Claims for Patent: 8,476,225

Summary for Patent: 8,476,225

Title:	Antiviral compounds
Abstract:	The invention is related to anti-viral compounds, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.
Inventor(s):	Casarez; Anthony (Princeton, NJ), Ji; Mingzhe (Union City, CA), Kim; Choung U. (San Carlos, CA), Sheng; Xiaoning C. (Foster City, CA), Wu; Qiaoyin (Foster City, CA)
Assignee:	Gilead Sciences, Inc. (Foster City, CA)
Application Number:	12/958,086
Patent Claims:	1. A compound of formula 1: ##STR00213## or a pharmaceutically acceptable salt thereof; wherein: R.sub.1 is R.sub.2--, R.sub.2--C(O)--, R.sub.2--O--C(O)-- or R.sub.2--N(H)--C(O)-- R.sub.2 is optionally substituted C.sub.1-C.sub.8 alkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.7-C.sub.14 cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocycle or optionally substituted heterocyclylalkyl; R.sub.3 is optionally substituted C.sub.1-C.sub.8 alkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.7-C.sub.14 cycloalkylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted heterocycle, or R.sub.3 and R.sub.8, along with the atoms that connect them, form a 12 to 18 membered saturated, partially unsaturated or unsaturated heterocycle wherein the 12 to 18 membered saturated, partially unsaturated or unsaturated heterocycle is optionally substituted with C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6-haloalkyl, halo, oxo or cyano and wherein 0, 1, 2, or 3 carbon atoms of R.sub.3 are optionally replaced by O, N, or S; R.sub.4 is R.sub.6--, R.sub.6--R.sub.5--, R.sub.6--W--, R.sub.6--W--C(O)--, R.sub.6--C(O)--, R.sub.6--C(O)--W--, R.sub.6--W--O--C(O)--, R.sub.6--S(O).sub.m--, R.sub.6--W--S(O).sub.m--, R.sub.6--N(H)--C(O)--, R.sub.6--N(H)--S(O).sub.m--, R.sub.6--R.sub.5--S(O).sub.m--, or R.sub.6--N(H)--R.sub.5--; R.sub.5 is optionally substituted arylene or optionally substituted heteroarylene; R.sub.6 is optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted aryl or optionally substituted heterocycle; m is 0, 1 or 2: W is C.sub.1-C.sub.4 alkylene, C.sub.2-C.sub.4 alkenylene, or C.sub.2-C.sub.4alkynylene wherein the C.sub.1-C.sub.4 alkylene, C.sub.2-C.sub.4 alkenylene, or C.sub.2-C.sub.4 alkynylene is optionally substituted with C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl, cyano or halo; R.sub.7 is: ##STR00214## R.sub.8 is C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl or C.sub.2-C.sub.4-alkynyl wherein the C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl or C.sub.2-C.sub.4-alkynyl is optionally substituted with halo or cyano; R.sub.9 is R.sub.10, R.sub.10--NH-- or R.sub.10--O-- R.sub.10 is C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.7 cycloalkyl or C.sub.4-C.sub.9 cycloalkylalkyl wherein the C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.7 cycloalkyl or C.sub.4-C.sub.9 cycloalkylalkyl is optionally substituted with C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano or halo; R.sub.11 is C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.7 cycloalkyl or C.sub.4-C.sub.9 cycloalkylalkyl wherein the C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.7 cycloalkyl or C.sub.4-C.sub.9 cycloalkylalkyl is optionally substituted with C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, C.sub.1-C.sub.4-alkylthio, cyano or halo; each R.sub.12 is independently H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl or C.sub.4-C.sub.9 cycloalkylalkyl wherein the C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl or C.sub.4-C.sub.9 cycloalkylalkyl is optionally substituted with C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano or halo; R.sub.13 is H, OH, OR.sub.14, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.4-C.sub.12 cycloalkylalkyl, aryl, arylalkyl, heterocycle or heterocyclylalkyl wherein the C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.4-C.sub.12 cycloalkylalkyl, aryl, arylalkyl, heterocycle or heterocyclylalkyl is optionally substituted with C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl cyano or halo; R.sub.14 is