- { [(2R,3R,4R,5R)—5 -(2,4-Di0x0-3 ,4-dihydr0-2H-pyrimidin- l -yl)-4-
`fluoro-3 -hydr0xy-4-methyl-tetrahydro-furan-2-ylmeth0xy]-phenoxy-ph0sphorylamino} -
`propionic acid sec-butyl ester;
`25 (S)-2- { [(2R,3R,4R,5R)—5 -(2,4-Di0x0-3 ,4-dihydr0-2H-pyrimidin- l -yl)-4-
`fluoro-3 -hydr0xy-4-methyl-tetrahydro-furan-2-ylmeth0xy]-phenoxy-ph0sphorylamino} -
`propionic acid isopropyl ester;
`26 (S)-2-[[(2R,3R,4R,5R)-5 -(2,4-Di0x0-3 ,4-dihydr0-2H-pyrimidin- l -yl)-4-
`fluoro-3 -hydroxy-4-methyl-tetrahydr0-furan-2-ylmeth0xy] -(4-meth0xy-phen0xy)-
`phosphorylamino]-pr0pi0nic acid butyl ester;
`27 (S)-2-[[(2R,3R,4R,5R)-5 -(2,4-Di0x0-3 ,4-dihydr0-2H-pyrimidin- l -yl)-4-
`fluoro-3 -hydr0xy-4-methyl-tetrahydr0-furan-2-ylmeth0xy]-(4-fluoro-phenoxy)—
`phosphorylamino]-pr0pi0nic acid ethyl ester;
`28 (S)-2-[[(2R,3R,4R,5R)-5 -(2,4-Di0x0-3 ,4-dihydr0-2H-pyrimidin- l -yl)-4-
`fluoro-3 -hydr0xy-4-methyl-tetrahydr0-furan-2-ylmeth0xy]-(4-fluoro-phenoxy)—
`phosphorylamino]-propionic acid isopropyl ester;
`29 (S)-2-[[(2R,3R,4R,5R)-5 -(2,4-Di0x0-3 ,4-dihydr0-2H-pyrimidin- l -yl)-4-
`fluoro-3 -hydr0xy-4-methyl-tetrahydr0-furan-2-ylmeth0xy]-(4-fluoro-phenoxy)—
`phosphorylamino]-pr0pi0nic acid benzyl ester;
`30 (S)-2-[[(2R,3R,4R,5R)-5 -(2,4-Di0x0-3 ,4-dihydr0-2H-pyrimidin- l -yl)-4-
`fluoro-3 -hydroxy-4-methyl-tetrahydr0-furan-2-ylmeth0xy] -(4-meth0xy-phen0xy)-
`phosphorylamino]-propionic acid isopropyl ester;
`
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`Docket No. 60137.0034USP2
`
`3 1 (S)-2- {(2-Chlor0-phenoxy)- [(2R,3R,4R,5R)-5 -(2,4-di0X0-3 ,4-dihydro-2H-
`pyrimidin- l -yl)-4-flu0ro-3 -hydr0xy-4-rnethyl-tetrahydro-fi1ran-2-ylrnethoxy]-
`phosphorylarnino} -pr0pi0nic acid benzyl ester;
`32 (S)-2- {(2,4-Dichlor0-phenoxy)-[(2R,3R,4R,5R)-5 -(2,4-di0X0-3 ,4-dihydr0-2H-
`pyrimidin- l -yl)-4-flu0ro-3 -hydr0xy-4-rnethyl-tetrahydro-fi1ran-2-ylrnethoxy]-
`phosphorylarnino} -pr0pi0nic acid butyl ester;
`33 (S)-2- { [(2R,3R,4R,5R)—5 -(2,4-Di0x0-3 ,4-dihydr0-2H-pyrirnidin- l -yl)-4-
`fluoro-3 -hydroxy-4-rnethyl-tetrahydr0-furan-2-ylrnethoxy]-p-tolyloxy-
`phosphorylarnino} -propionic acid isopropyl ester;
`34 (S)-2-[[(2R,3R,4R,5R)-5 -(2,4-Di0x0-3 ,4-dihydr0-2H-pyrirnidin- l -yl)-4-
`fluoro-3 -hydr0xy-4-rnethyl-tetrahydr0-furan-2-ylrnethoxy]-(4-fluoro-phenoxy)—
`phosphorylarnino]-pr0pi0nic acid butyl ester;
`35 (S)-2- {(3 ,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5 -(2,4-di0X0-3 ,4-dihydr0-2H-
`pyrimidin- l -yl)-4-flu0ro-3 -hydr0xy-4-rnethyl-tetrahydro-fi1ran-2-ylrnethoxy]-
`phosphorylarnino} -pr0pi0nic acid ethyl ester;
`36 (S)-2- {(2-Chlor0-phenoxy)- [(2R,3R,4R,5R)-5 -(2,4-di0X0-3 ,4-dihydro-2H-
`pyrimidin- l -yl)-4-flu0ro-3 -hydr0xy-4-rnethyl-tetrahydro-fi1ran-2-ylrnethoxy]-
`phosphorylarnino} -propionic acid isopropyl ester;
`37 (S)-2-[[(2R,3R,4R,5R)-5 -(2,4-Di0x0-3 ,4-dihydr0-2H-pyrirnidin- l -yl)-4-
`fluoro-3 -hydroxy-4-rnethyl-tetrahydr0-furan-2-ylrneth0xy] -(4-rneth0xy-phen0xy)-
`phosphorylarnino]-pr0pi0nic acid benzyl ester;
`38 (S)-2- { [(2R,3R,4R,5R)—5 -(2,4-Di0x0-3 ,4-dihydr0-2H-pyrirnidin- l -yl)-4-
`fluoro-3 -hydr0xy-4-rnethyl-tetrahydro-furan-2-ylrneth0xy]-phenoxy-ph0sphorylarnino} -
`propionic acid pentyl ester;
`39 (S)-2- {(4-Chlor0-phenoxy)- [(2R,3R,4R,5R)-5 -(2,4-di0X0-3 ,4-dihydro-2H-
`pyrimidin- l -yl)-4-flu0ro-3 -hydr0xy-4-rnethyl-tetrahydro-fi1ran-2-ylrnethoxy]-
`phosphorylarnino} -propionic acid isopropyl ester;
`40 (S)-2- {(4-Chlor0-phenoxy)- [(2R,3R,4R,5R)-5 -(2,4-di0X0-3 ,4-dihydro-2H-
