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Claims for Patent: 8,580,765

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Claims for Patent: 8,580,765

Title:Nucleoside phosphoramidate prodrugs
Abstract: Disclosed herein are phosphoramidate prodrugs of nucleoside derivatives for the treatment of viral infections in mammals, which is a compound, its stereoisomer, salt (acid or basic addition salt), hydrate, solvate, or crystalline form thereof, represented by the following structure: ##STR00001## Also disclosed are methods of treatment, uses, and processes for preparing each of which utilize the compound represented by formula I.
Inventor(s): Sofia; Michael Joseph (Doylestown, PA), Du; Jinfa (New Hope, PA), Wang; Peiyuan (Totowa, NJ), Nagarathnam; Dhanapalan (Bethany, CT)
Assignee: Gilead Pharmasset LLC (Foster City, CA)
Application Number:13/609,614
Patent Claims: 1. A compound, or a stereoisomer thereof, represented by formula (I): ##STR00092## wherein P* is a chiral phosphorous atom, and wherein (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, or a substituted or unsubstituted phenyl, where the substitutent of the substituted phenyl is at least one of a CH.sub.3, OCH.sub.3, F, Cl, Br, I, nitro, cyano, and a CH.sub.3-qX.sub.q, where X is F, Cl, Br, or I, and q is 1-3; (b) R.sup.2 is hydrogen or CH.sub.3; (c-i) R.sup.3a is H and R.sup.3b is H, CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl, --CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H, CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH, CH.sub.2CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2, --CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl, CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or lower cycloalkyl, or (c-ii) R.sup.3a is CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl, --CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H, CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH, CH.sub.2CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2, --CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl, CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or lower cycloalkyl and R.sup.3b is H; (d) R.sup.4 is hydrogen, CH.sub.3, Et, .sup.iPr, .sup.nPr, .sup.nBu, 2-butyl, .sup.tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl; and (e) R.sup.7 and R.sup.8 are independently H, F, Cl, Br, I, OH, OCH.sub.3, SH, SCH.sub.3, NH.sub.2, NHCH.sub.3, N(CH.sub.3).sub.2, CH.sub.3, CH.sub.3-qX.sub.q, where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO.sub.2H, CO.sub.2CH.sub.3, CONH.sub.2, CONHCH.sub.3, or CON(CH.sub.3).sub.2, wherein R' is a C.sub.1-20 alkyl; a C.sub.1-20 cycloalkyl; a C.sub.2-C.sub.6 alkenyl, a C.sub.2-C.sub.6 alkynyl.

2. The compound according to claim 1, wherein: (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl; and (c-i) R.sup.3a is H and R.sup.3b is H, CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, CH.sub.2-indol-3-yl, --CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CO.sub.2H, CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2COOH, CH.sub.2CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2, --CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2-imidazol-4-yl, CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2((4'-OH)-Ph), CH.sub.2SH, or lower cycloalkyl.

3. The compound according to claim 1, wherein: (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl; (c-i) R.sup.3a is H and R.sup.3b is H, CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl; and (e) R.sup.7 and R.sup.8 are independently H, F, Br, SCH.sub.3, CH.sub.3, CH.sub.3-qX.sub.q, where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO.sub.2CH.sub.3, CONH.sub.2, CONHCH.sub.3, or CON(CH.sub.3).sub.2.

4. The compound according to claim 1, wherein: (a) R.sup.1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl; (b) R.sup.2 is hydrogen; (c-i) R.sup.3a is H and R.sup.3b is H, CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl; and (e) R.sup.7 and R.sup.8 are independently H, F, Br, SCH.sub.3, CH.sub.3, CH.sub.3-qX.sub.q, where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO.sub.2CH.sub.3, CONH.sub.2, CONHCH.sub.3, or CON(CH.sub.3).sub.2.

5. The compound according to claim 1, wherein: (a) R.sup.1 is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl; (b) R.sup.2 is hydrogen; (c-i) R.sup.3a is H and R.sup.3b is H, CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2Ph, or lower cycloalkyl; and (e) R.sup.7 and R.sup.8 are independently H, F, Br, SCH.sub.3, CH.sub.3, CH.sub.3-qX.sub.q, where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO.sub.2CH.sub.3, CONH.sub.2, CONHCH.sub.3, or CON(CH.sub.3).sub.2.

6. A composition comprising the compound according to claim 1.

7. A composition comprising the compound according to claim 1 and a pharmaceutically acceptable medium.

8. A composition comprising an effective amount of the compound according to claim 1 to treat a hepatitis C virus infection and a pharmaceutically acceptable medium.

9. A method of treating a subject infected by a virus selected from among hepatitis C virus, West Nile virus, yellow fever virus, dengue virus, rhinovirus, polio virus, hepatitis A virus, bovine viral diarrhea virus or Japanese encephalitis virus, which comprises administering to the subject an effective amount of the compound according to claim 1.

10. The method of claim 9, wherein the virus is hepatitis C virus.

11. The method of claim 10, which further comprises administering to the subject an effective amount of another antiviral agent.

12. The method of claim 10, wherein the subject is a human.

13. A process for preparing the compound according to claim 1 comprising reacting a compound 4'' with a nucleoside analog 5': ##STR00093## wherein (f) X' is a leaving group.

14. The method of claim 11, wherein the subject is human.
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