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Claims for Patent: 8,188,104

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Claims for Patent: 8,188,104

Title:Anti-infective agents and uses thereof
Abstract: This invention relates to: (a) compounds and salts thereof that, inter alia, inhibit HCV; (b) intermediates useful for the preparation of such compounds and salts; (c) compositions comprising such compounds and salts; (d) methods for preparing such intermediates, compounds, salts, and compositions; (e) methods of use of such compounds, salts, and compositions; and (f) kits comprising such compounds, salts, and compositions.
Inventor(s): Flengte; Charles A. (Salem, WI), Hutchinson; Douglas K. (Antioch, IL), Betebenner; David A. (Libertyville, IL), DeGoey; David A. (Salem, WI), Donner; Pamela L. (Mundelein, IL), Kati; Warren M. (Gurnee, IL), Krueger; Allan C. (Gurnee, IL), Liu; Dachun (Waukegan, IL), Liu; Yaya (Buffalo Grove, IL), Longenecker; Kenton L. (Grayslake, IL), Maring; Clarence J. (Palatine, IL), Motter; Christopher E. (Oak Creek, WI), Pratt; John K. (Kenosha, WI), Randolph; John T. (Libertyville, IL), Rockway; Todd W. (Grayslake, IL), Stewart; Kent D. (Gurnee, IL), Wagner; Rolf (Antioch, IL), Chen; Shuang (Gurnee, IL), Gao; Yi (Vernon Hills, IL), Lou; Xiaochun (Long Grove, IL), Zhang; Geoff G. Z. (Libertyville, IL)
Assignee: Abbott Laboratories (Abbott Park, IL)
Application Number:12/212,323
Patent Claims: 1. A compound or salt thereof, wherein: the compound corresponds in structure to formula I-L0: ##STR00163## is selected from the group consisting of single carbon-carbon bond and double carbon-carbon bond; R.sup.1 is hydrogen; R.sup.2 is hydrogen; R.sup.3 is hydrogen; R.sup.4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein: (a) the amino, aminocarbonyl, and aminosulfonyl optionally are substituted with: (1) one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl, or (2) two substituents that, together with the amino nitrogen, form a single-ring heterocyclyl, and (b) the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, and alkylsulfonyl, optionally are substituted with one or more substituents independently selected from the group consisting of halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl, and heterocyclyl, wherein: the amino optionally is substituted with: (1) one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl, or (2) two substituents that, together with the amino nitrogen, form a single-ring heterocyclyl, and (c) the carbocyclyl and heterocyclyl optionally are substituted with up to three substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl, and heterocyclyl, wherein: the amino optionally is substituted with: (1) one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl, or (2) two substituents that, together with the amino nitrogen, form a single-ring heterocyclyl; R.sup.5 is selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, carbocyclylsulfonyloxy, haloalkylsulfonyloxy, and halo; R.sup.6 is naphthalenyl, optionally substituted with substituents independently selected from the group consisting of R.sup.H and R.sup.J; each R.sup.H is alkyloxy; and each R.sup.J is alkylsulfonylamino, wherein: (a) the amino portion of such substituents optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkenyl, alkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein: (1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl optionally are substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano, azido, oxo, and amino, and (2) the amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl, and (b) the alkyl portion of such substituents optionally is substituted with one or more substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, and alkynyloxy, wherein: the alkyl optionally is substituted with one or more hydroxy.

2. The compound or salt of claim 1, wherein is a single carbon-carbon bond.

3. The compound or salt of claim 1, wherein is a double carbon-carbon bond.

4. The compound or salt of claim 1, wherein R.sup.4 is selected from the group consisting of halo, C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl, amino, C.sub.1-C.sub.4-alkylsulfonyl, C.sub.3-C.sub.6-carbocyclyl, and 5-6-membered heterocyclyl, wherein: (a) the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl, (b) the C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl, and C.sub.2-C.sub.4-alkynyl optionally are substituted with one or more substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and (c) the C.sub.3-C.sub.6-carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with up to three substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, and amino, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl.

5. The compound or salt of claim 1, wherein R.sup.4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl.

6. The compound or salt of claim 1, wherein R.sup.4 is selected from the group consisting of C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-carbocyclyl, and 5-6-membered heterocyclyl.