R.sub.15--, R.sub.15--C(O)--, R.sub.15--O--C(O)--, or R.sub.15O--C(O)--X-- R.sub.15 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.7-C.sub.12 cycloalkylalkyl, aryl, arylalkyl, heterocycle, or heterocyclylalkyl wherein the C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, or C.sub.7-C.sub.12 cycloalkylalkyl is optionally substituted with C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano or halo; X is C.sub.1-C.sub.5 alkylene or C.sub.3-C.sub.6 spiroalkylene; R.sub.16 is H, R.sub.17--C(O)--, R.sub.17--O--C(O)-- or R.sub.17O--C(O)--X--; each R.sub.17 is independently H, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.7 cycloalkyl or C.sub.4-C.sub.9 cycloalkylalkyl wherein the C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.7 cycloalkyl or C.sub.4-C.sub.9 cycloalkylalkyl is optionally substituted with C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano or halo, or two R.sub.17, along with the carbon to which they are attached, form a 3-6 membered spirocyclic carbocycle or heterocycle wherein any carbon of said carbocycle or heterocycle is optionally substituted with C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano or halo and any nitrogen of said heterocycle is optionally substituted with C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, C.sub.3-C.sub.5 cycloalkyl or C.sub.1-C.sub.3 acyl, or, taken together, two instances of R.sub.17 together with the carbon atom to which they are attached form a carbonyl group. 2. A compound according to claim 1 wherein R.sub.7 is ##STR00215## 3. A compound according to claim 1 wherein R.sub.9 is R.sub.10. 4. A compound according to claim 3 wherein R.sub.1 is R.sub.2--O--C(O)--. 5. A compound according to claim 4 wherein R.sub.2 is optionally substituted C.sub.1-C.sub.8 alkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl or optionally substituted C.sub.7-C.sub.14 cycloalkylalkyl. 6. A compound according to claim 1 wherein each R.sub.17 is independently H or substituted alkyl. 7. A compound of claim 1 wherein R.sub.4 is ##STR00216## ##STR00217## ##STR00218## ##STR00219## 8. A compound according to claim 2 wherein R.sub.1 is cyclopentyloxycarbonyl, t-butyloxycarbonyl, or 2,2,2-trifluoro-1,1-dimethylethyloxycarbonyl. 9. A compound according to claim 2 wherein R.sub.2 is cyclopentyl, t-butyl or 2,2,2-trifluoro-1,1-dimethylethyl. 10. A compound according to claim 2 wherein R.sub.3 is t-butyl. 11. A compound according to claim 2 wherein R.sub.3 and R.sub.8 together form ##STR00220## 12. A compound according to claim 2 wherein R.sub.4 is R.sub.6-alkylene-, R.sub.6-alkylene-C(O)--, R.sub.6--C(O)-alkylene-, R.sub.6--C(O)--, R.sub.6--S(O).sub.2--, R.sub.6-alkylene-S(O).sub.2--, R.sub.6--NH--C(O)--, R.sub.6--NH--S(O).sub.2--, R.sub.6--, R.sub.6--R.sub.5--, R.sub.6--R.sub.5--S(O).sub.2--, or R.sub.6--NH--R.sub.5--. 13. A compound according to claim 2 wherein R.sub.5 is ##STR00221## 14. A compound according to claim 2 wherein R.sub.6 is ##STR00222## 15. A compound according to claim 1 wherein R.sub.7 is ##STR00223## 16. A compound according to claim 1 wherein R.sub.7 is ##STR00224## 17. A compound according to claim 1 wherein R.sub.7 is ##STR00225## 18. A compound according to claim 1 wherein R.sub.7 is ##STR00226## 19. A compound according to claim 2 wherein R.sub.8 is ethyl or ethylene. 20. A compound according to claim 2 wherein R.sub.9 is R.sub.10. 21. A compound according to claim 2 wherein R.sub.10 is cyclopropyl or 1-methylcyclopropyl. 22. A compound according to claim 15 wherein R.sub.11 is cyclobutylmethyl or n-propyl. 23. A compound according to claim 15 wherein each R.sub.12 is independently H or cyclopropyl. 24. A compound according to claim 18 wherein R.sub.13 is alkyl, optionally substituted alkyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl. 25. A compound according to claim 24 wherein R.sub.16 is H, R.sub.17--C(O)--, R.sub.17--O--C(O)-- or R.sub.17--O--C(O)--X--. 