USOO8476225B2 (12) United States Patent (10) Patent No.: US 8.476,225 B2 Casarez et al. (45) Date of Patent: Jul. 2, 2013 (54) ANTIVIRAL COMPOUNDS (56) References Cited (75) Inventors: Anthony Casarez, Princeton, NJ (US); U.S. PATENT DOCUMENTS Mingzhe Ji, Union City, CA (US); 8,163,693 B2 4/2012 Chen et al. Choung U. Kim, San Carlos, CA (US); Xiaoning C. Sheng, Foster City, CA FOREIGN PATENT DOCUMENTS EP 2272858 A2 1, 2011 (US); Qiaoyin Wu, Foster City, CA (US) WO WO-2006O20276 A2 2, 2006 WO WO-2007OO9109 A2 1, 2007 (73) Assignee: Gilead Sciences, Inc., Foster City, CA WO WO-2008OO5565 A2 1, 2008 (US) WO WO-2009005.676 A2 1, 2009 WO WO-200900.5677 A2 1, 2009 (*) Notice: Subject to any disclaimer, the term of this OTHER PUBLICATIONS patent is extended or adjusted under 35 Ettmayer P. et al. J. Med. Chem. (2004) 47(10), pp. 2393-2404.* U.S.C. 154(b) by 211 days. Singh, Yashveeretal, “Recent Trends in Targeted Anticancer Prodrug and Conjugate.” DesignCurr MedChem. 2008; 15(18): 1802-1826.* (21) Appl. No.: 12/958,086 Muller, Christa E. "Prodrug Approaches for Enhancing the Bioavail ability of Drugs with Low Solubility.” Chemistry & Biodiversity, vol. (22) Filed: Dec. 1, 2010 6 (2009), pp. 2071-2083.* Beaumont, et, al"Design of Ester Prodrugs to Enhance Oral Absorp (65) Prior Publication Data tion of Poorly Permeable Compounds: Challenges to the Discovery Scientist.” Current Drug Metabolism, 2003, 4,461-485.* US 2011 FO1356O4A1 Jun. 9, 2011 Han, H.-K. AAPS Pharmsci. (2000) 2(1), Article 6, pp. 1-11.* Testa Prodrug research: futile or fertile? Biochemical Pharmacology (2004) 2097-2106.* Related U.S. Application Data (60) Provisional application No. 61/266,890, filed on Dec. * cited by examiner 4, 2009. Primary Examiner — Thomas Heard (51) Int. Cl. (57) ABSTRACT A6 IK38/00 (2006.01) The invention is related to anti-viral compounds, composi (52) U.S. Cl. tions containing such compounds, and therapeutic methods USPC ........................................................... S14/37 that include the administration of such compounds, as well as (58) Field of Classification Search to processes and intermediates useful for preparing Such com None pounds. See application file for complete search history. 45 Claims, No Drawings US 8,476,225 B2 1. 2 ANTIVIRAL COMPOUNDS R is optionally substituted C-Co cycloalkyl, optionally substituted aryl or optionally substituted heterocycle; This application is filed under 35 U.S.C. 111 (a) claiming m is 0, 1 or 2 the benefit under 35 U.S.C. 119(e) of U.S. provisional appli W is C-C alkylene, C-C alkenylene, or C-C alkynylene wherein the C-C alkylene, C-C alkenylene, or cation 61/266,890 filed Dec. 4, 2009 which is herein incor C-C alkynylene may be optionally substituted with porated by reference in its entirety for all purposes. C-C-alkyl, C-C-haloalkyl, cyano or halo; FIELD OF THE INVENTION R, is: 10 The invention relates generally to compounds with HCV Q O O O inhibitory activity. \/ -R 12 1n N n BACKGROUND OF THE INVENTION N R9. R or Hepatitis C is recognized as a chronic viral disease of the 15 Rs R11 O liver which is characterized by liver disease. Although drugs targeting the liver are in wide use and have shown effective ness, toxicity and other side effects have limited their useful -R ness. Inhibitors of HCV are useful to limit the establishment OR16 and progression of infection by HCV as well as in diagnostic Rs assays for HCV. There is a need for new HCV therapeutic agents. Rs is C-C alkyl, C-C alkenyl or C-C alkynyl wherein the SUMMARY OF THE INVENTION C-C alkyl, C-C alkenyl or C-C alkynyl may be 25 optionally substituted with halo or cyano; In one embodiment the invention provides a compound of Ro is Ro Ro NH- or Rio O formula 1 Ro is C-C alkyl, C-C, cycloalkyl or C-C cycloalkylalkyl wherein the C-C alkyl, C-C, cycloalkyl or C-C, cycloalkylalkyl may be optionally substituted with C-C- 30 alkyl, C-C-haloalkyl, cyano or halo: R is C-C alkyl, C-C, cycloalkyl or C-C cycloalkylalkyl wherein the C-C alkyl, C-C, cycloalkyl or C-C, N cycloalkylalkyl may be optionally substituted with C-C- alkyl, C-C-alkylthio, cyano or halo; 7 N 35 each R is independently H, C-C alkyl, C-C, cycloalkyl or N R C-C cycloalkylalkyl wherein the