Antiviral compounds and uses thereof
| Title: | Antiviral compounds and uses thereof |
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| Patent Number: | 8,748,443 |
| Publication Date: | June 10, 2014 |
| Appl. No: | 13/260199 |
| Application Filed: | March 25, 2010 |
| 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. |
| Inventors: | Betebenner, David A. (Grayslake, IL, US); Pratt, John K. (Kenosha, WI, US); DeGoey, David A. (Salem, WI, US); Donner, Pamela L. (Mundelein, IL, US); Flentge, Charles A. (Salem, WI, US); Hutchinson, Douglas K. (Antioch, IL, US); Kati, Warren M. (Gurnee, IL, US); Krueger, Allan C. (Gurnee, IL, US); Longenecker, Kenton L. (Grayslake, IL, US); Maring, Clarence J. (Palatine, IL, US); Randolph, John T. (Libertyville, IL, US); Rockway, Todd W. (Gurnee, IL, US); Tufano, Michael D. (Chicago, IL, US); Wagner, Rolf (Antioch, IL, US); Liu, Dachun (Vernon Hills, IL, US) |
| Assignees: | AbbVie Inc. (North Chicago, IL, US) |
| Claim: | 1. A compound or salt thereof, wherein the compound corresponds in structure to formula I-1: [chemical expression included] is selected from the group consisting of single carbon-carbon bond and double carbon-carbon bond; R 5 and R 6 are independently selected from the group consisting of hydrogen, methyl, and nitrogen-protecting group; R 7 is selected from the group consisting of hydrogen and methyl; R 2 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, al kyloxycarbonyl, 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, al kyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl, or (2) two substituents that, together with the amino nitrogen, form a single-ring heterocyclyl; R 3 is selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, amino, carbocyclylsulfonyloxy, haloalkylsulfonyloxy, and halo; as to L and R 4 : L is a bond, and R 4 is selected from the group consisting of fused 2-ring carbocyclyl and fused 2-ring heterocyclyl, wherein each such substituent optionally is substituted with one or more substituents independently selected from the group consisting of R E , R F , R G , R H , R I , R J , and R K ; each R E is independently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, cyano, amino, imino, azido, and aldehydo, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl; each R F is independently selected from the group consisting of alkyl, alkenyl, and alkynyl, wherein: each such substituent optionally is substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, azido, oxo, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, imino, aminosulfonyl, aminocarbonyl, carbocyclyl, and heterocyclyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkylsulfonylamino, hydroxy, and alkyloxy, wherein: the amino portion of the alkylsulfonylamino optionally is substituted with a substituent selected from the group consisting of alkyl, alkenyl, and alkynyl; each R G is independently selected from the group consisting of carbocyclyl and heterocyclyl, wherein: each such substituent optionally is substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl; each R H is independently selected from the group consisting of alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, alkenylsulfonyloxy, and alkynylsulfonyloxy, wherein: each such substituent optionally is substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, al kylcarbonyloxy, al kenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl; each R I is independently selected from the group consisting of alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, aminocarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl, and heterocyclylcarbonyl, wherein: (a) the alkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl optionally are substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, al kyloxycarbonyl, al kenyloxycarbonyl, alkynyloxycarbonyl, al kylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, and (b) the aminocarbonyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyloxyalkyl, carbocyclyl, heterocyclyl, alkylsulfonyl, and alkylsulfonylamino, wherein: the carbocyclyl and heterocyclyl optionally are substituted with one or two substituents independently selected from the group consisting of halo, alkyl, and oxo; each R J is independently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, alkyloxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, aminocarbonylamino, alkyloxycarbonylaminoimino, alkylsulfonylaminoimino, alkenylsulfonylaminoimino, and