26. A compound according to claim 25 wherein R.sub.17 is alkyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocycle, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl. 27. A compound selected from the group consisting of ##STR00227## ##STR00228## ##STR00229## ##STR00230## ##STR00231## ##STR00232## ##STR00233## ##STR00234## ##STR00235## ##STR00236## ##STR00237## ##STR00238## ##STR00239## ##STR00240## ##STR00241## ##STR00242## ##STR00243## ##STR00244## ##STR00245## 28. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. 29. The pharmaceutical composition of claim 28, further comprising at least one additional therapeutic agent. 30. The pharmaceutical composition of claim 29, wherein said additional therapeutic agent is selected from the group consisting of interferons, ribavirin analogs, NS5a inhibitors, NS4b inhibitors, NS3 protease inhibitors, NS5b polymerase inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, and non-nucleoside inhibitors of HCV. 31. The pharmaceutical composition of claim 29, further comprising at least one additional therapeutic agent selected from the group consisting of pegylated rIFN-alpha 2b (PEG-Intron), pegylated rIFN-alpha 2a (Pegasys), rIFN-alpha 2b (Intron A), rIFN-alpha 2a (Roferon-A), interferon alpha (MOR-22, OPC-18, Alfaferone, Alfanative, Multiferon, subalin), interferon alfacon-1 (Infergen), interferon alpha-n1 (Wellferon), interferon alpha-n3 (Alferon), interferon-beta (Avonex, DL-8234), interferon-omega (omega DUROS, Biomed 510), albinterferon alpha-2b (Albuferon), IFN alpha XL, BLX-883 (Locteron), DA-3021, glycosylated interferon alpha-2b (AVI-005), PEG-Infergen, PEGylated interferon lambda (PEGylated IL-29), and belerofon. 32. The pharmaceutical composition of claim 28, further comprising at least one additional therapeutic agent selected from the group consisting of ribavirin (Rebetol, Copegus), and taribavirin (Viramidine). 33. The pharmaceutical composition of claim 29, further comprising at least one additional therapeutic agent selected from the group consisting of boceprevir (SCH-503034 , SCH-7), telaprevir (VX-950), VX-813, TMC-435 (TMC435350), ABT-450, BI-201335, BI-1230, MK-7009, SCH-900518, VBY-376, VX-500, GS-9256, GS-9451, BMS-790052, BMS-605339, PHX-1766, AS-101, YH-5258, YH5530, YH5531, and ITMN-191 (R-7227). 34. The pharmaceutical composition of claim 29, further comprising at least one additional therapeutic agent selected from the group consisting of celgosivir (MX-3253), Miglitol, and UT-231B. 35. The pharmaceutical composition of claim 29, further comprising at least one additional therapeutic agent selected from the group consisting of emericasan (IDN-6556), ME-3738, GS-9450 (LB-84451), silibilin, and MitoQ, 6) nucleoside or nucleotide inhibitors of HCV NS5B polymerase, R1626, R7128 (R4048), IDX184, IDX-102, PSI-7851, BCX-4678, valopicitabine (NM-283), and MK-0608. 36. The pharmaceutical composition of claim 29, further comprising at least one additional therapeutic agent selected from the group consisting of filibuvir (PF-868554), ABT-333, ABT-072, BI-207127, VCH-759, VCH-916, JTK-652, MK-3281, GS-9190, VBY-708, VCH-222, A848837, ANA-598, GL60667, GL59728, A-63890, A-48773, A-48547, BC-2329, VCH-796 (nesbuvir), GSK625433, BILN-1941, XTL-2125, and GS-9190. 37. The pharmaceutical composition of claim 29, further comprising at least one additional therapeutic agent selected from the group consisting of AZD-2836 (A-831), AZD-7295 (A-689), and BMS-790052. 38. The pharmaceutical composition of claim 29, further comprising at least one additional therapeutic agent selected from the group consisting of imiquimod, 852A, GS-9524, ANA-773, ANA-975, AZD-8848 (DSP-3025), PF-04878691, and SM-360320, cyclophillin inhibitors, e.g., DEBIO-025, SCY-635, and NIM811 and HCV IRES inhibitors, e.g., MCI-067. 39. The pharmaceutical composition of claim 29, further comprising at least one additional therapeutic agent selected from the group consisting of BAS-100, SPI-452, PF-4194477, TMC-41629, GS-9350, GS-9585, and roxythromycin. 