C-C alkyl, C-C, R e O cycloalkyl or C-C cycloalkylalkyl may be optionally Sub stituted with C-C-alkyl, C-C haloalkyl cyano or halo; O R3 R is H, OH, OR, C-C alkyl, C-C cycloalkyl, Ca-C 40 cycloalkylalkyl, aryl, arylalkyl, heterocycle or heterocy clylalkyl wherein the C-C alkyl, C-C cycloalkyl, or a racemate, enantiomer, Solvate, polymorph or salt thereof. C-C cycloalkylalkyl, aryl, arylalkyl, heterocycle or het wherein; erocyclylalkyl may be optionally substituted with C-C- R is R. , R. C(O)—, R O C(O)— or R. N(H) alkyl, C-C-haloalkyl cyano or halo; C(O)– 45 Ra is Rs Rs—C(O)—, Rs—O—C(O) s Ris O C R is optionally substituted C-Cs alkyl, optionally Substi (O)—X— tuted C-C cycloalkyl, optionally substituted C7-Ca Rs is C-C alkyl, C-C cycloalkyl, C7-C cycloalkylalkyl, cycloalkyl alkyl, optionally Substituted aryl, optionally aryl, arylalkyl, heterocycle, heterocyclylalkyl wherein the substituted arylalkyl, optionally substituted heterocycle or C-C alkyl, C-C, cycloalkyl, C7-C cycloalkylalkyl may optionally substituted heterocyclylalkyl: 50 be optionally Substituted with C-C2-alkyl, C-C-ha R is optionally substituted C-Cs alkyl, optionally Substi loalkyl, cyano or halo; tuted C-Co cycloalkyl, optionally Substituted C7-Ca X is C-C alkylene or C-C spiroalkylene; cycloalkylalkyl, optionally substituted heterocyclylalkyl, R is H. R. C(O)—, R-O-C(O) or R, O C or optionally substituted heterocycle, or R and Rs, along (O)—X—; with the atoms that connect them, form a 12 to 18 mem 55 each R, is independently H, C-C alkyl, C-C cycloalkyl or bered saturated, partially unsaturated or unsaturated het C-C cycloalkylalkyl wherein the C-C alkyl, C-C, erocycle wherein the 12 to 18 membered saturated, par cycloalkyl or C-C cycloalkylalkyl may be optionally Sub tially unsaturated or unsaturated heterocycle may be stituted with C-C2-alkyl, C-C-haloalkyl cyano or halo, optionally Substituted with C-C alkyl, C-C-haloalkyl, or two R, may, along with the carbon they are attached to, halo, oxo and cyano and wherein 0, 1, 2, or 3 carbon atoms 60 form a 3-6 membered spirocyclic carbocycle or hetero of R can be replaced by O, N, or S; cycle wherein any carbon of said carbocycle or heterocycle R is R. , R. Rs , R. W. , R. W. C(O)—, R. C may be substituted with C-C2-alkyl, C-C-haloalkyl, (O) , R. C(O)—W , R. W. O. C(O) , R. S cyano or halo and any nitrogen of said heterocycle may be (O), , R. W. S(O), , R. N(H)—C(O)—, R. N Substituted with C-C-alkyl, C-C-haloalkyl, C-Cs (H)—S(O), . Re-Rs S(O) - or R. N(H)—Rs—: 65 cycloalkyl or C-C acyl, or, taken together, two instances Rs is optionally substituted arylene or optionally substituted of R, together with the carbon they are attached to form a heteroarylene; carbonyl group; US 8,476,225 B2 3 4 In one embodiment of the invention R, is -continued N x N s n 4. 2 Os R3 10 F Br F Br In one embodiment of the invention R is Ro Ro NH Xsé, As4. or Rio O—: HCI, | | || In one embodiment of the invention R is Ro: 2 21 In one embodiment of the invention R is R O C 15 O O O (O) ; In one embodiment of the invention R is optionally sub stituted C-C alkyl, optionally Substituted C-Co cycloalkyl or optionally Substituted C7-C cycloalkylalkyl, In one embodiment of the invention each of R, is inde pendently H or substituted alkyl, In one embodiment of the invention R is 25 30 O O O 35 40 O, s O, 45 Halogen, s N N SAS s --F, --Cl, 50 21 2 2 >s so >s so >s so 55 N 60 HBr s s 21 65 US 8,476,225 B2 5 6 -continued -continued MeO N , MeO N N s n n N 21 N 2 F 15 h Ol F, CN 25 OMe, Alkoxy, 2y. 2/ 30 S N 35 40 O NH2 45 N ON 50 s e s es. 55 In one embodiment of the invention R is cyclopentyloxy carbonyl, t-butyloxycarbonyl, or 2.2.2-trifluoro-1,1-dimeth ylethyloxycarbonyl. C N OMe, MeS 60 In one embodiment of the invention R is cyclopentyl, t-butyl or 2.2.2-trifluoro-1,1-dimethylethyl. In one embodiment of the invention R is t-butyl. r In one embodiment of the invention R and Rs together form a C to Cs alkylene, wherein the alkylene may be option 65 ally unsaturated. In one embodiment of the invention R and Rs together form US 8,476,225 B2 8 In one embodiment of the invention R, is x-y O x-y R3 In one embodiment of the invention R is Re-alkylene-, 10 Re-alkylene-C(O)—, R.