alkynylsulfonylaminoimino, 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, (b) the alkyl, alkenyl, and alkynyl 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; (c) the carbocyclyl and heterocyclyl portions of such substituents 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, and amino, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl; and each R K is independently selected from the group consisting of aminosulfonyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl, wherein: (a) the alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl optionally are substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, al kyloxycarbonyl, al kenyloxycarbonyl, al kynyloxycarbonyl, al kylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl; and (b) the aminosulfonyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl. |
| Claim: | 2. The compound or salt of claim 1 , wherein R 5 is selected from the group consisting of hydrogen and methyl. |
| Claim: | 3. The compound or salt of claim 1 , wherein R 6 is selected from the group consisting of hydrogen and methyl. |
| Claim: | 4. The compound or salt of claim 1 , wherein R 7 is hydrogen. |
| Claim: | 5. The compound or salt claim 1 , wherein R 2 is selected from the group consisting of C 1 -C 4 -alkyl, C 3 -C 6 -carbocyclyl, and 5-6-membered heterocyclyl, wherein: (a) the C 1 -C 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 3 -C 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. |
| Claim: | 6. The compound or salt of claim 1 , wherein R 2 is selected from the group consisting of halo, alkyl, and alkyloxy. |
| Claim: | 7. The compound or salt of claim 1 , wherein R 2 is selected from the group consisting of tert-butyl, perfluoroethyl, trifluoromethyl, and 5-6-membered heterocyclyl optionally substituted with methyl. |
| Claim: | 8. The compound or salt of claim 1 , wherein R 2 is selected from the group consisting of furanyl, pyrazolyl, and thiophenyl, wherein each such substituent optionally is substituted with methyl. |
| Claim: | 9. The compound or salt of claim 1 , wherein R 3 is selected from the group consisting of hydrogen, hydroxy, C 1 -C 3 -alkenyl, C 1 -C 3 -alkyl, alkyloxy, amino, and halo. |
| Claim: | 10. The compound or salt of claim 1 , wherein R 3 is selected from the group consisting of hydrogen, hydroxy, and methoxy. |
| Claim: | 11. The compound or salt of claim 1 , wherein L is a bond. |
| Claim: | 12. The compound or salt of claim 1 , wherein: L is a bond; and R 4 is selected from the group consisting of fused 2-ring heterocyclyl and fused 2-ring carbocyclyl, wherein each such substituent is substituted with one, two, or three substituents independently selected from the group consisting of R E , R F , and R J . |
| Claim: | 13. The compound or salt of claim 1 , wherein: L is a bond; R 4 is a fused 2-ring carbocyclyl selected from the group consisting of naphthalenyl, di hydronaphthalenyl, tetrahydronaphthalenyl, hexahydronaphthalenyl, octahydronaphthalenyl, decahydronaphthalenyl, indenyl, di hydroindenyl, hexahydroindenyl, octahydroindenyl, pentalenyl, octahydropentalenyl, and hexahydropentalenyl, wherein each such substituent is substituted with a substituent selected from the group consisting of R F and R J ; R F is alkylsulfonylaminoalkyl; and R J is alkylsulfonylamino. |
| Claim: | 14. The compound or salt of claim 1 , wherein: L is a bond; R 4 is a fused 2-ring carbocyclyl selected from the group consisting of naphthalenyl, indenyl, and dihydroindenyl, wherein each such substituent is substituted with a substituent selected from the group consisting of R F and R J ; R F is alkylsulfonylaminoalkyl; and R J is alkylsulfonylamino. |