7. The compound or salt of claim 1, wherein R.sup.4 is selected from the group consisting of halo, tert-butyl, C.sub.3-C.sub.6-carbocyclyl, and 5-6-membered heterocyclyl.

8. The compound or salt of claim 1, wherein R.sup.4 is selected from the group consisting of tert-butyl, C.sub.3-C.sub.6-carbocyclyl, and 5-6-membered heterocyclyl.

9. The compound or salt of claim 1, wherein R.sup.4 is alkyl.

10. The compound or salt of claim 1, wherein R.sup.4 is tert-butyl.

11. The compound or salt of claim 1, wherein R.sup.5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy, and halo.

12. The compound or salt of claim 1, wherein R.sup.5 is selected from the group consisting of hydrogen, methoxy, and halo.

13. The compound or salt of claim 1, wherein R.sup.5 is methoxy.

14. The compound or salt of claim 1, wherein R.sup.6 is substituted with R.sup.J.

15. The compound or salt of claim 1, wherein each R.sup.J is an independently selected alkylsulfonylamino, wherein: the amino portion of the alkylsulfonylamino is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl.

16. The compound or salt of claim 1, wherein each R.sup.J is methylsulfonylamino.

17. The compound or salt of claim 1, wherein: R.sup.4 is selected from the group consisting of halo, C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-carbocyclyl, and 5-6-membered heterocyclyl, wherein: (a) the C.sub.1-C.sub.4-alkyl optionally is substituted with up to three substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and (b) the C.sub.3-C.sub.6-carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, halo, and alkylsulfonylamino; and R.sup.5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy, and halo.

18. The compound or salt of claim 1, wherein: R.sup.4 is tert-butyl; and R.sup.5 is methoxy.

19. The compound or salt of claim 1, wherein: R.sup.4 is tert-butyl; and R.sup.5 is selected from the group consisting of hydroxy and methoxy.

20. The compound or salt of claim 1, wherein: is double carbon-carbon bond; R.sup.4 is tert-butyl; and R.sup.5 is selected from the group consisting of hydrogen, hydroxy, methoxy, and halo.

21. The compound or salt of claim 1, wherein: R.sup.4 is tert-butyl; R.sup.5 is selected from the group consisting of hydroxy and methoxy; and R.sup.6 is substituted with R.sup.J.

22. The compound or salt of claim 1, wherein: is double carbon-carbon bond; R.sup.4 is tert-butyl; R.sup.5 is methoxy; and R.sup.6 is substituted with R.sup.J, wherein R.sup.J is methylsulfonylamino.

23. The compound or salt of claim 1, wherein: R.sup.6 is substituted with R.sup.J, wherein R.sup.J is methylsulfonylamino.

24. The compound or salt of claim 1, wherein: is double carbon-carbon bond; R.sup.4 is tert-butyl; R.sup.5 is selected from the group consisting of hydroxy and methoxy; and R.sup.6 is substituted with R.sup.J.

25. The compound or salt of claim 1, wherein: R.sup.4 is selected from the group consisting of C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-carbocyclyl, and 5-6-membered heterocyclyl, wherein: (a) the C.sub.1-C.sub.4-alkyl optionally is substituted with up to three substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and (b) the C.sub.3-C.sub.6-carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, halo, and alkylsulfonylamino; R.sup.5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy, and halo; R.sup.6 is substituted with heterocyclyl, wherein each such substituent is substituted with one, two, or three substituents wherein: (a) the amino portion of such substituents optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein: (1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and (2) the amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl, (b) the alkyl portion of such substituents optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, wherein: the alkyl optionally is substituted with one or more hydroxy.