40. The pharmaceutical composition of claim 29, further comprising at least one additional therapeutic agent selected from the group consisting of thymosin alpha 1 (Zadaxin), nitazoxanide (Alinea, NTZ), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101), GS-9525, KRN-7000, civacir, GI-5005, XTL-6865, BIT225, PTX-111, ITX2865, TT-033i, ANA 971, NOV-205, tarvacin, EHC-18, VGX-410C, EMZ-702, AVI 4065, BMS-650032, BMS-791325, Bavituximab, MDX-1106 (ONO-4538), Oglufanide, FK-788, and VX-497 (merimepodib). 41. The pharmaceutical composition according to claim 29, further comprising a nucleoside analogue. 42. The pharmaceutical composition according to claim 41, further comprising an interferon or pegylated interferon. 43. The pharmaceutical composition according to claim 42, wherein said nucleoside analogue is selected from ribavirin, viramidine, levovirin, a L-nucleoside, and isatoribine and wherein said interferon is .alpha.-interferon or pegylated interferon. 44. A method of treating HCV infection, said method comprising administering to an individual a pharmaceutical composition which comprises a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof. 45. A compound of formula 1: ##STR00246## or a pharmaceutically acceptable salt thereof; wherein: R.sub.1 is R.sub.2--O--C(O)--; R.sub.2 is C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.10 cycloalkyl or C.sub.7-C.sub.14cycloalkylalkyl, wherein each C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.10 cycloalkyl and C.sub.7-C.sub.14 cycloalkylalkyl is optionally substituted with one or more F, Cl, Br, or I; R.sub.3 is t-butyl; or R.sub.3 and R.sub.8 together form: ##STR00247## R.sub.4 is R.sub.6--, R.sub.6--R.sub.5--, R.sub.6--W--, R.sub.6--W--C(O)--, R.sub.6--C(O)--, R.sub.6--C(O)--W--, R.sub.6--W--O--C(O)--, R.sub.6--S(O).sub.m--, R.sub.6--W--S(O).sub.m--, R.sub.6--N(H)--C(O)--, R.sub.6--N(H)--S(O).sub.m--, R.sub.6--R.sub.5--S(O).sub.m--, or R.sub.6--N(H)--R.sub.5--; R.sub.5 is optionally substituted arylene or optionally substituted heteroarylene, wherein said arylene or heteroarylene is optionally substituted with one or more alkyl, alkoxy, haloalkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heterocyclylalkyl, aryl, heterocycle, halogen, cyano, azido, amino, nitro, sulfonamide, alkylsulfonyl, or carboxamido; R.sub.6 is C.sub.3-C.sub.10 cycloalkyl, aryl or heterocycle, wherein said C.sub.3-C.sub.10 cycloalkyl, aryl or heterocycle is optionally substituted with one or more alkyl, alkoxy, haloalkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heterocyclylalkyl, aryl, heterocycle, halogen, cyano, azido, amino, nitro, sulfonamide, alkylsulfonyl, and carboxamido; m is 0, 1 or 2; W is C.sub.1-C.sub.4 alkylene, C.sub.2-C.sub.4 alkenylene, or C.sub.2-C.sub.4 alkynylene wherein the C.sub.1-C.sub.4 alkylene, C.sub.2-C.sub.4 alkenylene, or C.sub.2-C.sub.4 alkynylene is optionally substituted with C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl, cyano or halogen; R.sub.7 is: ##STR00248## ##STR00249## R.sub.8 is C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl or C.sub.2-C.sub.4-alkynyl wherein the C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl or C.sub.2-C.sub.4-alkynyl is optionally substituted with halogen or cyano; R.sub.9 is R.sub.10; R.sub.10 is C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.7 cycloalkyl or C.sub.4-C.sub.9 cycloalkylalkyl wherein the C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.7 cycloalkyl or C.sub.4-C.sub.9 cycloalkylalkyl is optionally substituted with C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano or halogen; R.sub.11 is cyclobutylmethyl or n-propyl; each R.sub.12 is independently H or cyclopropyl; and each R.sub.17 is independently H or C.sub.1-C.sub.4 alkyl.

Details for Patent 8,476,225

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132	06/04/1986		2029-12-04
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132			2029-12-04
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	Injection	103132			2029-12-04
Hoffmann-la Roche Inc.	ROFERON-A	interferon alfa-2a	For Injection	103145	06/04/1986		2029-12-04
Biogen Inc.	AVONEX	interferon beta-1a	For Injection	103628	05/17/1996		2029-12-04
Biogen Inc.	AVONEX	interferon beta-1a	Injection	103628	05/28/2003		2029-12-04