| Claim: | 15. The compound or salt of claim 1 , wherein the compound is selected from the group consisting of: N-((6-(3-tert-butyl-5-(2,4-dioxo-1 ,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxyphenyl)-1 H-inden-3-yl)methyl)methanesulfonamide; N-((6-(3-tert-butyl-2-methoxy-5-(1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyI)-1 H-inden-3-yl)methyl)methanesulfonamide; N-(6-(3-tert-butyl-2-methoxy-5-(1 -methyl-2,4-dioxo-1 ,2,3,4-tetrahydropyrimidin-5-yl)phenyl)naphthalen-2-yl)methanesulfonamide; N-(6-(3-tert-butyl-5-(1 ,3-dimethyl-2,4-dioxo-1 ,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide; 5-(3-tert-butyl-4-methoxy-5-(1 -oxo-2,3-di hydro-1 H-inden-5-yl)phenyl)pyrimidine-2,4(1 H,3H)-dione; 5-(3-tert-butyl-5-(1 -hydroxy-2,3-di hydro-1 H-inden-5-yl)-4-methoxyphenyl)pyrimidine-2,4(1 H,3H)-dione; N-(6-(3-tert-butyl-5-(2,4-dioxo-1 ,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide; N-(6-(2-amino-3-tert-butyl-5-(2,4-dioxo-1,2,3,4-tetrahydro pyrimidin-5-yl)phenyl)naphthalen-2-yl)methanesulfonamide; N-(6-(3-tert-butyl-5-(2,4-dioxo-1 ,2,3,4-tetrahydropyrimidin-5-yl)-2-iodophenyl)naphthalen-2-yl)methanesulfonamide; N-(6-(3-tert-butyl-5-(2,4-dioxo-1 ,2,3,4-tetrahydropyrimidin-5-yl)-2-vinyl phenyl)naphthalen-2-yl)methanesulfonamide; N-(6-(3-tert-butyl-5-(2,4-dioxo-1 ,2,3,4-tetrahydropyrimidin-5-yl)-2-ethyl phenyl)naphthalen-2-yl)methanesulfonamide; N-(6-(5-(2,4-dioxo-1 ,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxy-3-(perfluoroethyl)phenyl)naphthalen-2-yl)methanesulfonamide; N-(6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-(furan-3-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide; N-(6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxy-3-(thiophen-2-yl)phenyl)naphthalen-2-yl)methanesulfonamide; N-(6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-(furan-2-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide; N-(6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)naphthalen-2-yl)methanesulfonamide; N-(6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxy-3-(5-methylfuran-2-yl)phenyl)naphthalen-2-yl)methanesulfonamide; N-(6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxy-3-(thiophen-3-yl)phenyl)naphthalen-2-yl)methanesulfonamide; N-((6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxy-3-(5-methylfuran-2-yl)phenyl)-1H-inden-3-yl)methyl)methanesulfonamide; N-(6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxy-3-(trifluoromethyl)phenyl)naphthalen-2-yl)methanesulfonamide; N-((6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxy-3-(trifluoromethyl)phenyl)benzo[b]thiophen-3-yl)methyl)methanesulfonamide; and N-((6-(2-methoxy-5-(1-(methylsulfonyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-(trifluoromethyl)phenyl)-1H-inden-3-yl)methyl)methanesulfonamide. |
| Claim: | 16. A pharmaceutical composition comprising one or more compounds and/or salts recited in claim 1 and one or more excipients. |
| Claim: | 17. The pharmaceutical composition of claim 16 , wherein the pharmaceutical composition further comprises one or more additional therapeutic agents. |
| Current U.S. Class: | 514/274 |
| Patent References Cited: | 8178547 May 2012 Steiner et al. 2256313 May 1973 2651750 May 1977 2722383 December 1977 1953147 August 2008 2017261 January 2009 2006120178 November 2006 2009007747 January 2009 2010072598 July 2010 |
| Other References: | International Preliminary Report on Patentability, PCT/US10/028560 (Feb. 27, 2011). cited by examiner Havelkova′ et al., 58 Tetrahedron 7431-7435 (2002). cited by examiner Beaulieu P.L., et al., “Recent Advances in the Development of NS5B Polymerase Inhibitors for the Treatment of Hepatitis C Virus Infection,” Expert Opinion on Therapeutic Patents, 2009, vol. 19 (2), pp. 145-164. cited by applicant International Search Report for Application No. PCT/US2010/028560, mailed on Feb. 23, 2011, 6 pages. cited by applicant Pedrazzoli A., et al., “p-Acetylaminophenol Derivatives. II. Mannich Bases and 3-substituted 3,4-dihydro-2H-1,3-benzoxazines,” Bollettino Chimico Farmaceutico, 1966, vol. 105 (7), pp. 503-511. X. cited by applicant Stout D.M., et al., “Synthesis and Antiarrhythmic and Parasympatholytic Properties of Substituted Phenols. 1. Heteroarylamine Derivatives,” Journal of Medicinal Chemistry, 1983, vol. 26 (6), pp. 808-813. cited by applicant Stout D.M., et al., “Synthesis and Antiarrhythmic and Parasympatholytic Properties of Substituted Phenols. 3. Modifications to the Linkage Region (region 3),” Journal of Medicinal Chemistry, 1985, vol. 28 (3), pp. 295-298. cited by applicant Suehiro T., “On the Rearangement of 5-oxo-2-methyl-4,4 -dibenzyl-3-ethoxycarbonyl-4,5-dihidro-indol catalyzed with Acid,” Chemische Berichte, 1967, vol. 100 (3), pp. 915-918. cited by applicant |
| Assistant Examiner: | Pagano, Alexander R |
| Primary Examiner: | Rao, Deepak |
| Attorney, Agent or Firm: | Davis, Bradley E. |
| Accession Number: | edspgr.08748443 |
| Database: | USPTO Patent Grants |
| Language: | English |
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