26. The compound or salt of claim 1, wherein the compound is selected from the group of compounds consisting of: N-(6-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methoxyphe- nyl)naphthalen-2-yl)methanesulfonamide; N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyp- henyl)naphthalen-2-yl)methanesulfonamide; 1-(3-tert-butyl-4-methoxy-5-(naphthalen-2-yl)phenyl)pyrimidine-2,4(1H,3H)- -dione; 1-(3-tert-butyl-4-methoxy-5-(6-methoxynaphthalen-2-yl)phenyl)pyrim- idine-2,4(1H,3H)-dione; N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl)naph- thalen-2-yl)methane sulfonamide; N-(6-(3-bromo-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl- )naphthalen-2-yl)methanesulfonamide; N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(5-methylfu- ran-2-yl)phenyl) naphthalen-2-yl)methanesulfonamide; N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(thiophen-3- -yl)phenyl) naphthalen-2-yl)methanesulfonamide; N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(thiophen-2- -yl)phenyl) naphthalen-2-yl)methanesulfonamide; N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(furan-2-yl)-2-methox- yphenyl)naphthalen-2-yl)methanesulfonamide; N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(furan-3-yl)-2-methox- yphenyl)naphthalen-2-yl)methanesulfonamide; N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-biphenyl-3-yl- )naphthalen-2-yl)methanesulfonamide; N-(6-(3'-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxybiph- enyl-3-yl) naphthalen-2-yl)methanesulfonamide; N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(5-methylth- iophen-2-yl)phenyl)naphthalen-2-yl)methanesulfonamide; N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(1-hydroxy-2-methylpr- opan-2-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide; N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(1-methoxy-- 2-methylpropan-2-yl)phenyl)naphthalen-2-yl)methanesulfonamide; methyl 2-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(6-(methylsulf- onamido) naphthalen-2-yl)phenyl)-2-methylpropanoate; 2-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(6-(methylsulf- onamido) naphthalen-2-yl)phenyl)-2-methylpropanoic acid; methyl 5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(6-(methylsulfona- mido) naphthalen-2-yl)benzoate; N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-iodo-2-methoxyphenyl)- naphthalen-2-yl)methanesulfonamide; N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-((trimethyl- silyl)ethynyl)phenyl)naphthalen-2-yl)methanesulfonamide; N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(methylsulf- onyl)phenyl) naphthalen-2-yl)methanesulfonamide; N-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(6-(methylsulf- onamido) naphthalen-2-yl)phenyl)methanesulfonamide; N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(trifluorom- ethyl)phenyl) naphthalen-2-yl)methanesulfonamide; N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(perfluoroe- thyl)phenyl) naphthalen-2-yl)methanesulfonamide; N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-ethoxyph- enyl)naphthalen-2-yl)methanesulfonamide; N-(6-(3-tert-butyl-2-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ph- enyl)naphthalen-2-yl)methanesulfonamide; N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-tert-pentyl- phenyl)naphthalen-2-yl)methanesulfonamide; and N,N'-(6,6'-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-1,3-phe- nylene)bis (naphthalene-6,2-diyl))dimethanesulfonamide.

27. The compound or salt of claim 1, wherein the compound is N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyp- henyl)naphthalen-2-yl)methanesulfonamide.

28. The salt of claim 1, which is N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-pyrimidin-1(2H)-yl)-2-methoxy- phenyl)naphthalen-2-yl)methanesulfonamide, sodium salt.

29. The salt of claim 1, which is N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyp- henyl)naphthalen-2-yl)methanesulfonamide, monosodium salt.

30. The salt of claim 1, which is N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-pyrimidin-1(2H)-yl)-2-methoxy- phenyl)naphthalen-2-yl)methanesulfonamide, disodium salt.

31. The salt of claim 1, which is N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-pyrimidin-1(2H)-yl)-2-methoxy- phenyl)naphthalen-2-yl)methanesulfonamide, potassium salt.

32. A compound or salt thereof, wherein the compound is selected from the group of compounds shown in Tables (2).

33. A pharmaceutical composition comprising one or more compounds and/or salts recited in claim 1 and one or more excipients.

34. The pharmaceutical composition of claim 33, wherein the pharmaceutical composition further comprises one or more additional therapeutic agents.

35. A method for inhibiting replication of a hepatitis C ribonucleic acid (RNA) virus, wherein the method comprises exposing the virus to one or more compounds and/or salts recited in claim 1.

36. A method for treating hepatitis C in a mammal in need of such treatment, wherein the method comprises administering to the mammal one or more compounds and/or salts recited in claim 1.

37. The method of claim 36, wherein the mammal is human.

38. The method of claim 36, wherein the method further comprises administering to the mammal one or more additional therapeutic agents.

39. The method of claim 38, wherein one or more additional therapeutic agents are selected from the group consisting of interferon agent, ribavirin, HCV inhibitor, and HIV inhibitor.

40. The method of claim 39, wherein the HCV inhibitor is an HCV protease inhibitor.
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