`pyrimidin- l -yl)-4-flu0ro-3 -hydr0xy-4-rnethyl-tetrahydro-fi1ran-2-ylrnethoxy]-
`phosphorylarnino} -pr0pi0nic acid butyl ester;
`4 1 (S)-2- {(4-Chlor0-phenoxy)- [(2R,3R,4R,5R)-5 -(2,4-di0X0-3 ,4-dihydro-2H-
`pyrimidin- l -yl)-4-flu0ro-3 -hydr0xy-4-rnethyl-tetrahydro-fi1ran-2-ylrnethoxy]-
`phosphorylarnino} -pr0pi0nic acid ethyl ester;
`42 (S)-2- { [(2R,3R,4R,5R)—5 -(2,4-Di0x0-3 ,4-dihydr0-2H-pyrirnidin- l -yl)-4-
`fluoro-3 -hydroxy-4-rnethyl-tetrahydr0-furan-2-ylrnethoxy]-p-tolyloxy-
`phosphorylarnino} -pr0pi0nic acid butyl ester;
`43 (S)-2- { [(2R,3R,4R,5R)—5 -(2,4-Di0xo- 3 ,4-dihydro-2H-pyrirnidin- l -yl)-4-
`fluoro-3 -hydroxy-4-rnethyl-tetrahydr0-furan-2-ylrnethoxy]-p-tolyloxy-
`phosphorylarnino} -pr0pi0nic acid benzyl ester;
`44 (S)-2- { [(2R,3R,4R,5R)—5 -(2,4-Di0x0-3 ,4-dihydr0-2H-pyrirnidin- l -yl)-4-
`fluoro-3 -hydr0xy-4-rnethyl-tetrahydro-furan-2-ylrneth0xy]-phenoxy-ph0sphorylarnino} -
`butyric acid methyl ester;
`45 (S)-2- { [(2R,3R,4R,5R)—5 -(2,4-Di0x0-3 ,4-dihydr0-2H-pyrirnidin- l -yl)-4-
`fluoro-3 -hydr0xy-4-rnethyl-tetrahydro-furan-2-ylrneth0xy]-phenoxy-ph0sphorylarnino} -
`propionic acid 4-fluoro-benzyl ester;
`
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`

`Docket No. 60137.0034USP2
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`46 (S)-2- {(2-Chloro-phenoxy)- [(2R,3R,4R,5R)-5 -(2,4-dioxo-3 ,4-dihydro-2H-
`pyrimidin- l -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- l -yl)-4-
`fluoro-3 -hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino} -
`propionic acid 3 -methyl-butyl ester;
`48 (S)-2- {(2,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5 -(2,4-dioxo-3 ,4-dihydro-2H-
`pyrimidin- l -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- l -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- l -yl)-4-
`fluoro-3 -hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino} -
`propionic acid butyl ester;
`5 1 (R)-2- {[(2R,3R,4R,5R)-5 -(2,4-Dioxo-3 ,4-dihydro-2H-pyrimidin- l -yl)-4-
`fluoro-3 -hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino} -
`propionic acid isopropyl ester;
`52 (R)-2- {[(2R,3R,4R,5R)-5 -(2,4-Dioxo-3 ,4-dihydro-2H-pyrimidin- l -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- l -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- l -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-yl)-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 of the 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
`
`5 2-D eoxy-2'-fluoro-2'-C-methyluridine 5'-(phenyl methoxy-alanyl phosphate
`((S)-2- {[(2R,3R,4R,5R)-5-(2,4-Dioxo-3 ,4-dihydro-2H-pyrimidin- l -yl)-4-fluoro-3-
`hydroxy-4-methyl-tetrahydro-fi1ran-2-ylmethoxy] -phenoxy-phosphorylamino} -propionic
`acid methyl ester);
`6 2-D eoxy-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- l -yl)-4-fluoro-3-
`
`-15-
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`

`Docket No. 60137.0034USP2
`
`hydroxy-4-methyl-tetrahydro-fi1ran-2-ylmethoxy] -phenoxy-pho sphorylamino} -3 -methyl-
`butyric acid methyl ester;
`7 2-D eoxy-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- l -yl)-4-fluoro-3 -hydroxy-4-methyl-tetrahydro-fi1ran-2-ylmethoxy]-
`phosphorylamino} -3 -methyl-butyric acid methyl ester);
`8 2-D eoxy-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- l -yl)-4-fluoro-3 -hydroxy-4-methyl-tetrahydro-fi1ran-2-ylmethoxy]-
`phosphorylamino} -propionic acid methyl ester);
`9 N4-(N,N-dimethylformamidinyl)—2'-deoxy-2'-fluoro-2'-C—methylcytidine;
`10 2-D eoxy-2'-fluoro-2'-C-methylcytidine 5'-(phenyl methoxy-alanyl phosphate
`((